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Review Article
Th1 and Th17 Cells in Tuberculosis:
Protection, Pathology, and Biomarkers
I. V. Lyadova and A. V. Panteleev
Immunology Department, Central Tuberculosis Research Institute, Yauza Alley 2, Moscow 107564, Russia
Correspondence should be addressed to I. V. Lyadova; ivlyadova@mail.ru
Received 7 August 2015; Accepted 11 October 2015
Academic Editor: Shen-An Hwang
Copyright © 2015 I. V. Lyadova and A. V. Panteleev. is is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
e outcome of Mycobacterium tuberculosis (Mtb) infection ranges from a complete pathogen clearance through asymptomatic
latent infection (LTBI) to active tuberculosis (TB) disease. It is now understood that LTBI and active TB represent a continuous
spectrum of states with dierent degrees of pathogen “activity,” host pathology, and immune reactivity. erefore, it is important
to dierentiate LTBI and active TB and identify active TB stages. CD4+T cells play critical role during Mtb infection by mediating
protection, contributing to inammation, and regulating immune response. 1 and 17 cells are the main eector CD4+Tcells
during TB. 1 cells have been shown to contribute to TB protection by secreting IFN-𝛾and activating antimycobacterial action in
macrophages. 17 induce neutrophilic inammation, mediate tissue damage, and thus have been implicated in TB pathology. In
recent years new ndings have accumulated that alter our view on the role of 1 and 17 cells during Mtb infection. is review
discusses these new results and how they can be implemented for TB diagnosis and monitoring.
1. Introduction
Tuberculosis (TB) is one of the most common infections in
the world. Infection with Mycobacterium tuberculosis (Mtb)
most oen aects the lungs. e outcome of the pulmonary
infection is divergent and can range from the complete
pathogen clearance through asymptomatic latent infection
(LTBI) to active TB disease.
LTBI has long been considered as a uniform state char-
acterized by the immunological sensitization in the absence
of clinical signs and symptoms of active TB disease. Recently
it has become clear that LTBI includes a broad spectrum of
states that dier by the degree of host immune resistance,
inammatory markers, and pathogen replication (i.e., by
LTBI “activity”) [1].
e characteristics of the TB disease are in turn very
diverse. ey dier by the type of pathology developed
in the lungs (e.g., tuberculoma, cavitary TB, and caseous
pneumonia), the size of the aected lung tissue, the rate of
disease progression, the characteristics of immune activation
and inammation, and Mtb load and replication (i.e., the
presence, quantity, and replication activity of Mtb in the
sputum). Overall, the outcome of Mtb infection is not
a simple two-state distribution which includes LTBI and
active TB but represents a continuous spectrum of states
that dier by pathogen and host “activity,” have a dierent
contagiousness, and require dierent treatment strategies.
erefore, it is important to accurately diagnose the stage and
the status of Mtb infection.
It is generally assumed that the outcome of Mtb infection
depends on natural variations in host immune response
to mycobacteria, in particular on the type and extent of
immune activation and inammation. Immune activation
and inammatory reactions are essential for host protection
against mycobacteria [2–6]. On the other hand, unrestricted
immune responses are deleterious and may lead to the TB
exacerbation [7, 8]. Overall, the interplay between immune
activation, inammation, and TB pathogenesis is complex
and not completely understood. In spite of the complexity,
associations between Mtb infection activity and some param-
eters of immune/inammatory reactions have recently been
described; several dierent immunological parameters have
been suggested as markers of TB activity. Many of them are
related to T helper cells (discussed below).
Hindawi Publishing Corporation
Mediators of Inflammation
Volume 2015, Article ID 854507, 13 pages
http://dx.doi.org/10.1155/2015/854507
2Mediators of Inammation
ere are several populations (dierentiation lineages)
of T helper cells. e rst two populations, 1 and 2,
were described over 20 years ago [9]. Later, additional T
helper subsets were identied, including 17, 22, 9,
and TFH. Among dierent populations of T helper cells, 1
and 17 are the main eector populations which mediate
protection and pathology during TB. In this review we discuss
therolefor1and17cellsinprotectiveandinammatory
responses during Mtb infection and the prospective use of
their markers for the evaluation of pulmonary TB activity.
2. Th1 Cells in TB Protection and Pathology
Distinct populations of T helper cells dier by the expressed
cytokines and transcription factors and by their response to
dierent classes of pathogens. 1 cells produce IFN-𝛾and
depend on the transcription factor T-bet. ey are induced
upon infection with intracellular pathogens and mediate
protection mainly by activating macrophages which destroy
intracellular pathogens. 2 cells produce IL-4, IL-5, and
IL-13, depend on the transcription factor GATA3, and ght
extracellular parasites [9]. M. tuberculosis is an intracellular
pathogen and elicits 1 response.
2.1. 1 Induction and Dierentiation. Eector 1 cells
dierentiate from na¨
ıve lymphocytes. In general, the eector
cell dierentiation is driven by the signals received from
TCR, costimulatory receptors, and cytokines. In the most
simplied model, signals mediated by TCR and costimu-
latory receptors induce T cell activation and proliferation.
Cytokine-derived signals are the main signals determining
the dierentiation lineage of antigen-activated T cells. Lig-
ation of cytokines with their receptors activates the signal
transducer and activator of transcription (STAT) factors. e
STATs translocate to the nucleus and bind genes encoding
lineage-specifying transcription factors (“master regulators”)
and eector cytokines. ese events determine the lineage of
dierentiating T helper cells [10].
e main 1 inducing cytokines are IL-12 and IFN-𝛾.
IL-12 is produced by antigen-presenting cells. Interaction of
IL-12 with the IL-12 receptor, expressed on the surface of T
cells, induces STAT4, which in turn induces T-bet, a master
regulator of 1 cells. T-bet binds directly to many 1-
specic genes (Ifng,cxcr3,Il18r1,Il12rb2, etc.) and positively
regulates their expression [11]. T-bet also negatively regulates
the expression of 2- and 17-specic genes and inhibits
the dierentiation of 2 and 17 cells. In the absence
of T-bet, T helper cells dierentiate towards 2-like cells.
STAT4 also directly binds to Ifng locus and stimulates IFN-𝛾
production.STAT4andT-betcooperatetoinducemaximal
IFN-𝛾production. In the absence of STAT4, T-bet does not
induce optimal IFN-𝛾levels, and the combination of T-bet
and STAT4 deciency abolishes IFN-𝛾production [11–13].
IFN-𝛾acts by inducing STAT1. STAT1 synergizes with
STAT4 in activating T-bet in T helper cells and also can
directly activate 1-associated genes [14, 15]. IL-4 and IL-
10 inhibit 1 cell dierentiation and induce 2 cells. us,
generally, 1 and 2 are alternate and mutually exclusive
lineages of T helper cells. In some conditions, however, 1
and 2 cells retain their plasticity, can transdierentiate,
and even coexpress 1- and 2-specic cytokines and
transcription factors [16].
Cytokine milieu is the main factor that determines the
lineage of T helper cell dierentiation. However the dieren-
tiationisalsoaectedbythedoseandthestrengthofTCR
agonistic ligand. It has been shown that stimulation with a
high dose of TCR agonistic peptide or a strongly agonistic
ligand favors generation of 1 cells whereas a low dose or
a weakly agonistic ligand favors 2 cells [17]. erefore,
we may speculate that pathogen load, pathogen metabolic
activity, and the stage of the disease aect the composition
of the responding T helper population.
2.2. 1 Cells and IFN-𝛾during TB. It has long been assumed
that the central role of 1 cells in the defense against TB
is due to the ability of IFN-𝛾to activate macrophages and
stimulate phagocytosis, phagosome maturation, production
of reactive nitrogen intermediates, and antigen presentation
[18–20]. is has been supported by many observations.
In particular, mice decient in CD4+subset and 1 type
cytokines (i.e., IL-12p40, IFN-𝛾)succumbearlytoMtb
infection with high bacterial loads [21–23]. Similar eects are
observed in mice with the defects in enzymes involved in
the generation of host-bactericidal molecules, dependent on
IFN-𝛾axis [24–27]. Humans with the mutations in molecules
involved in 1 immunity (i.e., the IL-12p40 subunit, the IL-12
receptor 𝛽1 chain, the IFN-𝛾-receptor ligand binding chain,
and STAT1) exhibit extremely high susceptibility to infec-
tions induced by Mtb,Bacillus Calmette-Guerin (BCG), or
environmental mycobacteria [28–30]. HIV-infected patients
decient in CD4+cells have increased reactivation of latent
Mtb infection and altered histopathological characteristics
of TB disease (i.e., diuse necrotic lesions instead of struc-
tured granulomas) [31]. ese and other studies supported
the concept that 1 are prerequisite for TB defense and
act by stimulating the antimycobacterial immunity through
the 1 →IFN-𝛾→macrophage activation →Mtb
killing/restriction pathway. However some new unexpected
results, that contradict this paradigm, are now emerging.
Several studies in mice reported lack of correlation
between the degree of protection and the frequencies of Mtb-
specic IFN-𝛾producing cells or IFN-𝛾levels [32–35]. In
some studies, antigen-specic IFN-𝛾production by CD4+
T cells correlated with the decrease in Mtb load but did
not reect the strength of protection [34]. In other studies,
1 mediated protection against Mtb replication was IFN-𝛾
independent [36, 37]. Next, some authors reported that IFN-
𝛾mediated protection by inhibiting a deleterious response
of 17 cells rather than by inhibiting Mtb replication [38].
Finally, in some experimental models CD4+Tcellswere
deleterious [39, 40].
For example, Scanga and coauthors reported that in the
murine model of latent tuberculosis, depletion of CD4+cells
resulted in uncontrolled Mtb growthbutitdidnotalter
IFN-𝛾response [32]. Gallegos and colleagues [37] studied
protective properties of ESAT-6 specic 1, 2, and 17
cellsderivedfromthewildtypemiceormicedecientfor
factors associated with 1 activity (e.g., IFN-𝛾,TNF-𝛼). In
Mediators of Inammation 3
an adoptive transfer model, 1 cells were more protective
than 17 cells; 2 cells were not exhibiting any protective
activity against Mtb replication. Yet the ability of 1 cells to
mediate protection did not depend on IFN-𝛾or TNF-𝛼.
Nandi and Behar adoptively transferred IFN-𝛾−/− mem-
ory CD4+TcellsintoMtb-infected recipients and assessed
bacterial load and mice survival [38]. e latter is an
integrated parameter of TB severity that largely depends on
the extent of pathological inammatory response. IFN-𝛾−/−
memory CD4+T cells retained their antimicrobial activity
but failed to protect recipient mice against severe inamma-
tion and death. It was suggested that IFN-𝛾acts by inhibiting
IL-17 response and pathogenic neutrophil accumulation in
theinfectedlungs,thatis,thatIFN-𝛾mediates protection by
limiting host inammatory response rather than by inducing
macrophage antibacterial activity.
Finally, a deleterious role for the CD4+Tcellsduring
TB has been demonstrated. Several studies documented
that mice decient in PD-1 and infected with Mtb exhibit
unaltered or even increased CD4 and IFN-𝛾responses but
diebecauseofthesevereinfectioncharacterizedbythe
uncontrolled bacterial proliferation, increased lung tissue
pathology, neutrophilic inltration, and high lung expression
of proinammatory cytokines. Of note, CD4+T cell depletion
reduced production of IFN-𝛾and other proinammatory
cytokines and rescued PD-1−/− mice from early mortality [39,
40]. Interestingly, resistance to viral infections is increased
following PD-1 blockade [41], indicating that in TB an
imbalancedTcellresponsemaybemoredeleteriousthan
during other infections.
us, one important aspect of TB immunity is that 1
subset may mediate protection by mechanisms other than
IFN-𝛾production or activation of host antibacterial activity
and even may contribute to pathology.
Another puzzle comes from the studies in humans that
investigated 1/IFN-𝛾responses during LTBI and active TB.
LTBI is usually considered as a state of Mtb infection
that develops due to an eective anti-TB immune defense.
It is believed that the comparison of immune responses
during LTBI and active TB may help with uncovering
immunological correlates of protection. However, multiple
studies of 1/IFN-𝛾responsesinhumanshaveresultedin
contradictory conclusions. Some studies reported that the
antigen-driven secretion of IFN-𝛾by blood mononuclear
cells is reduced in TB patients and normalized upon TB
treatment [42–44]. On the other hand, frequencies of circu-
lating IFN-𝛾producing cells are generally increased in TB
patientsanddecreasefollowingthetreatment.Inlinewith
this, some studies showed increased plasma levels of IFN-𝛾
in TB patients; these levels correlated with disease activity
and normalized during the treatment [45]. Furthermore,
patients with newly diagnosed TB were reported to have
higher levels of IFN-𝛾compared to patients with chronic TB.
Finally, it is now well documented that interferon-gamma-
release assays (IGRAs) do not discriminate LTBI and active
TB [46–48]. is indicates that the two groups do not dier
consistently by the levels of Mtb-specic IFN-𝛾secretion
(detected in Quantiferon-TB Gold-in tube assay, QFT) or
by the frequencies of Mtb-specic IFN-𝛾producing cells
(dened in T-SPOT-TB assay). us, no steady dierences
in IFN-𝛾responses have been identied so far between LTBI
andactiveTB.
Considering TB patients, they are characterized by a great
variability in the immune responses. It has been shown that
IGRAs have suboptimal sensitivity for active TB, supposedly
due to the immune suppression developed during severe
disease. To verify this hypothesis, we have recently analysed
whether the levels of IFN-𝛾secretion determined in QFT
assay and the frequency of the antigen-specic IFN-𝛾produc-
ing cells determined by ow cytometry are associated with
TB severity. For that, we checked the correlation of IFN-𝛾
responses with the following characteristics of TB disease: the
presence and the quantities of Mtb in the sputum, the forms
of pulmonary pathology (i.e., tuberculoma, inltrative TB,
cavitary TB, caseous pneumonia), the degree of pulmonary
destruction, TB extent, clinical disease severity, and hemato-
logic abnormalities. We have found no signicant association
between these parameters and IFN-𝛾responses, which argues
against the direct association between TB disease severity
and the extent of IFN-𝛾response ([49], and our unpublished
results).
2.3. Section Summary. Altogether, 1 mediated IFN-𝛾
response activates Mtb killing in vitro and contributes to
the restriction of Mtb growth in vivo but also plays anti-
inammatory role during TB and can participate in TB
exacerbation. Assays based on the evaluation of Mtb-specic
IFN-𝛾responses are currently used to identify Mtb infection,
but these assays do not allow discriminating LTBI and TB
disease. Numerous comparisons of IFN-𝛾responses during
active TB and LTBI have revealed no consistent patterns.
ere are several possible explanations for that: dierent
anatomical distributions of eector 1 cells during active TB
and LTBI, functional exhaustion of eector 1 cells during
chronic TB disease, diversity of Mtb antigens expressed
duringLTBIandactiveTB,andagreatvariabilityofTB
patients with regard to TB stage, host immune reactivity,
and genetic and other factors. Irrespective of the underlying
mechanisms, IFN-𝛾response seems to be unreliable for the
evaluation of TB activity. However other markers of 1
reactivity may be valuable and will be discussed below.
3. Th17 Cells in TB Defense and Pathology
17 were rst described as a distinct population of the T
helper cells that are controlled by the transcription factor
ROR𝛾t and develop independent of T-bet, STAT4, GATA-3,
and STAT6 transcription factors that are critical for the 1
and 2 development [50, 51]. e main eector cytokine of
17 is IL-17; other cytokines are IL-22, IL-26, and GM-CSF
[52–56].
e family of IL-17 cytokines consists of the six similar
members, designated from IL-17A (oen referred to as IL-
17) to IL-17F. 17 cells produce IL-17A and IL-17F. Both
have similar biological activities and are the most thoroughly
studied members of the IL-17 family. e family of IL-17
receptors includes ve members (IL-17RA–IL17RE) that are
4Mediators of Inammation
expressed on dendritic cells (DC), macrophages, lympho-
cytes, epithelial cells, keratinocytes, and broblasts and allow
dierent organs to respond to IL-17. IL-17A and IL-17F bind
to IL-17RA [53, 57].
17 mediate pleiotropic activities that involve induction
of proinammatory genes (cytokines, chemokines, and met-
alloproteinases) and antimicrobial peptides, modulation of
extracellular matrix, stimulation of granulopoiesis, recruit-
ment, and activation of neutrophil granulocytes. erefore,
the main functions of 17 cells are protection against
extracellular pathogens and mediation of the inamma-
tory response, particularly during autoimmune and chronic
inammatory diseases.
3.1. 17 Induction and Dierentiation. e dierentiation,
expansion, and maintenance of 17 cells depend on TGF-
𝛽,IL-1𝛽, IL-6, IL-21, and IL-23. e role of these cytokines
in the induction and maintenance/stabilization of 17
cells is dierent in some species, in particular in mice
and humans [53, 58–63]. In general, the dierentiation of
mouse 17 cells depends on IL-6 and TGF-𝛽.IL-23,IL-
1𝛽,andTNF-𝛼maintain and amplify 17 cells. Data on
the dierentiation requirements for human 17 cells are
contradictory. In most studies, human 17 cells depended
on dierent combinations of IL-1𝛽, IL-6, and IL-23. TGF-
𝛽was dispensable or even inhibitory for their develop-
ment(reviewedindetailin[64]).Inbothhumansand
mice dierent combinations of cytokines may result in
the generation of dierent 17 subsets (see below). IFN-
𝛾, IL-12, IL-27, IL-4, and IL-2 inhibit 17 dierentiation
[54, 58, 65–67].
At the molecular level, the generation of 17 requires
induction of ROR𝛾t,akeyregulatorof17dierentiation,
which depends on the activation of the “pioneering factor”
STAT3[10].IL-6,IL-21,andIL-23activateSTAT3,thus
inducing the expression of ROR-𝛾t. Of note, IL-23 is able
to induce the phosphorylation of both STAT3 and STAT4,
but STAT3 phosphorylation is much stronger and biases T
cell dierentiation towards the formation of 17 cells (the
opposite is true for IL-12: it induces strong phosphorylation
of STAT4 but relatively weak phosphorylation of STAT3 [53]).
e role of TGF-𝛽in 17 dierentiation is largely mediated
through its capacity to inhibit the dierentiation of 1 cells
(which suppress 17) [68, 69]. It is assumed that, in the pres-
ence of TGF-𝛽, IL-6 contributes to the generation of 17 by
inhibiting the dierentiation of Treg. Indeed, TGF-𝛽is crit-
ical for the generation of Treg. IL-6 inhibits Treg generation
and thus in inammatory conditions favors the generation of
17; that is, it regulates 17/Treg balance [70]. IL-21 was
showntoupregulateitsownexpressionandthatofIL-21R
and IL-23R. Besides ROR𝛾t, optimal generation of the 17
cells also depends on other cofactors, such as IRF4, BATF, and
RUNX1, which cooperate with ROR-𝛾tin17dierentiation
[10].
3.2. 17/IL-17 Biological Activity. Pleiotropic activities of
17 cells involve activation and recruitment of neutrophils,
stimulation of granulopoietic lineage of dierentiation, and
supportofinammation.
Neutrophil recruitment is mediated through the produc-
tion of CXCL8 and GM-CSF [54, 71] and the induction of
CXCL1, CXCL2, CXCL5, CXCL6, CXCL8, and G-CSF in tis-
sue resident cells, in particular in human bronchial epithelial
and venous endothelial cells [72]. CXCL1, CXCL2, CXCL5,
CXCL6, and CXCL8 are neutrophil-attracting chemokines;
GM-CSF and G-CSF stimulate granulopoiesis and granulo-
cyte activation [73].
e ability of IL-17 to recruit neutrophils to mucosal
sites has been demonstrated in a number of studies [74–
77]. e role for IL-17 in modulating granulopoiesis is
evident from the expansion of the neutrophil progenitors
in the bone marrow and mature neutrophils in peripheral
blood of the mice overexpressing IL-17 [78]. In the model
of lung infection induced by Klebsiella pneumoniae, lack
of IL-17 hampered stress-induced granulopoiesis suggesting
that during infections intact IL-17 response may be required
for the eective granulocyte generation [79]. In primary
human bronchial epithelial cells 17 induce the expres-
sion of mucins MUC5AC and MUC5B [80] and antimi-
crobial peptides (e.g., human beta-defensins) [81, 82]. e
activity is mediated by IL-17 and IL-22 [83] and together
with neutrophil recruitment serves to clear extracellular
pathogens. Recent studies suggest that 17 are also involved
in host protection against some intracellular pathogens
[84].
17/IL-17 mediated induction of chemokines and
cytokines in tissue resident cells, as well as the recruitment
of neutrophils, promote local inammatory responses and
mayleadtotheserioustissuedamage.Accordingly,17
cellshavebeenimplicatedinthepathogenesisofseveral
autoimmune and chronic inammatory diseases. It has been
suggested that in autoimmunity and chronic inammation,
IL-17 synergizes with other proinammatory cytokines
abundantly produced in these pathological conditions, such
as TNF-𝛼and IL-1𝛽[53]. 17 cells may even coexpress
IL-17 and TNF-𝛼. It has been suggested that IL-17 rather
sustains preexisting inammation than induces it. is
means that 17 may be protective during acute infection
and deleterious during chronic one [85]. is concept may
be relevant to TB, as TB is accompanied by the abundant
inammatory responses.
3.3. 17 Phenotype and Subpopulations. Na¨
ıve and antigen-
experienced cells dier by the expression of their dierentia-
tion markers. Distinct lineages (populations) of T helper cells
dier by the expression of chemokine receptors. Finally, some
T cell lineages express lineage-specic markers. e majority
of IL-17 producing cells express CD45RA−phenotype of
antigen-experienced cells [86]. Characteristic feature of IL-
17 producing cells and their precursors is the expression of
CD161, the lectin receptor, and the human ortholog of murine
NK1.1 [87, 88].
With regard to chemokine receptor expression, the 17
population is heterogeneous. It contains cells expressing lym-
phoid tissue homing receptor CCR7 (in a higher proportion
than IFN-𝛾producing cells), B follicle homing receptor
CXCR5, and nonlymphoid tissue homing receptors CCR4,
CCR5, and CXCR6. Heterogeneous expression of these
Mediators of Inammation 5
receptors by 17 cells underlies their capacity to migrate to
dierent sites [89].
Chemokine receptors CXCR3, CCR4, and CCR6 discrim-
inate dierent lineages of T helper cells. 1 cells are char-
acterized by the expression of CXCR3, CXCR6, and CCR5;
2 cells express CCR3, CCR4, and CCR8. e chemokine
receptor associated with 17 is CCR6, the receptor for
CCL20 and defensins, mediating homing to skin and mucosal
sites. Correlation between the expression of CCR6, the
production of IL-17, and the expression of RORC (the human
ortholog of mouse ROR𝛾t) was directly demonstrated, and
17 cells were shown to express the CCR6+CCR4hiCXCR3lo
phenotype [90].
Further analysis, however, identied a population of
CCR6+CCR4loCXCR3hi cells that coexpress 17 (CCR6)
and 1 (CXCR3) associated receptors [91]. is phenotype
is associated with the coexpression of two master regulators,
ROR𝛾tandT-bet[10].Functionalanalysisshowedthat
CCR6+CCR4loCXCR3hi population contains cells producing
only IFN-𝛾,onlyIL-17,andpoly-functionalcellsableto
produce both IFN-𝛾and IL-17. Due to the simultaneous
production of IFN-𝛾and IL-17, the latter population was
named 1/17 [64, 90, 92–95].
Further heterogeneity of 17 cells comes from their
inammatory properties. In mice, “pathogenic” and “non-
pathogenic” populations of IL-17 producing cells have been
described. Generation of pathogenic cells depended on IL-
23.ecellsproducedIL-17,andtheiradoptivetransfer
caused experimental autoimmune encephalomyelitis. Non-
pathogenic cells coexpressed IL-17A and IL-10, were able
to suppress T cell proliferation and were called immune-
suppressive or regulatory 17 cells (r17) [96–99].
In humans, a population of 17.1 cells similar to the
“pathogenic” mouse 17 cells has recently been described.
e cells coexpressed CCR6 and CXCR3 and exhibited
transient expression of c-kit and stable expression of the mul-
tidrug transporter MDR1. Transcriptionally and functionally
17.1 cells resembled the pathogenic mouse 17 cells; that is,
they were highly sensitive to IL-23 stimulation and produced
both 17 and 1 cytokines [91]. Similarly, in some studies,
“pathogenic” 17 cells in mice were also characterized by
the coexpression of IL-17A, TNF-𝛼,andIL-2.Altogether,the
data raise questions on whether pathogenic potential of 17
cellsisassociatedwiththeCCR6
+CXCR3+population and
whether it depends on IL-17 or on a combination of factors
that these cells produce.
To summarize, the main phenotypic characteristic of IL-
17 producing cells is the expression of CD161 and CCR6.
17 are phenotypically and functionally heterogeneous and
contain at least two subpopulations, 17 and 1/17, that
dier by the expression of chemokine receptors (i.e., CCR4
and CXCR3) and eector cytokines (i.e., IL-17, IL-17 and IFN-
𝛾, IL-17 and IL-10) and may play dierent roles in immune
pathology and protection. eir exact role in these processes
is yet to be determined.
3.4.17andIL-17inTBProtectionandPathology. e fact
that 17 cells mediate both antibacterial and proinamma-
tory responses suggests that their role during infection is
complex. is is particularly true for TB, as the pathogenesis
of TB critically depends on the extent of inammation. Data
on 17 responses during TB are numerous but not uniform
and quite likely depend on the model and the degree of
inammation.
Following vaccination, 17 seem to contribute to mem-
ory response and protection. In mice immunized with BCG,
IL-17 supported 1 reactivity by downregulating IL-10 and
upregulating IL-12 production in dendritic cells [100, 101].
Following Mtb challenge of BCG vaccinated mice, 17
induced chemokines, recruited CD4+Tcellstothesite
of infection, favored granuloma formation, and accelerated
pathogen clearance [102]. In humans, generation of 17
and 1/17 cells in response to a novel TB vaccine, the
modied vaccinia virus Ankara expressing antigen 85A, was
documented [103]. Interestingly, BCG vaccination induces
dierent levels of IL-17 in genetically dierent mice. Garcia-
Pelayo and coauthors [35] have demonstrated that BALB/c
mice produce more IFN-𝛾and IL-17 and less IL-10 in
response to BCG as compared to C57BL/6 mice. is suggests
that (i) the extent of 17 reactivity is aected by the host
genetic factors; (ii) the pattern of 1/2/17 responses
may dier during TB infection and following BCG vaccina-
tion.
Data on the role for 17 during primary Mtb infection
are conicting.
In mice challenged via aerosol route with a low dose
of laboratory Mtb strain, IL-17 was dispensable for primary
immunity [104]. On the other hand, 17/IL-17 responses
were involved in the protection against highly virulent Mtb
isolate, HN878. Gopal and coauthors [105] reported that
mice challenged with HN878 exhibited elevated IL-17/17
responses as compared to mice challenged with laboratory
adapted Mtb strain. IL-17−/− mice infected with HN878
had elevated lung bacterial burden, diminished chemokine
response (CXL13, in particular), defective formation of
ectopic lymphoid follicles, and hampered colocalization of
T-lympho c yte s and m acrophages [105]. e involvement of
17 in TB protection is also supported by partial inhibition
of the Mtb growth following the adoptive transfer of 17 cells
[37].
e role for 17/IL-17 responses in TB protection in
humans was mainly studied by comparing these responses
in TB patients and healthy individuals. e results are
contradictory. Some authors reported similar levels of IL-17
in the blood and bronchoalveolar uids (BAL) of TB patients
and healthy controls [106]. In other studies, the frequencies
of blood IL-17 producing cells were reduced in TB patients
suggesting that 17 contribute to the protection [107]. is
idea is supported by the observation showing that the low
level of IL-17 in serum is associated with high mortality of
TB patients [108].
Other studies, however, suggest the involvement of 17
in TB pathology. Jurado and coauthors reported an aug-
mented 17 response in TB patients. e major source
of IL-17 was represented by IFN-𝛾+IL-17+CD4+Tcells,
and their proportion directly correlated with the clinical
parameters associated with the disease severity [109]. In
6Mediators of Inammation
line with this, Basile and others have associated augmented
17 response with persistent and high antigen load and
pathogen drug resistance [110]. It should be noted that IL-
17hasbeenimplicatedinneutrophilrecruitmentandstress-
induced granulopoiesis. Neutrophils have been suggested
to play a pathogenic role and exacerbate TB disease [7, 8,
111–113]. Recent studies performed in a mouse model have
suggested that immature myeloid cells are strong correlates
of severe TB [114–116]. us, the involvement of 17/IL-17
responses in the pathogenesis of severe TB is not surprising.
An important question is the interaction/s between 17
and1cellsandtheirrelativerolesduringactiveTBand
LTBI. As discussed above, 1 cells and IFN-𝛾suppress
the generation of 17. On the other hand, 17 do not
inhibit the generation of 1 in vitro and may even favor 1
response in vivo. e relationships between 1 and 17 cells
during TB infection are complex and not well understood.
Comparative analysis of 1 and 17 responses was per-
formed in several studies and the results are contradicting.
Mar´
ın and coauthors [117] studied the frequencies of IL-17
and IFN-𝛾producing cells in patients with active TB, LTBI,
and noninfected control donors. e frequency of IFN-𝛾
producingcellswaselevatedinLTBI,andIL-17producing
cells were more frequent in TB patients. e authors con-
cluded that active TB biases the protective 1 prole toward
the pathological 17 response. Another study compared
cytokine levels in tuberculin skin test (TST) positive and
TST negative individuals in TB endemic area. 1 and 2
cytokines were not dierent between the two groups; IL-17,
IL-23, and ROR𝛾t expressions were downregulated in TST
positive individuals. e authors suggested that lack of 17
cells predisposes to latent infection [118]. However this study
did not investigate active TB. Li and coauthors evaluated
studies of 1 and 17 responses in TB patients [119]. Of
226 studies, nine met their criteria and were selected for the
analysis. eir systematic review showed that in TB patients
the levels of IL-17 and IFN-𝛾were low; during LTBI IL-17 and
IFN-𝛾levels were generally high compared to active TB. In
contrast to TB disease, BCG vaccination in children induced
high level of IL-17 and IFN-𝛾.eauthorsconcludedthat
aer BCG vaccination and during Mtb infection IL-17 acts
as an eector molecule similar to IFN-𝛾and together with
IFN-𝛾contributes to TB protection.
An interesting question is which cells represent the
major source of IL-17 during TB. As discussed above, a
population of 1/17 cells coexpressing IFN-𝛾and IL-
17 exists. 17 may acquire expression of T-bet and IFN-
𝛾and even Foxp3 during their development; that is, they
exhibit substantial plasticity [10, 16, 120]. Whether “multi-
functional” 17 cells dier from “classical” 17 cells in
their pathogenicity is not completely clear. As noted above,
in some pathological conditions (e.g., in the gut of Crohn’s
disease patients), cells coexpressing 17 and 1 cytokines
are pathogenic. Similarly, in TB patients the accumulation
of IFN-𝛾+IL-17+cells correlated with the disease severity
[109]. Arlehamn and coauthors [121] have demonstrated
that TB-specic memory T cells are predominantly present
within the CCR6+CXCR3+CCR4low population and that
this population is signicantly increased in LTBI donors
compared to healthy controls. e CCR6+CXCR3+CCR4low
populationisknowntocontain1/17cells.However,
the authors did not detect IL-17 production in TB-specic
CCR6+CXCR3+CCR4−cells upon their ex vivo antigenic
stimulation. Note that in response to other antigens (e.g.,
Candida albicans)CCR6
+CXCR3+CCR4low cells readily pro-
duce IL-17 [90]. us, the accumulation of Mtb-specic
CCR6+CXCR3+CCR4−IL-17−cells may represent a charac-
teristic feature of Mtb infection. It would be interesting to
study if these cells also accumulate during active TB or if they
specically mark LTBI.
Another question concerns 17 responses that develop
locallyinthelungs.echaracteristicsoflocal17responses
couldprobablyshedalightontherolewhichthesecells
play in TB protection/pathology, but this aspect has not
been studied in detail yet. In one study, IL-17 was not
abundant in pleural or pericardial uid of TB patients; IL-17
expression by mycobacteria-specic disease site T cells was
not detected in healthy Mtb-infectedpersons,orpatientswith
TB pericarditis, allowing the authors to conclude that IL-17
does not play a major role at established TB disease sites in
humans [122].
3.5. Section Summary. To summarize, a number of studies
suggest that IL-17 producing T cells are eciently generated
following vaccination and involved in the memory response
to subsequent Mtb challenge. e role for these cells during
primary Mtb infection is less clear. In many studies, the extent
of 17 response during TB infection was low, which may be
interpreted as a defect in the protective response, but also
as a dispensable role for 17/IL-17 in TB protection and
pathology. However, other studies have associated 17/IL-
17 with TB pathology and progression. It is possible that
17 cells may play dierent roles at subsequent stages of
TB infection providing protection at early disease stage but
inducing pathology at advanced TB. Next, IL-17 producing T
helper cells contain at least two dierent populations, 17
and 1/17. eir role in TB protection and pathology
may dier and has not been evaluated separately as were
the peculiarities of local 17 responses. It should be noted
that experimental data on the role for 17 cells during Mtb
infection should be interpreted with caution. Indeed, unlike
1 and 2 cells, 17 cells dier between mice and humans.
In particular, mouse and human 17 cells depend on
dierent sets of cytokines, and the ecacy of their generation
during Mtb infection in mice and humans may dier. Next,
mouse models of TB infection do not fully reproduce pul-
monary TB in humans by the type of pulmonary pathology
and granuloma formation. us, in mice and humans cells
involved in granuloma formation may have a dierent impact
in local immune responses. Finally, clinical Mtb isolates and
laboratory Mtb strains induce a dierent extent of 17
response.
It should also be noted that discriminating between
protective and pathological responses during infectious dis-
eases is always extremely dicult, as the same cells may
be simultaneously involved in both processes. However
Mediators of Inammation 7
some parameters of cellular responses (regardless of their
protective or pathological impact) may be strongly associated
with the disease severity/activity and thus may be used as
biomarkers for disease evaluation and monitoring. Whether
biomarkers of 1 and 17 responses may be used to
assess activity of Mtb infection is discussed in the next
section.
4. T Cell Associated Biomarkers of TB Activity
As discussed in the introduction, evaluation of TB activity is
an important diagnostic goal, both to discriminate between
LTBIandactiveTBandtomonitorinfectionactivityatthe
dierent stages of TB disease. Whether and which parameters
oftheimmuneresponsemaybeusedasmarkersofTB
activity are an open question.
4.1. IFN-𝛾.Speaking about IFN-𝛾response, which has been
studied most extensively, the relations between its intensity
and Mtb infection activity are extremely complex. In the most
simplied model, the ecacy of IFN-𝛾response depends
on genetic and/or other Mtb infection-independent factors
(e.g., nutrition, stress, the use of immunosuppressive drugs,
and chronic infections) and this aects the outcome of Mtb
infection. In this model, the lower the IFN-𝛾response is,
thehighertheTBactivitywouldbe.Ontheotherhand,
all immune responses, including IFN-𝛾,arepathogen-driven
andthusthemoreactivetheinfectionis,thehigherthe
immune response should be. However, chronic infection
and persistent antigenic stimulation induce regulatory loops
and T cell exhaustion, aecting the relationships between
infection activity and IFN-𝛾production. e real situation is
even more complex because IFN-𝛾is produced by dierent
immune cells, including innate and adaptive cells, which may
react to the infection dierently. Finally, the IFN-𝛾producing
cells accumulate preferentially at the sites of infection, so their
reduced (or increased) response in peripheral blood may be
associated with increased (or diminished) local responses.
is complexity explains why a simple measure of IFN-𝛾
response does not allow to evaluate TB activity. Indeed, the
levels of antigen-specic IFN-𝛾production by mononuclear
cells or the frequencies of Mtb-specic IFN-𝛾producing
cells, evaluated in IGRAs or by ow cytometry, do not
discriminate between LTBI and active TB. Also, the levels of
IFN-𝛾response are not associated with the disease severity
in TB patients ([47–49, 123]; our unpublished observations).
However, some other parameters of 1 response may be used
as TB biomarkers.
4.2. Markers of 1 Dierentiation and Activation. Several
studies have demonstrated that phenotypic markers of T cell
activation and dierentiation are promising biomarkers of TB
activity. Following antigen-driven dierentiation, T lympho-
cytes pass through several stages (early, late, and terminally
dierentiated eector cells). Each stage is characterized by the
set of markers expressed on the surface of T lymphocytes. As
the dierentiation process depends on antigenic stimulation,
markers of T cell dierentiation may serve as indicators of TB
activity. Among such markers CD27 seems to be best studied.
CD27isamemberofTNFreceptorsuperfamily.Itis
constitutively expressed by the naive T cells and early eector
lymphocytes but downregulated at the late stages of eec-
tor cell dierentiation. erefore, late eector lymphocytes
exhibit low to no CD27 expression [124–130].
In mice, the CD27low phenotype has been linked to
ecient IFN-𝛾production and lung-homing properties of
the eector CD4+T cells [130, 131]. Moreover, it was demon-
strated that CD27low eector CD4+T cells can dierentiate
from CD27hi eector precursors directly in the lungs infected
with Mtb [131].edatasuggestthatCD27low population may
serve as a measure of pulmonary TB activity. is, indeed,
was demonstrated in several studies performed by several
scientic teams.
In the pilot study, Streitz and others [132] examined
the percentages of CD27−cells within the population of
blood Mtb-reactive CD4+T cells that were identied as
CD4+cells producing IFN-𝛾in response to the tuber-
culin stimulation. High (>49%) percentage of CD27−(IFN-
𝛾+CD4+) cells discriminated patients with smear and/or cul-
ture positive pulmonary TB from patients with smear/culture
negative TB and LTBI with 100% sensitivity and 85.7%
specicity.
e potential of “CD27/IFN-𝛾” approach to discriminate
active TB and LTBI was also reported by other authors [49,
133–135]. Some studies found an association between the
accumulation of blood CD27−Mtb-reactive CD4+Tcells
and bacillary load in TB patients [133]. In our study, the
frequencies of CD27−IFN-𝛾+CD4+cells strongly correlated
with a degree of pulmonary destruction. Evaluation of blood
CD27−IFN-𝛾+CD4+cells allowed not only to separate active
TB and LTBI, but also to assess the degree of pulmonary
destruction, that is, the activity of pathological process ongo-
ing in the lung tissue during TB and following the treatment
[49].Schuetzandcoauthorsmodiedthisapproachand
extended it to HIV+patients. e authors reported that
HIV+TB−patients have higher proportion of CD27−IFN-𝛾+
CD4+cells than HIV−TB−patients and suggested that in
HIV-infected individuals the accumulation of Mtb-reactive
CD27−CD4+cells mirrors a degree of Mtb replication
and may help to identify subclinical Mtb infection [134].
e same group has recently extended their study made in
adults to children. e assay the authors called “TAM-TB”
(for “T cell activation marker-tuberculosis”) detected culture
conrmed TB cases in children with 83.3% sensitivity and
96.8% specicity [135]. Petruccioli and coauthors compared
diagnostic accuracy of dierent variations of “CD27/IFN-𝛾”
approach and concluded that CD27 expression is a robust
biomarker for discriminating between TB stages [136].
To summarize, the “CD27/IFN-𝛾”approachhasbeen
validated in several studies made in few independent lab-
oratories. In addition, it relies on the mechanisms that
are generally well understood and involve promoted local
generation of CD27−cells in Mtb-infectedlungsandtheir
facilitatedemigrationfromthelungstothecirculationsystem
when lung tissue is destructed [49, 131].
Anothermarkerwhichcanbeusedtodierentiateactive
TB and LTBI is CD57. CD57, the human natural killer-1
8Mediators of Inammation
(HNK-1) glycoprotein, marks terminally dierentiated, pro-
liferatively incompetent cells [137]. Lee and others demon-
strated that increased frequencies of CD57+cells among
ESAT-6/CFP10-responding CD4+Tcellsdierentiateactive
TB from LTBI [138].
In contrast to dierentiation, which is an irreversible
process, the activation of T cells is a temporal state that
comesasaresultofTcellencounterwithacognateantigen.
T cell activation is characterized by upregulation of several
surface molecules. Some of them, in particular, CD38 and
HLA-DR,havebeenassociatedwithactiveTB.CD38isa
transmembrane glycoprotein that has ectoenzymatic proper-
ties and catalyzes the synthesis and hydrolysis of NAD and
cyclin ADP-ribose. HLA-DR is a member of MHC class II
molecules involved in antigen presentation. Both markers
are upregulated by antigen-responding T cells. Several recent
studies suggested that increased frequencies of CD38+and
HLA-DR+Mtb-reactive (IFN-𝛾producing) blood CD4 T
cells allow accurately separating active TB from LTBI and
even predicting the time of sputum conversion [123, 139].
4.3. Multifunctional T Cells. Besides IFN-𝛾,1cellsproduce
other cytokines, such as TNF-𝛼and IL-2. 1/17 cells
coexpress IFN-𝛾and IL-17. us, eector T cells may exhibit
multifunctional activities. It has been suggested that there
is an association between T cell multifunctionality and TB
activity.
Harari and coauthors reported that TB patients had
reduced frequencies of multifunctional (IFN-𝛾+TNF-𝛼+IL-
2+) cells and increased proportion of single-positive TNF-𝛼
producing cells (TNF-𝛼+IFN-𝛾−IL-2−) as compared to LTBI
patients [140]. e authors also showed that TB patients are
characterized by a higher content of Mtb-specic CD8+T
cells [141]. Combined determination of the frequencies of
single TNF-𝛼+cells and Mtb-specic CD8 T cells predicted
active TB with 86.5% specicity and 81.1% sensitivity [142].
Several other groups also reported reduced frequencies of
multifunctional cells in TB patients and their recovery fol-
lowing TB treatment [143].
In contrast, some other studies associated active TB
with increased proportions of multifunctional cells. Caccamo
and coauthors reported that patients with active TB had
high frequencies of multifunctional (IFN-𝛾+TNF-𝛼+IL-2+)
lymphocytes and these frequencies decreased following the
treatment; during LTBI single IFN-𝛾anddoubleIFN-𝛾+IL-2+
Mtb-responding cells predominated [144]. In another study,
active TB was associated with bifunctional (IFN-𝛾+TNF𝛼+)
CD4+T cells [145].
Chesov and coauthors using a novel dual cytokine detect-
ing uorescence-linked immunospot (FluoroSpot) assay
found that the number of single-positive IL2−IFN-𝛾+cells
was higher in patients with active TB compared with past
TB and LTBI. However, there was the overlap in cytokine
responses, which precluded distinction between the cohorts
and suggested that the combined analysis of IL-2 and IFN-𝛾
producing cells does not allow to separate dierent states of
Mtb infection in clinical practice [146].
In HIV-infected individuals, analyses of T cell cytokine
prole also gave contradictory results. Some studies reported
higher frequencies of single functional TNF-𝛼-only-secreting
TcellsinHIV
+TB+patients [147], while others found
comparable cytokine proles of Mtb-reactive CD4+Tcellsin
HIV-infected patients with and without active TB [148].
A separate population of multifunctional cells is repre-
sented by 1/17 lymphocytes expressing CCR6+CXCR3+
phenotype. Recently, Sette group described a remarkable
expansion of CCR6+CXCR3+cells in LTBI [95]. e cells
were multifunctional as they produced IFN-𝛾,TNF-𝛼,and
IL-2 upon stimulation with TB-derived epitopes, but the
cells did not produce IL-17. Besides that, the authors did not
analyze CCR6+CXCR3+cells during active TB. us, whether
1/17 and/or CCR6+CXCR3+cellscanserveasmarkersof
LTBI or TB disease is still an open question.
Overall, current data on whether and how multifunction-
ality of eector T cells is associated with TB activity are con-
tradictory. It also remains unclear whether multifunctional
cells are more protective or more pathological compared to
single TNF-𝛼or IFN-𝛾producers, whether dierent cytokine
proles mirror dierent degrees of T cell maturation, and
whether they may serve as reliable biomarkers of TB activity.
us, more studies are required for the further implementa-
tion of this approach.
5. Conclusions
During the past decade a number of attempts have been made
to discover reliable TB biomarkers. In the eld of TB, studies
are generally aimed to identify biomarkers for (i) rapid TB
diagnosis, including diagnosis of sputum-negative TB cases;
(ii) dierentiation of active TB and LTBI; (iii) monitoring TB
activity; (iv) prediction of LTBI conversion to active TB; (v)
assessment of treatment ecacy.
In this review we have mainly focused on T cell associated
markers that have been suggested to discriminate active
TB and LTBI. Analysis of these biomarkers shows that
most of them are at Phase I of discovery according to the
classication of the National Institutes of Health, need to be
validated in several independent laboratories, and undergo
other evaluations. It should also be noted that the most
promising T cell associated biomarkers described above are
detected by means of ow cytometry. eir implementation
in clinical laboratories may be challenging and will require
assay simplication. However if the value of the developed
approaches is conrmed, this might be possible.
It is understood that immunological approaches for TB
diagnosis and monitoring are inferior to the direct identi-
cation of Mtb.Howeverimmunologicalapproachesmay
be of great value for detecting paucibacillary and paediatric
tuberculosis cases, TB screening, and monitoring treatment
ecacy beyond sputum conversion. Uncovering immunolog-
ical TB biomarkers will also allow a better understanding of
TB pathogenesis.
Conflict of Interests
e authors declare that they have no conict of interests
associated with this work.
Mediators of Inammation 9
Acknowledgment
e study was supported by the Russian Science Foundation
(no. 15-15-00136).
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