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Vol.:(0123456789)
1 3
European Journal of Applied Physiology
https://doi.org/10.1007/s00421-021-04679-4
INVITED REVIEW
Does exercise attenuate age‑ anddisease‑associated dysfunction
inunconventional T cells? Shining alight onoverlooked cells
inexercise immunology
ErikD.Hanson1,2,3 · LaurenC.Bates1,3· DavidB.Bartlett4· JohnP.Campbell5
Received: 28 September 2020 / Accepted: 28 March 2021
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021
Abstract
Unconventional T Cells (UTCs) are a unique population of immune cells that links innate and adaptive immunity. Following
activation, UTCs contribute to a host of immunological activities, rapidly responding to microbial and viral infections and
playing key roles in tumor suppression. Aging and chronic disease both have been shown to adversely affect UTC numbers
and function, with increased inflammation, change in body composition, and physical inactivity potentially contributing to
the decline. One possibility to augment circulating UTCs is through increased physical activity. Acute exercise is a potent
stimulus leading to the mobilization of immune cells while the benefits of exercise training may include anti-inflammatory
effects, reductions in fat mass, and improved fitness. We provide an overview of age-related changes in UTCs, along with
chronic diseases that are associated with altered UTC number and function. We summarize how UTCs respond to acute
exercise and exercise training and discuss potential mechanisms that may lead to improved frequency and function.
Keywords Exercise training· MAIT cells· NKT cells· Gamma delta T cells
Abbreviations
αGalCer Alpha-galactosylceramide
CD Crohn’s disease
d Day
γδ T cell Gamma Delta T cell
GI Gastrointestinal
h Hour
IBD Inflammatory bowel disease
IFNγ Interferon gamma
IL Interleukin
MAIT cell Mucosal associated invariant T cell
MHC Major histocompatibility complex
MR1 Major histocompatibility complex class
I-related gene protein
NK cell Natural killer cell
NKT cell Natural killer T cell
OT Overtrained
PBMC Peripheral blood mononuclear cell
TCR T cell receptor
TNFα Tumor necrosis factor alpha
UC Ulcerative colitis
UTCs Unconventional T cells
wk Week
Overview ofUTCs withininnate
andadaptive immunity
Unconventional T Cells (UTCs) are a collection of
immune cells that bridge innate and adaptive immunities
and include Mucosal-Associated Invariant T (MAIT) cells,
Natural Killer T (NKT) cells, and Gamma Delta (γδ) T
cells. UTCs are multi-functional and recognize antigens
and cancerous cells, regulate inflammatory responses,
and play a role in allergy and autoimmunity with their
Communicated by Michael Lindinger.
* Erik D. Hanson
edhanson@email.unc.edu
1 Department ofExercise andSport Science, University
ofNorth Carolina atChapel Hill, ChapelHill, NC27517,
USA
2 Lineberger Comprehensive Cancer Center, University
ofNorth Carolina atChapel Hill, ChapelHill, NC, USA
3 Human Movement Science Curriculum, University ofNorth
Carolina atChapel Hill, ChapelHill, NC, USA
4 Division ofMedical Oncology, Duke Cancer Institute, Duke
University, Durham, NC, USA
5 Department forHealth, University ofBath, Bath, UK
European Journal of Applied Physiology
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development function recently reviewed elsewhere (Pel-
licci etal. 2020). These cells play key roles in barrier
immunology and reside in the mucosa of the lungs and
gastrointestinal (GI) tracts (Godfrey etal. 2000; Voillet
etal. 2018; Zhao etal. 2018a). Like many cells of the
immune system, aging and chronic disease adversely affect
UTCs (Godfrey etal. 2015). Systemic inflammation, a
hallmark characteristic of many chronic diseases, such as
diabetes, obesity and cancer, appears to be a modulating
factor that decreases UTC frequency and functional capac-
ity (Fay etal. 2016; Kumar and Ahmad 2018; Marrero
etal. 2015). Additionally, chronic inflammation promotes
immune cellular infiltration and creates a pro-tumor envi-
ronment that increases the risk for several different types
of cancer (Tan and Coussens 2007). UTCs are unique, with
a rapid response relative to conventional T cells while pos-
sessing both innate and adaptive immune qualities. UTCs
are found in high frequencies within selective tissues and
novel applications to utilize these cells within age or dis-
eased populations are emerging (Godfrey etal. 2015).
From an exercise immunology perspective, UTCs are
understudied. In contrast, modulation of conventional T
cells with acute exercise has been well-established (see
Sect.3.1). Increased hemodynamic shear stress and cat-
echolamine levels initiate endothelial detachment that
leads to cellular mobilization due to adhesion molecules
(e.g. CD62L and CD11b) alterations (Shephard 2003).
Following exercise, there is a redeployment of T cells
with greater effector function migrating to both lymphoid
and non-lymphoid tissues (Krüger etal. 2008), potentially
leading to a transient lymphopenia that returns to baseline
levels within hours unless the bout was particularly long
or intense (Peake etal. 2017). Given the paucity of evi-
dence in UTCs, a key objective of this review is to assess
the evidence of the effects of acute and regular exercise
on these cells, the possible therapeutic role of physical
activity of during aging and disease, and to outline future
directions for the field.
This review is divided into five sections. First, (i) an over-
view of UTCs and their function is provided, followed by
(ii) a summary of the effects of aging and disease. (iii) As
we hypothesize that increasing physical activity may help
offset age- and disease-related deficits in UTCs, the effects
of acute exercise and exercise training are presented. (iv)
Exercise-induced alterations in pro- and anti-inflammatory
cytokines are discussed as possible mechanisms contributing
to improved UTC frequency and function via (1) myokines
released with skeletal muscle contraction, (2) reductions in
total fat mass and sedentary behavior, or (3) via changes
in metabolites and hormones with acute exercise. Finally,
(v) future directions are identified to facilitate further
investigation of the role of exercise to improve the UTC
profile for aged and diseased populations.
MAIT Cells
MAIT cells were first described in 1999 (Tilloy etal. 1999)
and make up ~ 1–8% of all T cells in healthy adults (Le
Bourhis etal. 2010). In humans, MAIT cells are charac-
terized the invariant T cell antigen receptor (TCR) alpha-
chain Vα7.2-Jα33/12/20 (Wakao etal. 2017), high levels
of CD161 expression (Howson etal. 2015), and restriction
by the major histocompatibility complex class I-related
(MR1) protein (Tilloy etal. 1999; Le Bourhis etal. 2010).
CD8+ MAIT cells are the major (80–90%) subpopulation
(Dias etal. 2018), followed by CD4−CD8− cell with lim-
ited expression of CD4+ (Walker etal. 2012; Reantragoon
etal. 2013). MAIT cells are located in the blood and bar-
rier mucosal tissues (Voillet etal. 2018) that include the
lungs (Hinks, 2016), liver (Dusseaux etal. 2011), and GI
tract (Treiner etal. 2003). These innate-like lymphocytes
combat a wide range of microbial infections via interac-
tions between the invariant TCR and MR1 (Gold etal.
2010; Le Bourhis etal. 2010, 2011). Additionally, MAIT
cells can be activated independent of MR-1 via cytokines
(Suliman etal. 2019) and viral infections (Hinks etal.
2018; Ussher etal. 2018).
The ability to detect and control bacterial infections is
the most well-established MAIT cell function (Le Bourhis
etal. 2013; Meierovics etal. 2013; Ussher etal. 2014).
However, MAIT cell activation occurs during viral infec-
tions suggesting a possible functional role in immuno-
pathology (Cosgrove etal. 2013; van Wilgenburg etal.
2016). Following activation via either TCR-dependent or
-independent mechanisms (Fig.1), MAIT cells secrete
TNFα, IFNγ, IL-17, granzyme B, and perforin (Kurioka
etal. 2015; Howson etal. 2015; Bennett etal. 2017).
MAIT cells are also stimulated by innate cytokines, such
as interleukin (IL) 12, 15, 18 and type I interferon (Hinks
and Zhang 2020), leading to the release of pro-inflamma-
tory cytokines and cytotoxic proteins (Ussher etal. 2014).
MAIT cells express multiple chemokine receptors (Hanson
etal. 2019) that when bound to their ligands direct migra-
tion to inflammatory sites of inflammation (Vangelista
and Vento 2018) and to accumulate in the mucosal lamina
propria and the liver (Hinks 2016). Certain diseases may
cause MAIT cell hyper-activation, which may impede their
cytotoxicity and ability to elicit an inflammatory response
(Rudak etal. 2018). Current evidence suggests that MAIT
cells recruit other immune cells, exert cytotoxic responses
against bacteria and possibly viruses, and secrete pro-
inflammatory cytokines that may contribute to systemic
inflammation.
European Journal of Applied Physiology
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NKT cells
In the early 1990s, murine NKT cells were first described
as T cells in the thymus with low CD3 expression and
were positive for the NK cell marker NK1.1, also known
as CD161 in humans (Sykes 1990; Arase etal. 1993).
NKT cells reside mainly in the liver and can also be
found in the lung but make up only ~ 0.01–0.5% of blood
T cells (Berzins etal. 2005, 2011; Godfrey etal. 2015).
Of the different types of NKT cells, human type I invari-
ant NKT cells (iNKT) express the Vα24-Jα18 and Vβ11
semi-invariant TCR and are restricted to only lipid anti-
gens presented by the non-classical MHC-I-like protein
CD1d. Because the TCR is restricted to a handful of lipid
antigens, CD1d tetramers loaded with αGalCer or an anti-
Vα24-Jα18 CDR3 loop clonotypic monoclonal antibody
are the gold standard tool for iNKT identification (Berzins
etal. 2011; Krovi and Gapin 2018). iNKT cells can be
CD4−CD8− but typically express CD4, with a small popu-
lation of CD8+ iNKT cells found only in humans (Montoya
etal. 2007). Type II NKT cells (non-classical NKT cells)
are more abundant than iNKT cells in humans (Blood: 1%
vs. 0.1%), and have a more diverse (but not polyclonal)
CD1D-restricted TCR repertoire with broader lipid spe-
cificities (Rhost etal. 2012). Human Type II NKT cells
are mostly CD4+, but can also be CD8+ or double nega-
tive (Godfrey etal. 2004). A third population are CD161+
NKT-like cells that are classical MHC-restricted rather
than CD1d-restricted (Godfrey etal. 2004, 2015). Like
Type II NKT cells, these cells have diverse TCR α- and
β-chains, and are either CD4+, CD8+ or double negative
(Godfrey and Berzins 2007). These NKT cells are often
defined as CD3+CD161+CD56+ (Kronenberg and Gapin
2002). Co-expression of CD3 and CD56 alone to identify
NKT cells has also been used (Campbell etal. 2001; Chan
etal. 2013; Krijgsman etal. 2019). However, it is clear not
all CD3+CD56+, CD3+CD161+, or CD3+CD161+CD56+
cells are CD1d-restricted, so these populations are referred
to as “NKT-like” cells (Berzins etal. 2011).
A primary role of NKT cells is to modulate the immune
response by influencing the functional properties and activa-
tion of other cell types against allergens, infectious agents,
and tumors (Wu and Van Kaer 2011). A hallmark function
of NKT cells is rapid production of Th1 pro-inflammatory
and Th2 immune modulatory cytokines upon lipid-CD1d
recognition (Arase etal. 1993). Major Th1 cytokines include
IFNγ that activates dendritic cells, CD8+ T cells, and NK
cells (Terabe and Berzofsky 2008) and is one example of
how NKT cells link adaptive and innate immunities. With
IFNγ secretion and tumor recognition via CD1d, NKT cells
demonstrate direct invivo effects that make them strong
anti-cancer candidates (Brutkiewicz and Sriram 2002; Kri-
jgsman etal. 2018; Bae etal. 2019). Alpha-galactosylcer-
amide (αGalCer) is the most studied and widely used lipid
antigen for activating iNKT cells (Kronenberg and Gapin
2002). When administered therapeutically (e.g. soluble or
αGalCer pulsed APCs), iNKT number and function are
increased (Nair and Dhodapkar 2017). αGalCer stimulates
potent NKT cell actions that are being extensively tested as
an immunotherapeutic agent in diseases like cancer (Nair
and Dhodapkar 2017), with activated iNKT cells directly
killing tumor cells by CD1d-dependent and -independent
(e.g. perforin and granzymes) mechanisms (Wolf etal.
2018). When NKT cells are not present, multiple chronic
Fig. 1 Unconventional T cells
(UTCs) are activated (1) via
their T cell receptors (TCR)
following interactions with
antigen presenting cells or
(2) through cytokines using
TCR-independent signaling.
(3) Upon activation, UTCs
release cytokines and cytotoxic
molecules that activate other
immune cells or kill target cells,
respectively. Activating signals
are represented by dashed lines
and effector functions via solid
lines
Antigen Presenting Cell
CD1d
Perforin
Granzyme B
TNF
IFN
IL-17
IL-12
IL-18
2
1
3
MAIT NKT
NKG2D
γδT
TCR
European Journal of Applied Physiology
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conditions are worsened (Balato etal. 2009), including
increased risk of infections, asthma, allergies, atherosclero-
sis, cancer and graft-versus-host disease (Ambrosino etal.
2007; Berzins etal. 2011).
γδ T cells
While most TCR molecules express α and β chains, γδ T
cells contain disulfate-linked or non-linked gamma and
delta chains (Kabelitz 1992). First discovered in 1987
(Born etal. 1987), γδ T cells account for 1–10% ofadult
human peripheral blood T lymphocytes (Beetz etal. 2008)
and are found in two different types. γδ T cells in human
peripheral blood mainly express the Vγ9JγPCγ1 chain
paired with a Vδ2 chain within the TCR (Lefranc and
Rabbitts 1990). Vδ1 (Type-1) cells are found in the thy-
mus and peripheral tissues, such as the intestine and lungs,
and recognize various stress-related antigens (Vantourout
and Hayday 2013; Lawand etal. 2017). In general, γδ T
cells are ~ 70% of CD4−CD8−, with the remaining ~ 30%
being CD8+CD4− and very few are CD4+CD8− (Garcillan
etal. 2015). Similar to MAIT and NKT cells, γδ T cells
have both innate and adaptive immune qualities. From an
innate perspective, γδ T cells rapidly respond following
activation but also possess the TCR and pleiotropic effec-
tor functions associated with longer-term immunity (Van-
tourout and Hayday 2013). With broad antigen recognition
and cytotoxic function, γδ T cells contribute to the body’s
defense against a wide array of pathogens (Lawand etal.
2017).
γδ T cells are a unique subset of T lymphocytes because
of their ability to detect lipid antigens, even without the pres-
ence of MHC molecules (Heng and Heng 2013; Lawand
etal. 2017). This allows them to attack target cells directly
via cytotoxic activity, or indirectly via activating other
immune cells. γδ T cells have a protective role against both
viral and bacterial infections (Latha etal. 2014; Lawand
etal. 2017; Zhao etal. 2018a). The functional response ini-
tiates with antigen recognition, which then drives cytokine
production and regulates the clearance of pathogens, inflam-
mation, and promotes tissue homeostasis in response to
stress (Lawand etal. 2017). When activated (Fig.1), γδ T
cells express high levels of IFNγ, TNFα, and IL-17 and col-
lectively these effector functions allow for participation in
the efferent phase of immune responses (Vantourout and
Hayday 2013). The ability of γδ T cells to produce IFNγ,
TNFα, and IL-17 suggests a regulatory role (Beetz etal.
2008) but are also involved in tumor management (Galluzzo
etal. 2007). Additionally, activated γδ T cells may regu-
late the organization of B cells by producing large amount
of CXC-chemokine ligand 13 within the lymphoid tissues
(Vantourout and Hayday 2013). In humans, γδ T cells con-
tribute to immunity through both their cytotoxic potential
and inflammatory phenotype (Lawand etal. 2017), which is
consistent with MAIT and NKT cells.
UTCs duringaging andchronic disease
Aging
The aging process has a profound impact on the immune
system, which in turn has implications for health later in
life, typically manifesting as sustained low-grade inflam-
mation, a decreased ability to fight infection, higher
incidences of cancer and autoimmunity, and decreased
vaccination responsivity (Akha 2018). Overall, UTCs
demonstrate consistent age-related declines. Compared to
younger individuals, older adults have lower absolute γδ
T cells counts in circulation (Argentati etal. 2002; Pis-
tillo etal. 2013). Moreover, the proportion of blood γδ T
cells expressing the senescence marker CD57 is increased
in individuals greater than 60years (Bruni etal. 2019).
MAIT cell prevalence in peripheral blood peaks between
age 30 and 40 and then declines such that absolute counts
and percentages are 10 times lower by age 80 (Novak etal.
2014). Most studies also indicate age-related declines in
NKT cells (Mocchegiani and Malavolta 2004; Molling
etal. 2005; Chen and Liao 2007) although reports of
increased cell number and functions do exist (Faunce etal.
2005). However, some aspects of functional capacity of
UTCs may be preserved in older adults. In response to
invitro isopentenyl pyrophosphate (IPP) and IL-2 stimula-
tion, γδ T cell cytokine production and cytotoxicity against
tumor cells is maintained across the lifespan (Argentati
etal. 2002), while MAIT cells from elderly individuals
displayed similar upregulation of inflammatory cytokines
and cytotoxic proteins following E. coli simulation (Loh
etal. 2020). Similarly, in very old adults, NKT cytotoxic-
ity and IFNγ production are preserved with IL-12 stimula-
tion (Mocchegiani and Malavolta 2004). While absolute
numbers decline with age, the preservation of functional
capability in the remaining UTCs suggests they retain
importance in the immune response of older adults, with
potential benefits being most likely with interventions that
boost cell numbers.
Inflammatory bowel diseases
Crohn’s disease (CD) and ulcerative colitis (UC) are the
two inflammatory bowel diseases (IBD) that demonstrate
alterations in UTCs. CD is characterized as a systemic
inflammatory disease that largely effects the GI tract
and is associated with immune disorders (Baumgart
and Sandborn 2012). UC is also associated with chronic
European Journal of Applied Physiology
1 3
inflammation but involves only the innermost mucosa of
the colon and rectum (Head and Jurenka 2003). There is
growing evidence that UTCs are implicated in the patho-
genesis of IBD (Catalan-Serra etal. 2018; Giuffrida etal.
2018; Hinks & Zhang, 2020). Blood MAIT cell frequency
was reduced several-fold during IBD; however, MAIT
cell proliferation was higher in CD and there was greater
accumulation of cells within the inflamed ileum (Serriari
etal. 2014). Moreover, CD exhibited decreased IFNγ pro-
duction while UC showed elevated IL-22 production with
greater IL-17 levels in both CD and UC. Similarly, γδ
T cells localize to areas of inflammation in IBD patients
and are a source of IFNγ production in the effected tissue
(McVay etal. 1997). Furthermore, declines in blood γδ
T cells are associated with negative clinical implications
in CD (Catalan-Serra etal. 2018). NKT cells may have
dual roles in UC, as iNKT cells demonstrate protective
contributions via enhanced cytokine production but type
II NKT cells may promote inflammation in the intestines
(Giuffrida etal. 2018; Lai etal. 2019). In summary, UTCs
appear to migrate towards inflamed tissue, thus reducing
circulating levels in IBD patients with greater disease pro-
gression, with further research needed to fully understand
the implications of UTCs and IBD.
Obesity
Increased adiposity shifts the immune system toward a pro-
inflammatory phenotype (Saltiel and Olefsky 2017). Blood
UTCs are reduced with obesity and negatively correlate with
the severity of adiposity (Apostolopoulos etal. 2016; Car-
olan etal. 2015; Costanzo etal. 2015; Magalhaes, Pingris
etal. 2015a, b; Touch etal. 2017). Obese individuals have
more differentiated γδ T cells with a reduced ability to pro-
duce IFNγ and IL-2 that lowers anti-viral capacity (Costanzo
etal. 2015). Obesity also attenuates NKT and MAIT cell
cytokine production, especially IFNγ (Lynch etal. 2012;
Carolan etal. 2015; Magalhaes etal. 2015b; Apostolopoulos
etal. 2016). Weight loss (through diet or bariatric surgery)
partially rescues both cell counts and cytokine productions
(Magalhaes etal. 2015b). As exercise training also influ-
ences body composition, increased physical activity either
alone or in conjunction with dietary changes is another ave-
nue by which UTCs may be targeted to potentially improve
cell number and function.
Diabetes
Type I and type II diabetes are involved in autoimmunity
and inflammation, respectively, especially the relationship
between the gut microbiota, intestinal epithelial cells, and
the mucosal immune system (Moffa etal. 2019). Similar to
obesity, both types of diabetes are associated with decreased
iNKT and MAIT cell frequency and function (Magalhaes
etal. 2015b) but it is unclear if this is due to nutritional
variation or from disease progression (Touch etal. 2017).
UTCs may play a regulatory role in metabolism (Magalhaes
etal. 2015a; Touch etal. 2017), suggesting that MAIT and
NKT cells may have protective roles against type II diabe-
tes but the potential mechanism is unclear (Magalhaes etal.
2015b; Xia etal. 2017). γδ T cell proportions and counts are
elevated in the peripheral blood of individuals at high risk
for type I diabetes (elevated islet cell antibody titers) and
may be predictive of disease progression (Lang etal. 1993).
Additionally, low absolute γδ T cell counts were associ-
ated with a diminished insulin response to an intravenous
glucose tolerance test. As Type II diabetes and obesity are
often intertwined, it is presently unclear which factor(s) are
driving the relationships within UTCs.
Asthma
Asthma is characterized as a chronic inflammatory disease
affecting the airway (Lambrecht etal. 2019). A recent review
on NKT cells, MAIT cells, and asthma highlighted many
mechanistic questions, such as age (NKT and MAIT cells are
not fully mature in children when asthma first develops) and
the pathophysiology of UTCs and asthma, remain unclear
(Lezmi and Leite-de-Moraes 2018). Blood iNKT cell fre-
quency appears similar between individuals with asthma
and healthy controls (Koh and Shim 2010) and there is no
relationship between asthma and IL-4 or IFNγ production
(Chandra etal. 2018). iNKT cell frequency from bronchial
tissues or bronchoalveolar-lavage fluid (BALF) produced
inconsistent results (Iwamura and Nakayama 2018). In con-
trast, both circulating and sputum MAIT cells and circulat-
ing γδ T cell frequency are reduced in adults with asthma
compared to controls (Hinks etal. 2015; Krejsek et al.
1998), with the MAIT cell reductions being associated with
disease severity (Lezmi and Leite-de-Moraes 2018). How-
ever, the clinical significance of γδ T cell changes has been
questioned recently given the complex role these cells may
play in asthma and further research is needed to substanti-
ate any association with aging (Victor etal. 2020). Because
asthma is typically diagnosed during childhood when the
functional capabilities of UTCs are likely still developing,
evidence from individuals across the lifespan is needed to
better understand if detriments in UTC function and number
are linked to disease implications or from age of the popula-
tion studied.
Cancer
Anti-cancer therapies, such as chemotherapy and radiation,
elicit profound damage to the immune system, including
the depletion of lymphocyte populations (Kaur and Asea
European Journal of Applied Physiology
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2012; Bracci etal. 2014). UTCs have been proposed as
promising targets for immunotherapy (Godfrey etal. 2018),
with NKT cells inhibiting tumor growth in murine models
(McEwen-Smith etal. 2015; Nair and Dhodapkar 2017).
Peripheral blood NKT cell numbers are reduced in human
cancers, including breast (Molling etal. 2005) and lung
cancer (Motohashi etal. 2002). NKT cell function, such as
stimulated IFNγ production, is unaffected by tumor load
(Molling etal. 2005) while increased tumor-infiltrating
NKT cell offers favorable prognosis (Tachibana etal. 2005;
Bricard etal. 2009). Because MAIT cells share many quali-
ties (e.g. cytotoxicity, cytokine production) with NKT cells,
this raises the possibility of an anti-tumor role (Peterfalvi
etal. 2008). Indeed, circulating MAIT cells are reduced in
mucosal associated cancers that include lung, colon, gastric
tumors but cytokine producing abilities were preserved with
an elevated presence within cancerous tissue (Ling etal.
2016; Won etal. 2016). Interestingly, UTCs may exhibit a
differential response to chemotherapy, with MAIT cells pro-
portions remaining constant during breast cancer (Dusseaux
etal. 2011) while γδ T cell counts decrease with advanced
colorectal cancer (Bruni etal. 2019). γδ T cells have been
linked to cancer due to an ability to produce IFNγ early
on in tumor immunosurveillance, with γδ T cell-deficient
mice demonstrating higher tumor loads (Gao etal. 2003).
Recent reviews on UTCs and immunotherapy for cancer
report that γδ T cells promote tumor rejection via IFN-γ
and TNFα secretion, direct cytotoxic effects, and activation
of additional components of the immune system (Godfrey
etal. 2018; Zhao etal. 2018a, b), making them good can-
didates for clinical trials. Furthermore, many UTCs reside
in non-lymphoid tissue that allows tumors in these specific
areas to be targeted by potential immunotherapies (Godfrey
etal. 2018). However, subsets of γδ T cells contribute to
progression in certain cancer types via greater angiogenesis,
metastasis, and immune escape (Zhao etal. 2018a, b). While
UTCs have clear potential to assist with cancer management,
further investigations are needed to understand their full
potential for use in immunotherapy and to further explore
how tumors and treatments affect cytotoxic function.
Summary
Considering the impact of aging and chronic disease,
decreased blood UTC cell count emerges as a common
thread. Additionally, obesity, low-grade inflammation and
inactivity present as key components in disease-related det-
riments on UTC function (Fig.2). Consequently, therapies
that activate the immune system and reduce chronic inflam-
mation and adiposity would likely be beneficial for UTCs.
As exercise frequently has demonstrated these effects, we
hypothesize that regular physical activity may attenuate
or even reverse some disease-related detriments in UTCs.
In the next section, the effects of acute and regular exer-
cise on MAIT, NKT, and γδ T cells are presented to begin
evaluating our hypothesis as to whether physical activity
has the potential to prevent declines in UTC cell counts and
function.
UTCs andexercise
The effects of acute and chronic exercise on UTC number
and function are presented in the next section. Antigen rec-
ognition, regulation of inflammation, and barrier immunity
all fall within the domain of UTCs (Pellicci etal. 2020).
As these aspects are enhanced following exercise, it raises
the possibility that UTCs may contribute to the improved
immune function with regular physical activity. Because
of a relative low number of studies for some UTC subsets,
the use of acute psychological stress is included when
AgingDisease
Inflammation, obesity, reduced
physical activity
Decline in circulating UTC
counts, frequencies, and functions
MAIT
NKT
γδT
Fig. 2 Model of circulating unconventional T cell (UTC) decline and
dysfunction with aging and disease
European Journal of Applied Physiology
1 3
available to provide additional context. Acute exercise
was defined as a single exercise session with blood sam-
ples collected (at minimum) at baseline (rest) and then
immediately following exercise. Exercise training refers
to studies where blood samples were obtained before and
after the exercise intervention.
Conventional T cells
To help contextualize the UTC response to exercise, a
brief overview of conventional T cells is provided. Fol-
lowing acute exercise, robust mobilization of conven-
tional T cells occurs that is influenced by duration and
intensity (Gabriel etal. 1992; Nieman etal. 1994; Bishop
etal. 2014) and also cell type (CD3+CD8+ > CD3+CD4+)
(Campbell etal. 2009). Conventional T cell counts exhibit
a biphasic response, with mobilization increasing circulat-
ing cell frequency immediately following exercise with
levels falling below baseline in the initial hours following
recovery (Hansen etal. 1991; Gleeson and Bishop 2005;
Simpson etal. 2008). This “open window” no longer rep-
resents exercise-induced immunosuppression (Campbell &
Turner, 2018), rather an egress of cells into lymphoid and
non-lymphoid tissues that is partially dependent on activa-
tion status (Westermann etal. 2001). Additionally, conven-
tional T cells demonstrate a more mature effector pheno-
type (e.g., CD57+ or KLRG1+ cells) with acute exercise
that is partially age-dependent (Simpson etal. 2008) along
with decreased proliferation and IFNγ production (Shaw
etal. 2018). Exercise training may also have beneficial
effects on T cells, with cross-sectional studies reporting
trained individuals have higher naïve vs. senescent T cell
ratios, T cell proliferation, and IL-2, IL-4 and IFNγ levels
compared to untrained (Nieman and Wentz 2019; Bart-
lett and Duggal 2020). Interestingly, longitudinal investi-
gations (range 12 wk to 12months) did not consistently
support these findings, although exercise training within
more “at risk” populations (e.g., obese, cancer survivors)
may show greater T cell benefits (Simpson etal. 2012).
MAIT cells
MAIT cells and exercise is an emerging topic. However,
MAIT cell publications have increased exponentially in the
past 5years. With the association between MAIT cell defi-
ciencies and chronic conditions, this is an area ripe for future
investigations. Exercise as a low cost, scalable option that
has multiple physiological benefits that may extend to MAIT
cells. The establishment of exercise efficacy would open up
additional therapies to offset the side effects of low MAIT
cell counts.
Acute exercise
The effects of acute exercise in MAIT cells are summarized
in Table1. MAIT cell mobilization was initially investigated
in recreationally active young men following a maximal
effort graded exercise test on a cycle ergometer (Hanson
etal. 2017). Maximal aerobic exercise increased MAIT cell
counts by 2.2-fold immediately after acute exercise. There
was also a 0.8% increase in MAIT cell frequency, indicat-
ing that MAIT cells are preferentially mobilized within
the T cell populations. In a follow-up study also using
healthy young men, 40min of sub-maximal aerobic exer-
cise increased MAIT cell counts increased by 92% and cell
frequency by 1.0% relative to total T cells (Hanson etal.
2019). One hour after exercise, counts returned to baseline
while cell frequency remained elevated. Similar patterns
were observed within CD8+ and CD4−CD8− MAIT cell
subpopulations. Acute exercise increased the proportion of
MAIT cells expressing TNFα, suggesting greater MAIT cell
sensitivity to PMA and ionomycin stimulation. Neither IFNγ
or chemokine (homing marker) expression changed with
Table 1 Summary of acute exercise and exercise training on mucosal associated invariant T (MAIT) cells
Data are mean (SD). #, cell counts; freq, cell frequency; ↑, increase; ↓, decrease; ↔, no change
YM, young men; VT, ventilatory threshold; TNF⍺, tumor necrosis factor alpha; IFNɣ, interferon gamma; IL-17, interleukin 17; NAFLD = non-
alcoholic fatty liver disease; AE, aerobic exercise; MFI, mean fluorescent intensity; d, day; wk, week
Population NAge (y) % F Exercise Outcomes References
Acute
Healthy YM 20 28 (5) 0 Graded exercise test Cell # ↑ 116% and cell freq ↑ 0.8% at 0h Hanson (2017)
Healthy YM 20 22 (4) 0 40min at 86% of VTCell # ↑ 92% and freq ↑ 1.0% at 0h.
TNF⍺ freq ↑ by 8% at 0h but IFNɣ and
IL-17 ↔
Hanson (2019)
Training
NAFLD 16 58 (range: 20–71) 56 AE 5d / wk for 12 wk Intrahepatic cell freq % ↓ post-training;
Circulating & intrahepatic CD95 MFI ↑
post-training
Naimimohassess (2019)
European Journal of Applied Physiology
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acute exercise and IL-17 expression was minimal, likely
due to participants with normal body mass being used com-
pared to obese individuals (Carolan etal. 2015; Magalhaes
etal. 2015a). Ultimately, MAIT cell counts appear to show
a dose response to exercise intensity in young men, which is
consistent with conventional T cells (Scanzano and Cosen-
tino 2015). As MAIT cells express β2 adrenergic receptors
(Fergusson etal. 2014), this response may be modulated
by increasing levels of catecholamines as observed in other
immune cells (Ortega etal. 2007; Scanzano and Cosentino
2015) but still needs to be confirmed.
To our knowledge, there are no published MAIT cell and
exercise data in women. However, our laboratory recently
examined the effects of acute aerobic and resistance exer-
cise in older women. Compared to a lean, non-exercising
reference group (n = 8), overweight women (n = 8) had two-
fold and 4.7-fold lower resting lymphocyte and MAIT cell
counts, respectively (Bates etal. 2020 (abstract)). The lower
MAIT cell count is consistent with previous reports (Carolan
etal. 2015; Magalhaes etal. 2015b). Moreover, overweight
women (vs. lean reference group) also had 20% lower resting
MAIT cell TNFα expression following PMA and ionomy-
cin stimulation that suggests impaired function. Immediately
following 25min of walking at 70–80% heart rate reserve
and performing 2 sets of 8 different resistance training exer-
cises, lymphocyte counts increased by 63% while MAIT cell
counts were unchanged. The lack of a MAIT cell response to
acute exercise contrasts existing literature in healthy young
male populations (Hanson etal. 2017, 2019) and is some-
what surprising given that acute exercise induced a lym-
phocyte response. Possible reasons for the lack of MAIT
cell change are greater levels of adiposity or lower fitness
levels, along with age and sex differences that may have
confounded the response and need to be investigated.
Exercise training
There is a lack of published exercise training studies in
MAIT cells, although several recent unpublished works
have been identified. Although 12 wk of aerobic training
did not change circulating MAIT cell frequency, intrahepatic
frequency was reduced and CD95 expression was increased
during non-alcoholic fatty liver disease (Naimimohasses
etal. 2019 (abstract)). Further investigations are required
to determine the significance of these findings. Our group
recently examined the acute exercise response before and
after 16 wk of combined exercise training in 13 breast can-
cer survivors compared to 13 age-matched healthy controls
(Bates 2020 (thesis)). Prior to exercise training, acute exer-
cise increased MAIT cell counts in controls (137%) to a
greater extent than in breast cancer survivors (46%), with
preferential mobilization of MAIT cell frequency in con-
trols only, but no change in cytokine production. Following
training, breast cancer survivors now demonstrated nearly
twofold increases in MAIT cell counts with acute exercise
that approached levels in controls. These initial data are
promising and suggest exercise training partially rescues
the attenuated MAIT cell numbers following breast cancer
treatment.
NKT cells
We are unaware of any human exercise studies that have
specifically identified (e.g. Vα24i or CD161 expression)
NKT cells. Instead, numerous studies use combinations of
CD3, CD16, and CD56 that do not reflect the true NKT
cell population (Berzins etal. 2011). As such, the effects
of acute and chronic exercise on these NKT-like cells are
presented, along with the phenotype of each populations.
However, as the absence of NKT cells affects disease pro-
gression (Balato etal. 2009), an understanding if exercise
also influences these cells and how mobilization compares
to previous NKT-like cells would fill an important gap in
the current literature.
Acute exercise
NKT-like cells are responsive to short bouts of acute exer-
cise in healthy young men and women (Table2). In young
healthy women, a 30min treadmill run increased circulat-
ing CD3+CD56+ NKT-like cell numbers by 3-fourfold,
before returning to pre-exercise levels one hour later (Zela-
zowska etal. 1997). In young healthy men, 60min of tread-
mill running elicited a similar response for CD3+CD56+
NKT-like cells (Pizza etal. 1995). Vigorous cycling for
84min increased CD3+CD16+CD56+ NKT-like cells by
84% (Gabriel etal. 1992) while 60min of cycling elicited
2-threefold increases in CD3+CD56+ NKT-like cells in
young men (Timmons etal. 2004). Carbohydrate ingestion
prior to cycling attenuated the CD3+CD56+ NKT-like cell
increase immediately post exercise in these men, suggesting
that metabolic stress plays a role in NKT-like cell mobiliza-
tion that is analogous to NK cells (Wentz etal. 2018).
Similar to other effector immune cells, NKT-like cells
respond differently to additional physiological stressors.
Supine cycling to exhaustion in hypoxia (14% O2) resulted
in a larger CD3+CD16+CD56+ NKT-like cell egress than
normoxia (21% O2) during 60min of recovery (Gabriel
etal. 1993). This effect was not influenced by differences
between hypoxia and normoxia for cell mobilization dur-
ing exercise, or catecholamine responses. In fact, NKT-
like cells may be less responsive to catecholamines than
NK cells, and thus preferentially respond to alternative
exercise responses (Søndergaard etal. 1999). For exam-
ple, muscle damage from downhill running induces greater
mobilization of CD3+CD56+ NKT-like cells into the blood
European Journal of Applied Physiology
1 3
Table 2 Summary of acute exercise and exercise training on natural killer T (NKT) cells
Population NAge (y) % F Exercise Outcomes References
Acute
Healthy Subjects 14 28 (4) NR 100% of AT to exhaustion Cell # ↑ by 84% in first
10min of exercise,
remained ↑, then
reduced to resting
levels
Gabriel (1992)‡
Sedentary 10 28 (4) NR GXT in normoxia vs.
hypoxia
twofold ↑ in cell # at 0h
(both conditions). At
1h only hypoxia caused
a 50% ↓ below resting
levels
Gabriel (1993)‡
Athletes 9 Range: 36–68 22 100km ultra-marathon Cell # ↑ by 99%
10–33min into race
Gabriel (1994)‡
Trained runners 10 26 (5) 0 60min at 70% of VO2max Downhill running ↑ cell #
by 2.2-fold vs. 1.1-fold
on level grade at 0h. ↔
during recovery
Pizza (1995)†
Healthy YW 9 29 (1) 100 20min run at 50–90% of
VO2max
Cell freq ↑ ~ 26% with
acute exercise; ↔ time
of day (morning vs.
evening)
Zelazowska (1997)‡
Athletes 15 23 (7) 0 10% above LT to exhaus-
tion
Cycling ↑ cell # (57%
↑ normal and 49% ↑
overtrained)
Gabriel (1998)‡
Healthy boys & YM 22 10 (1) & 22 (1) 0 60min at 70%
VO2max ± CHO inges-
tion
Only men without CHO
ingestion had ~ 11% ↑ in
cell freq post-cycling
Timmons (2004)†
Training
Athletes 15 23 (7) NR 19 (3) mo of cycling or
triathlon
Overtrained condition
resulted in ↑ 33% cell
# vs. healthy post
exercise
Gabriel (1998)‡
Athletes 15 20 (1) 100 5h/d, 6 d/wk, for 1 mo Cell # ↑ 38% during and
after intensive volley-
ball training vs. CON
Suzui (2004)$
Healthy OW 60 55 (21) 100 60min, 4 d/wk for 6 mo
Tai Chi
Cell freq ↑by ~ 3.5% in
EX vs. ↔ CON
Liu (2012)‡
Healthy YM 21 31 (8) 0 3d/wk for 2 mo
RT ± vibration
Cell # ↑ by ~ 60% during
bedrest. No differences
between EX or CON
Hoff (2015)†
Breast cancer 20 48 (3) 100 Walk 35–50min/day, 5 d/
wk for 12 wk
Non-significant 20% ↓ in
cell freq during walking
at 40–60% of HRR
Kim (2015)?
European Journal of Applied Physiology
1 3
compared to a level gradient (Pizza etal. 1995). Elevated
NKT-like cell number (as well as NK cells, CD8+, and
CD4+ T cells) in the blood following damage-inducing
exercise is suggestive of a rapid stress/damage immune
response requiring specialized effector cells (Pizza
etal. 1995). This is consistent with the involvement of
NKT cells, specifically iNKT cells, in sterile inflamma-
tion responses, such as tissue injury (Ferhat etal. 2018).
Damage-associated molecular patterns and alarmins (e.g.,
IL-33) are released from injured cells and rapidly acti-
vate iNKT cells to produce IL-17 and IFNγ, which in turn
recruit neutrophils to the damaged tissue. Depending on
the severity of damage, NKT cells will sequester in the
tissue and be part of a coordinated regeneration process
(Ferhat etal. 2018). This would explain the NKT-like
and neutrophil responses during downhill running (Pizza
etal. 1995), as well as the prolonged 30–70% reduction
of blood NKT-like cells following a 100km ultra-mara-
thon race where severe sterile tissue damage is common
(Gabriel etal. 1994). Exhaustive cycling at 10% above
lactate threshold increased CD3+CD16+CD56+ NKT cells
2–threefold in 15 young athletes (Gabriel etal. 1998).
Interestingly, when comparing the immune response to
acute exercise at different periods of a training regimen,
NKT-like cells were higher when athletes were overtrained
(OT). The magnitude of mobilization and egress in NKT-
like cell counts was similar, but greater absolute cell num-
bers during OT suggesting that this may be a stimulus to
increase NKT-like cell production (Gabriel etal. 1998).
As no comparisons were made between non-OT and OT
athletes at the same point of the training program, it is
difficult to determine if increased NKT-like cells in OT
are because of exercise training or the exercise volume
leading to OT.
Exercise training
In breast cancer survivors, 12 week of walking during chem-
otherapy (Kim etal. 2015) or 16 wk of resistance training
following treatment (Hagstrom etal. 2016) had no effect on
the frequency of CD3+CD56+ NKT-like cells. Neither study
converted frequency into absolute cell number and only
resistance training reduced TNFα expression after overnight
mitogen stimulation (Hagstrom etal. 2016). There were no
additional effects on NKT-like cell measures (e.g., IFNγ
production), and serum TNFα concentrations were low and
unchanged, making it difficult to determine the importance
of this finding. Following 6months of Tai Chi in healthy,
middle-aged to older women, the frequency of NKT-like
cell frequency increased by ~ 3% and the production of IFNγ
and IL-4 from CD3+CD4+ lymphocytes (of which some are
NKT cells) also increased (Liu 2012). In non-small cell
lung cancer survivors, 16 wk of Tai Chi was associated
Data are mean (SD). NR, not reported; #, cell counts; freq, cell frequency; ↑, increase; ↓, decrease; ↔, no change; AT, Anaerobic Threshold; GXT, graded exercise test; RT, resistance training;
EX, exercise; CON, controls; LT, lactate threshold; HRR, heart rate reserve; d, day; wk, week; mo, month
† CD3+CD56+ cells
‡ CD3+CD16+CD56+
^ NKR-P1A (CD161) cells
$ CD3+CD16−CD56dim cells
? NKT phenotype unknown
Table 2 (continued)
Population NAge (y) % F Exercise Outcomes References
Lung cancer 32 E: 63 (8); C: 61 (7) 44 60min, 3 d/wk, 16 wk
Tai Chi
NKT cell freq ↓ ~ 1%
in CON but ↔ in EX
(~ 0.2%) at post-training
Liu (2015)‡
Breast cancer 39 52 (9) 100 16 wk for 60min/d, 3 d/
wk RT
NKT cell freq ↔.EX ↓
TNFα freq by 3% vs.
baseline
Hagstrom (2016)†
European Journal of Applied Physiology
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with CD3+CD16+CD56+ NKT-like cell frequency mainte-
nance (0.2% increase) while controls decreased by 1.0% that
resulted in a group difference (Liu etal. 2015). These results
suggest that Tai Chi in healthy women improves function
and may prevent declines during lung cancer.
No studies that we are aware of have assessed NKT-like
cells following exercise interventions that improve health
parameters (e.g., cardiorespiratory fitness or cardiometa-
bolic health) in young adults. Following 1month of inten-
sive volleyball training, CD3+CD16negCD56+ cells (rather
than NKT-like CD3+CD16+CD56+) increased from baseline
by ~ 75% after training and remained ~ 50% elevated after
1 wk (Suzui etal. 2004) and is consistent with acute exer-
cise performed during OT (Gabriel etal. 1998). This cel-
lular shift is most similar to that of CD56bright NK cells, a
population typically defined as CD16dim/negative that produces
greater amounts of cytokines and has lower cytolytic func-
tion compared to CD56dim NK cells (Poli etal. 2009). Inter-
estingly, intensive volleyball training was associated with
impaired NK cytolytic activity (Suzui etal. 2004), which is
consistent with a redistribution of NK and NKT cell subsets
that are less cytotoxic, although cytotoxicity on a per cell
basis was not determined. As none of the athletes reported
illness (Gabriel etal. 1998; Suzui etal. 2004), it may be that
increased NKT cell frequency is a consequence of intensive
exercise training rather than overtraining per se.
Alternatively, looking at 60d of bed rest to mimic space
flight or inactivity, immune-endocrine parameters were
assessed with or without resistance exercises or vibration
exercises (Hoff etal. 2015). When the control group and
two exercise groups were combined, there was ~ 60%
more CD3+CD56+ NKT-like cells at the end of the study.
Although exercise appeared to reduce total lymphocyte num-
bers, no group differences were reported for NKT-like cells,
making it difficult to ascertain why cell counts increased
during bed rest.
Taken together, both acute and chronic exercise train-
ing have the ability to modify NKT-like cell counts and
frequency. However, there may be differential responses
depending on the age, disease state, and the phenotype of
the NKT-like cells, which limits comparisons.
γδ cells
Acute exercise
Numerous studies have investigated the effects of acute
exercise on γδ T cells in humans (Table3). Long-duration
cycling in men evoked an ~ threefold increase in blood γδ
T cell counts immediately after exercise but were nearly
undetectable following 2h of recovery (Krzywkowski etal.
2001), presumably due to the exercise-induced redistribu-
tion of leukocytes to peripheral tissues (Kruger and Mooren
2007). It was strongly indicated that β-adrenergic stimulation
prompts γδ T cell mobilization into circulation (Anane etal.
2009). The infusion of the β-agonist isoproterenol caused
circulating γδ T cell counts to increase by > 2.5-fold, and this
mobilization was dose-dependent and emulated the exercise
Table 3 Summary of acute exercise and exercise training on gamma delta (γδ) T cells
Data are mean (SD). NR, not reported; #, cell counts; %, cell frequency; ↑, increase; ↓, decrease; ⇔, no change
PPO, peak power output; YM, young men; OM = old men; YW, young women; VO2max, maximal oxygen uptake; HR, heart rate; LT, lactate
threshold; d, day; wk, week; mo, month
Population NAge (y) % F Exercise Outcomes References
Acute
Elite athletes 10 37 (range: 25–48) NR 120min at 75% VO2max Cell # ↑ threefold at 0h. Minimal
# 2h post exercise
Krzywkowski (2001)
Active YM 11 21 (2) 0 16min at 35% or 85% of PPO Cell # ↑ 56% with low intensity
and by 219% with high intensity
Anane (2009)
Active YM & OM 34 29 (4) & 55 (4) 0 30min at 80–85% of PPO Cell # ↑ 140% (independent of
age). Resting cell freq was 3.5%
↓ in OM vs. YM
Pistillo (2013)
Healthy YM 10 27 (8) 0 60min at 90% of time trial watt-
age
Cell # ↑ by 90% in disrupted vs.
normal sleep. Egress (cell #)
was ↑ by 10% following sleep
disruption
Ingram (2015)
Active YM & YW 11 31 (4) 36 30min at 80% HR maximum Cell # ↑ by 119% at 0h and
remained elevated during
30min of recovery
Rooney (2018)
Trained cyclist 14 30 (6) 14 30min at 10–15% above LTCell # ↑ by 1.8-fold after 14d
expansion at 0h. 5% ↑ freq of
NKG2D activation receptor
and ~ 50% ↑ in cytotoxicity
Baker (2020)
European Journal of Applied Physiology
1 3
(> 200%) response while exceeding acute psychological
stress (53%). Akin to long-duration acute exercise (Krzy-
wkowski etal. 2001), γδ T cell sensitivity to high-intensity
exercise—as well as during acute psychological stress and
isoproterenol infusion—was relatively greater than αβ T
cells (Anane etal. 2009). The mobilization and egress of γδ
T cells appears to mirror that of CD16+CD56dim NK cells,
which have high β-adrenergic receptor expression (Benschop
etal. 1994) and are profoundly exercise-sensitive (Campbell
etal. 2009), albeit to a slightly lesser extent (Krzywkowski
etal. 2001; Anane etal. 2009). In a follow-up study, the
phenotypic analysis of γδ T cells was extended to under-
stand the effects of β-adrenergic stimulation on distinct γδ T
cells, including memory phenotypes (naïve, central memory,
effector memory, and CD45RA+ effector memory) within
δ1 and δ2 γδ T cell population (Anane etal. 2010). Acute
psychological stress mobilized δ1 and δ2 T cells to a similar
extent during and analogous to the mobilization patterns of
αβ T cells observed in other studies (Campbell etal. 2009),
although γδ T cells with a highly differentiated phenotype
and high cytotoxic potential were preferentially mobilized
(Anane etal. 2010). Examining adhesion molecules, it was
apparent that γδ T cells with low CD62L and high CD11a
expression were preferentially mobilized. In addition, these
preferentially mobilized γδ T cells expressed CD94 (NKG2),
which is an innate receptor also expressed by NK cells,
showing that the γδ T cells mobilized to tissues may play
a role in cytotoxic or regulatory responses against aberrant
MHC, such as those expressed by cancer or virally infected
cells (Anane etal. 2010).
More recent studies have explored the effects of age and
latent virus seropositivity on γδ T cell mobilization during
exercise, with the intended purpose of evaluating how immu-
nosenescence impacts γδ T cell mobilization. Healthy older
adults (age 50–64 years) had fewer γδ T cells than healthy
younger adults (age 23–35years) and 30min of cycling
evoked only a marginal increase in γδ T cell frequency in
the peripheral blood of the older adults (~ 35%), yet a larger,
archetypal increase (~ 120%) was observed in younger adults
(Pistillo etal. 2013). Among older adults, CMV serostatus
did not appear to be associated with γδ T cell sensitivity
to exercise; however, a positive CMV serostatus resulted
in greater γδ T cell responsivity in younger adults. One
hour after exercise cessation, γδ T cells exhibited greater
cytopenia in younger adults, perhaps reflecting a greater
redeployment of γδ T cells for immunosurveillance in these
individuals. The temporal egress of γδ T cells during the
recovery from vigorous exercise has been studied in young
healthy adults (Rooney etal. 2018). γδ T cell frequency in
the blood was reduced by > 25% after only a few minutes,
somewhat mirroring heart rate reductions and likely corre-
sponds with a rapid decline in adrenaline post exercise, that
was similar to other T cells but less than NK cells. Lastly,
acute exercise led to ~ threefold increases in circulating γδ T
cells following vigorous exercise in trained cyclists (Baker
etal. 2020). Following exvivo expansion of the δ2 subset
using zoledronic acid and IL-2, exercise enhanced NKG2
receptor expression and cytotoxicity against several differ-
ent tumor cell lines. In a subset of participants, mobiliza-
tion was abrogated using the non-selective β1/β2 antagonist
nadolol but not the β1 antagonist bisoprolol, indicating γδ T
mobilization with exercise largely occurs via a β2 adrenergic
receptor activity. The ability of exercise to increase cellular
expansion potentially improves the therapeutic potential of
these cells, which is currently limited by the low frequency
in circulation.
The effects of sleep on immune cell kinetics have become
of interest to researchers in exercise immunology, due in part
to a desire to understand the dysregulating effects of sleep
and circadian rhythm disruption on immunity (Besedovsky
etal. 2012) interact with the exercise–stress response. In
young men performing vigorous cycling, there was a ten-
dency for γδ T cell mobilization to be more pronounced
following a night of sleep disruption vs. undisturbed sleep
(Ingram etal. 2015). Disturbed sleep may upregulate the
stress hormone response to exercise, and therefore appears
to prime immune cell mobilization in a conserved evolution-
ary response.
Exercise training
To the authors’ knowledge, there are no human studies that
investigated the effects of regular exercise on γδ T cells and
only two rodent studies (Lee etal. 2019; Estruel-Amades
etal. 2019). The lack of literature using exercise training
to potentially alter γδ T cells (along with MAIT and clearly
defined NKT cell populations) counts or frequency repre-
sents an important gap in the exercise immunology literature
that would benefit from additional work.
Animal models ofUTCs andexercise
While animal models of exercise in UTCs are beyond the
scope of the current review, a brief summary of the existing
literature is provided. We are presently unaware of acute or
regular exercise in MAIT cells. However, four studies exist
using murine models that examine NKT and γδ T cells, with
three of them using intensive or OT protocols. Treadmill
training did not change NKT cell frequency at 36h after the
last session but exercise, but there was a 1.5% decrease one
week after training that was mostly prevented using αGalCer
treatment (Ru and Chen 2009; Ru and Peijie 2009). Short-
term (2 wk) treadmill training altered neither NKT cells or
γδ T cells, whereby longer training (5 wk) decreased NKT
frequency by 25% that was exacerbated when preceded
by exhaustive acute exercise (Estruel-Amades etal. 2019)
European Journal of Applied Physiology
1 3
that had minimal effects on γδ T cells. Finally, compared
to body temperature water, swimming in thermoneutral
water resulted in 1.5-fold and 2.5-fold higher γδ T cells and
NKT cell counts, respectively (Lee etal. 2019). In align-
ment with other exercise and tumor models used in rodents
(Pedersen etal. 2016), swimming elicited reduced tumor
volume and mass but only in thermoneutral water with a
lack of cold stress being hypothesized to be responsible for
the differences.
Exercise training: apotential stimulus
forUTCs?
Decreased UTC numbers present with aging, asthma, dia-
betes, cancer, and autoimmune disorders have several com-
mon links, including inflammation, excess body fat, and
reduced physical activity. Sustained low-grade elevations
in pro-inflammatory cytokines (e.g. IL-6, TNFα, IFNγ) are
observed in aging (Brüünsgaard and Pedersen 2003), chronic
disease (Head and Jurenka 2003; Lambrecht etal. 2019;
Moffa etal. 2019) and faster tumor progression (Koelwyn
etal. 2015) but differs from the large, transient changes seen
with acute exercise (Pedersen and Febbraio 2012). Obesity
is associated with many chronic diseases and contributes to
inflammation via cytokine production from activated UTCs
within adipose tissues (Carolan etal. 2015; Magalhaes etal.
2015b), while sedentary behavior is one factor leading to
increased adiposity (Whitaker etal. 2017).
Lifelong exposure to physical activity has well-estab-
lished immunoregulatory effects (Duggal etal. 2018, 2019)
in both circulation and skeletal muscle that appear to con-
fer benefits in men (Lavin etal. 2020a) more than women
(Lavin etal. 2020b). There are several potential mechanisms
by which regular exercise may influence UTCs (Fig.3).
Exercise training reduces sympathetic nervous system
activity (Mueller 2007) and increases vagal tone (Gourine
and Ackland 2019) while also attenuating immune cell pro-
inflammatory cytokine production (Tracey 2009) seen with
aging (Woods etal. 2012), cancer (Khosravi etal. 2019), and
a murine model of asthma (Vieira etal. 2014). Additionally,
exercise induces anti-inflammatory effects via the release of
myokines, such as IL-6 and IL-10, from contracting muscle
fibers as well as catecholamine secretion with vigorous exer-
cise that collectively inhibit pro-inflammatory cytokine pro-
duction (Gleeson etal. 2011; Woods etal. 2012). However,
chronic stress that promotes sympathetic nervous system and
hypothalamic–pituitary–adrenal axis activity impairs innate
and adaptive immune functions (Godbout and Glaser 2006),
which likely includes UTCs. For example, MAIT cells from
breast cancer survivors have reduced IFNγ expression (Bates
etal. 2020) that is also observed with obesity (Carolan etal.
2015) and suggests potential cellular exhaustion (Rudak
etal. 2018). Attenuated rises in epinephrine from acute exer-
cise during breast and prostate cancer treatment (Evans etal.
2016; Hanson etal. 2018) support altered stress-induced
immune dysregulation (Godbout and Glaser 2006). Reduced
exercise-induced catecholamine rises may alter UTC mobili-
zation, such as attenuated MAIT cell mobilization, in breast
cancer survivors that resolves following training (Bates etal.
2020). Psychosocial interventions (including exercise train-
ing) showed improvements in cytokine levels and NK and
T cell frequencies and function but results were inconsistent
and did not include UTCs (Subnis etal. 2014).
Additionally, increased physical activity disrupts seden-
tary behavior that is associated with diabetes and cancer
(Gleeson etal. 2011) and improves glycemic control, insulin
sensitivity, and the tumor microenvironment (Koelwyn etal.
Fig. 3 Proposed mechanisms
by which regular bouts of
acute exercise may increase
unconventional T cell (UTC)
number and function. Moderate
to vigorous exercise stimulates
catecholamine release, increas-
ing lipolysis and fat oxidation
that reduces adipocyte mass,
immune cell infiltration and
adipokine secretion. Along with
shear stress, catecholamines
increases circulating immune
cell numbers from the marginal
pools. Myokines, such as IL-6
and IL-15, released from con-
tracting skeletal muscle increase
UTC proliferation and cytotoxic
function while inhibiting TNFα
and stimulating IL-1ra and
IL-10
European Journal of Applied Physiology
1 3
2015; Dethlefsen etal. 2017; Hojman etal. 2018). While we
are unaware of any direct effects on UTCs, these changes
are likely to improve overall well-being, which includes the
immune system and mental health. For example, while hom-
ing marker frequency remains constant after acute exercise
(Hanson etal. 2019), overall circulating UTC levels are
higher. This combination may increase the absolute number
of cells that migrate to the lungs and GI tract to help allevi-
ate the elevated pathogen exposure from increased venti-
lation and food and fluid intake during exercise. Exercise
training also improves body composition during chronic dis-
ease (Hanson etal. 2016; Kujala 2009; Mcleod etal. 2019),
particularly when combined with nutritional interventions
(Fiatarone Singh 2002; Rozentryt etal. 2010). The loss of
adipose tissue, visceral fat in particular, reduces immune cell
infiltration and adipokine secretion (Gleeson etal. 2011),
with bariatric surgery partially restoring MAIT cell num-
ber and function (Magalhaes etal. 2015b). Furthermore,
myokines (e.g. IL-6, IL-15) released during skeletal mus-
cle contraction inhibit TNFα production and stimulate the
release of anti-inflammatory IL-1ra and IL-10 into circu-
lation (Petersen and Pedersen 2005; Gleeson etal. 2011).
IL-15 also has direct effects on UTCs, including activation
of MAIT cells (Hinks and Zhang 2020), iNKT maturation
and regulation (Gordy etal. 2011), and increased γδ T cells
proliferation and cytotoxicity (Van Acker etal. 2016). Inter-
estingly, plasma IL-15 levels following 1h of cycling are
higher in obese individuals (Pierce etal. 2015), providing
support that exercise could improve UTC function.
Lower circulating UTC levels during many chronic
conditions are likely multi-factorial, but we postulate that
increased egress into the diseased tissues provides a likely
explanation. Exercise training may play a role in re-estab-
lishing homeostatic balance through mobilization of UTCs
while also reducing the adverse effects of inflammation, sed-
entary behavior, and excess body fat on these cells. Pres-
ently, definitive evidence is lacking as much of the acute and
regular exercise involving UTCs utilizes healthy individuals.
Moreover, beyond greater cytokine frequency in MAIT cells
(Hanson etal. 2019), the functional benefits have yet to be
determined. However, with the expansion of exercise immu-
nology into new diseases and cellular populations, the inclu-
sion of UTCs will help fill in these gaps and to provide the
direct evidence needed to determine the efficacy of exercise
to improve UTC number and function.
Implications andfuture directions
UTCs contribute to immunity in multiple ways, with MAIT,
NKT, and γδ T cells all being capable of cytotoxic poten-
tial and cytokine secretion (e.g., TNFα, IFNγ, and IL-17),
that is potentially problematic in an aberrant inflammatory
phenotype. Moreover, UTCs target a wide range of infec-
tions and contribute to tumor suppression, providing a broad
degree of protection while also bridging the gap between
innate and adaptive immunity. With aging, UTC frequency is
lower but function may be maintained while chronic disease
adversely affects both UTC numbers and function. Greater
adiposity, inflammation and sedentary behavior appear as a
link between the UTCs, aging and disease.
Exercise may provide beneficial effects in rescuing UTC
number and frequency. UTCs demonstrate robust changes
with acute exercise in healthy individuals, with mobilization
that is analogous to conventional T cell populations, with
evidence that γδ T cells (but not likely MAIT or NKT cells)
respond in a catecholamine-dependent manner. Moreover,
NKT cells increase during heavy training periods or with
acute tissue damage, suggesting that these cells could serve
as a marker of OT or injury. However, the effects of exercise
in clinical populations and whether functional improvements
occur both remain unknown and loom as key next steps.
Regarding exercise training, evidences supporting beneficial
effects are strongest in NKT-like cells, although age and dis-
ease state may modulate this response, and specific (iNKT
vs. type II) cell types are yet to be assessed. Emerging work
from our group provides preliminary evidence that MAIT
cell mobilization may be rescued in breast cancer survivors
after training. Exercise training and γδ T cells are restricted
to animal work, with a clear need to examine these cells in
humans. Although not central to this review, exercise and
diet are often intertwined and nutritional considerations are
relevant in future UTC investigations. MAIT and γδ T cells
within the GI tract are influenced by the gut microbiota (Lin
etal. 2020). Caloric deficiency decreases immunity and has
the most prominent effects in older, clinical populations with
poorer nutritional habits (Walsh 2019) and may even coin-
cide with some populations (e.g. IBD, diabetes) who have
low UTC numbers (Catalan-Serra etal. 2018; Giuffrida etal.
2018; Moffa etal. 2019; Hinks and Zhang 2020). Exercise
training augments the gut microbiota [reviewed elsewhere
(Monda etal. 2017)], with body composition and exercise
mode influencing the training response (Nieman and Pence
2020). Additionally, advances in “multi-omics” technology
are unlocking new opportunities for exercise immunology
that may help contribute to the mechanisms responsible for
these improvements.
In summary, there is a clear need to assess the efficacy of
exercise-induced mobilization as a potential low risk, high
reward means of alleviating UTC deficiencies or to expand
these cells for allogenic stem cell transplant or immune ther-
apies. The inclusion of UTCs in exercise studies, particularly
within populations with low UTC frequency, is required to
assess the effects of and to determine if disease burden and
quality of life can be improved.
European Journal of Applied Physiology
1 3
Declarations
Conflict of interest The authors have no conflict of interest to disclose.
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