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REVIEW
Multiple checkpoints keep follicular helper T cells under
control to prevent autoimmunity
Di Yu
1
and Carola G Vinuesa
2
Follicular helper T (Tfh) cells select mutated B cells in germinal centres, which can then differentiate into long-lived high affinity
memory B cells and plasma cells. Tfh cells are regulated by a unique molecular programme orchestrated by the transcriptional
repressor Bcl6. This transcription factor turns down expression of multiple genes, including transcriptional regulators of other T helper
lineages and a vast amount of microRNAs. This enables Tfh cells to express a suite of chemokine receptors, stimulatory ligands and
cytokines that enable migration into B-cell follicles, and provision of effective help to B cells. Not surprisingly, dysregulation of this
powerful helper subset can lead to a range of autoantibody-mediated diseases; indeed, aberrant accumulation of Tfh cells has been
linked with systemic lupus erythematosus, Sjogren’s disease and autoimmune arthritis. Here we dissect multiple checkpoints that
operate throughout Tfh cell development and maturation to maintain immunological tolerance while mounting robust and long-lasting
antibody responses.
Cellular & Molecular Immunology (2010) 7, 198–203; doi:10.1038/cmi.2010.18; published online 5 April 2010
Keywords: autoimmunity; germinal centre; Tfh
INTRODUCTION
The enormously diversified repertoire of T-cell receptors (TCRs) cap-
able of recognising innumerable combinations of peptide–major his-
tocompatibility complex molecules, enable the adaptive immune
system to fight any invading pathogen. The trade-off of the random
process of receptor diversification is the unavoidable recognition of
self-antigens with potentially dangerous affinity. The adaptive immune
system faces the constant challenge of maintaining tolerance to self-
components of the body while mounting robust responses to foreign
pathogens. CD4
1
helper T (Th) cells orchestrate mammalian adaptive
immunity and are subjected to several tolerance checkpoints from their
earlier developmental stages in the thymus, through to their matura-
tion in the periphery and differentiation into effector and memory
subsets. The checkpoints that are common to all CD4
1
helper subsets
include: (i) clonal deletion of self-reactive T cells in the thymus; (ii)
biochemical tuning that limits activation downstream of chronic TCR
signalling from self-reactive receptors; (iii) limiting immunogenic cost-
imuli; (iv) control of the lifespan of the effector populations
1
and (v)
suppression of immune responses by regulatory T (Treg) cells.
2
Defects
in any of these tolerance mechanisms can lead to a wide range of
systemic and organ-specific autoimmune diseases. Further tolerance
mechanisms exist to control the accumulation and function of indi-
vidual CD4
1
helper subsets. Those that pertain to follicular helper T
(Tfh) cells have emerged as being critical to prevent autoantibody-
driven autoimmune diseases and are the subject of this review.
Tfh cells were originally identified as a subset of Th cells found to
reside in close proximity to follicular dendritic cells within germinal
centres.
3
Soon after, their phenotype was described to differ from that
of Th1 and Th2 cells.
4
It took more than 20 years to place Tfh cells in a
subset separate from other helper subsets: the recent identification of
Bcl6 as the transcriptional regulator of Tfh cells has firmly established
these cells as an independent lineage. This was supported by the
demonstration that Th1, Th2 and Th17 cells develop normally in
the absence of Bcl6 but Tfh cells were completely dependent on this
transcription factor.
5–7
The unique ability of Tfh cells to select
mutated high affinity B cells destined to live for decades in an indi-
vidual places them at a critical vulnerable spot for immunological
tolerance.
The process of somatic hypermutation typically occurs in germinal
centres—although it can also occur at extrafollicular sites in auto-
immune-prone mice—and targets immunoglobulin (Ig) variable
region genes of rapidly dividing germinal centre B cells (centroblasts).
8
This can lead to an increase in the affinity of the B-cell receptor for the
immunising antigen, but there is abundant evidence that this stoch-
astic process can also generate self-reactive specificities.
8
Furthermore,
once self-reactive B cells have been vaguely selected in germinal cen-
tres, their differentiated offspring can live and produce antibodies
unchecked, subject to virtually no further control. It has been long
known that most anti-double stranded DNA antibodies detected in
humans and in animal models of systemic lupus erythematosus (SLE)
are high-affinity IgG antibodies, which suggests that they may have
been generated in germinal centre reactions.
9
Thus, a tightly con-
trolled process of germinal centre B-cell selection by antigen-specific
Tfh cells is normally in place to ensure positive selection of those cells
1
Department of Immunology and Inflammation, Garvan Institute of Medical Research, Sydney, NSW, Australia and
2
Department of Immunology and Genetics, John Curtin School
of Medical Research, Canberra, ACT, Australia
Correspondence: Dr D Yu, Department of Immunology and Inflammation, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
E-mail: d.yu@garvan.org.au
Received 3 February 2010; accepted 28 February 2010
Cellular & Molecular Immunology (2010) 7, 198–203
ß
2010 CSI and USTC. All rights reserved 1672-7681/10 $32.00
www.nature.com/cmi
with the highest affinity towards foreign antigens while preventing
selection of cells that have become self-reactive. The randomness of
the mutation process, together with the longevity of post-germinal
centre memory B cells and plasma cells, and the abundance of exposed
nuclear antigens on the surface of numerous germinal centre cells
undergoing apoptosis, rank germinal reactions the highest in the risk
of triggering and maintaining autoantibody-driven autoimmunity.
8
While Tfh cells are to a large extent responsible for maintaining
tolerance in germinal centers, it is important to note this is not the
only mechanism operating at this stage of immune responses. Mutated
germinal centre B cells that fail to receive prosurvival signals are pro-
grammed to die by apoptosis, providing a mechanism that prevents
the production of high-affinity, long-lived self-reactive B cells.
10
A
critical checkpoint that can rapidly eliminate self-reactive germinal
centre B cells is the need to establish an immunological synapse with
follicular dendritic cells: germinal centre B cells that bind soluble
antigen without receiving integrin-mediated signals from follicular
dendritic cells die very rapidly—within 4–6 h.
11,12
In mice that lack
Dock8, required to accumulate intercellular adhesion molecule-1 in
the B-cell immunological synapse, germinal centres are short-lived.
13
This highlights the need for antigen to be presented in the form of
immune complexes, which will readily happen in the case of foreign
antigens, but not self-antigens. Germinal centre B cells then need to be
selected by Tfh cells.
What are the unique features of Tfh cells that ensure that not only
are they completely devoid of self-reactive specificities, but also can
ruthlessly eliminate all germinal centre B cells that have acquired
crossreactivity against self-antigens during the process of SHM? The
answer partly lies in: (i) the Tfh phenotype that facilitates follicular
homing and B-cell helper function depends on a sophisticated gene
expression programme controlled by Bcl6 that represses multiple tar-
get genes including several transcription factors and microRNAs
(miRNAs); (ii) strong TCR signalling, which in the presence of normal
thymic selection is likely to occur only in response to foreign antigens,
favours Tfh differentiation; (iii) Tfh development is dependent on the
ability to form highly stable cognate T–B cell interactions; (iv) Tfh cells
turn down production of potentially proinflammatory cytokines such
as interferon-c(IFN-c) and interleukin (IL)-17, and rely on the
actions of IL-21 and IL-4 that cooperate with CD40 ligand (CD40L)
to maintain germinal centres; (v) Tfh cells, like other T-helper subsets,
are also subject to Treg cell control, and (vi) Tfh cells and germinal
centre B cells turn on a proapoptotic programme that limits their
survival. When any of these features destined to promote self-tol-
erance and prevent autoimmunity, goes awry, Tfh cells can aberrantly
accumulate and/or aberrantly select self-reactive germinal centre B
cells. The key regulatory role of Tfh cells in germinal centres has placed
this population in the frontline of immunological tolerance. In this
review, we will summarise the emerging evidence for participation of
Tfh cells in autoimmune diseases and examine the known checkpoints
during Tfh development and maturation to prevent autoimmunity. It
is important to emphasise that this field is in its infancy, and there is
great need to increase our understanding of the molecular mechan-
isms that enable Tfh cell-mediated selection of high affinity and non-
self-reactive germinal centre B cells, and control Tfh differentiation
and lifespan.
DEVELOPMENT OF A SELF-REACTIVE TFH CELL
COMPARTMENT
In the thymus, TCRs that bind strongly to self-peptide–MHC com-
plexes trigger the death of thymocytes, a process known as negative
selection. When this process is defective due to defects in self-antigen
presentation, TCR signalling or apoptosis, autoreactive T cells reach
the periphery and cause systemic or organ specific autoimmunity.
1
Failed negative selection of self-reactive T cells resulting in a non-
self tolerant Tfh population has been shown to contribute to the
autoimmune arthritis of K/BxN mice. These mice develop an aggress-
ive form of arthritis that has many of the clinical, histological and
immunological features of rheumatoid arthritis in humans.
14
K/BxN
mice were originally generated by crossing KRN TCR-transgenic mice
on the C57BL6/J genetic background (K/B) with non-obese diabetic
mice. This TCR transgene is specific for a bovine ribonuclease peptide
(RNase 42–56) but was subsequently also found to recognise glucose-
6-phosphate isomerase (GPI), a ubiquitously expressed self-antigen
that is also present on the surface of inflamed joints, presented by the
MHC class II molecule I-A
g714
. KRN CD4
1
T cells escape clonal dele-
tion in the thymus and mature T cells appear in the periphery at 3
weeks of age, albeit in reduced numbers.
15
Primed KRN CD4
1
T cells
provide help to GPI-reactive B cells leading to the production of high
titres of anti-GPI antibodies.
14
Expression of the transgenic TCR is an
absolute requirement for the development of the arthritic phenotype
14
and adoptive transfer of CD4
1
T cells from healthy K/B donors into
mice of BxG7 (C57BL/6J 3B6.H2
g7
F1) genetic background was
sufficient to initiate germinal centre responses, produce anti-GPI
autoantibodies and develop arthritis.
16
Importantly, this model of autoimmune arthritis is autoantibody-
dependent: transfer of K/BxN serum or purified polyclonal GPI anti-
bodies are sufficient to trigger arthritis in Rag-1
2/2
recipient mice.
17
This corroborates that it is the B-cell helper activity of KRN Tfh cells
that triggers the autoimmune process. Furthermore, in the adoptive
transfer model described above, T cells deficient in CXC-motif che-
mokine receptor 5 (CXCR5) expression were precluded from entering
the follicles, an important step during Tfh-cell differentiation,
18
and
essentially lost the capability to induce germinal centre formation,
autoantibody production and arthritis development.
16
ABERRANT TFH ACCUMULATION
Although the signals that drive Tfh formation are not completely
understood, it has been shown that strong TCR signalling and
inducible costimulator (ICOS)-mediated costimulation favour Tfh
differentiation, which also requires a stable signalling lymphocyte
activation molecule-associated protein (SLAM-associated protein,
SAP)-mediated T–B interaction and is promoted by IL-21.
18,19
.
The pathogenic consequences of Tfh cell accumulation in the
absence of immunisation have been demonstrated in sanroque mice,
an N-ethyl-N-nitrosourea-induced strain bearing a homozygous point
mutation in the Roquin gene.
20
Sanroque mice develop a systemic
autoimmune syndrome with many features typical of SLE including
high-affinity anti-double stranded DNA antibodies, focal proliferative
glomerulonephritis with deposition of IgG-containing immune com-
plexes, anaemia and autoimmune thrombocytopenia as well as other
autoimmune manifestations such as lymphadenopathy, splenomeg-
aly, necrotising hepatitis and plasmacytosis.
20
Spontaneous germinal
centre formation is detected in sanroque mice as early as 4 weeks after
birth, accompanied by massive accumulation of CD4
1
T cells in ger-
minal centres. Sanroque CD4
1
cells express high amounts of CXCR5,
programme cell death-1 (PD-1), ICOS and IL-21, characteristic of a
Tfh phenotype.
20
Roquin was found to act T cell-autonomously to
cause Tfh cell accumulation.
21
Adoptively transferred Tfh cells from
sanroque mice into C57BL/6 mice enhanced germinal centre forma-
tion in wild-type recipient mice in the absence of immunisation.
Tfh cells in autoimmunity
D Yu and CG Vinuesa
199
Cellular & Molecular Immunology
Evidence for a causal role of Tfh dysregulation in the autoimmune
phenotype came from the demonstration that sanroque mice made
genetically deficient in SAP, completely abrogated Tfh cell accumula-
tion and formation of spontaneous germinal centers, prevented lupus-
like disease and end-organ damage.
21
Further evidence that sanroque
lupus is of Tfh/germinal center origin came from studies in which the
gene dose of Bcl6—the transcriptional regulator of both germinal
centre B and Tfh cells—was halved: lupus was significantly amelio-
rated in sanroque Bcl6
1/2
mice.
21
Taken together, these studies suggest
that aberrant positive selection by excessive and dysregulated Tfh cells
in sanroque mice is a key factor in the development of systemic auto-
immunity, suggesting that tight control of Tfh-cell numbers and func-
tion is a key checkpoint in the maintenance of immunological
tolerance.
We recently identified an increase of otherwise rare circulating Tfh-
like (cTfh) CXCR5
high
ICOS
high
PD-1
high
CD4
1
T cells in the blood of a
subset of SLE and Sjo
¨gren’s syndrome patients (20–30%). This
‘cTfh
high
’ phenotype was stable over time and closely correlated with
disease severity. Of note, a comparable cTfh population was seen in the
blood of sanroque mice, which correlated with the increase in resident
Tfh within secondary lymphoid organs.
22
Although cTfh cells from
SLE patients do not express high levels of the Tfh transcription factor
Bcl6,
22
the similarity in phenotype suggests that they might be either
Tfh progenitors capable of terminal differentiation into Tfh cells upon
entry into secondary lymphoid tissues, or they derive from Tfh cells
that have emigrating from germinal centres into the circulation. Thus,
excessive Tfh cell formation may be a common feature of at least a
proportion of patients with autoimmune diseases.
Roquin binds to Icos mRNA (unpublished observation) and regu-
lates its stability acting in concert with miRNAs.
23
Wild-type Roquin
represses ICOS post-transcriptionally, but this regulation is impaired
by the presence of mutant Roquin, leading to ICOS overexpression on
sanroque CD4
1
T cells, which contributes in part to the accumulation
of Tfh cells.
23
As the cellular and molecular mechanisms responsible
for maintaining tolerance are being deciphered, it is becoming clear
that spatiotemporal control of gene expression underpins most suc-
cessful tolerance mechanisms. miRNAs, as a group of short non-
coding RNAs of about 20–22 nucleotides modulating the stability
and translational efficiency of target mRNAs, present an important
new layer controlling gene expression to prevent different types of
polygenic disorders.
24
miRNAs target immune transcripts to fine-tune
gene expression and turn on negative feedback loops that maintain
the delicate balance between protective versus autoimmune res-
ponses.
25,26
Our recent description of Bcl6-mediated repression of
over 30 miRNAs, including miR-17–92 shown to repress CXCR5
expression,
7
underscores the role of this layer of regulation in Tfh
differentiation. Thus, it is likely that miRNA-regulated checkpoints
also operate to prevent autoimmunity of Tfh-germinal centre origin.
FAILED FOLLICULAR EXCLUSION OF UNSUITABLE TH CELLS
Each Th subset has a distinct cytokine production profile: Th1 cells are
potent IFN-cproducers, Th2 cells mainly secrete IL-4, IL-13 and IL-
15, and Th17 cells produce IL-17F, IL-22 and IL-21.
27
Tfh cells differ
from these subsets by their predominant production of two cytokines,
IL-21 and IL-4,
28–33
with only low amounts of IFN-cand IL-17 being
produced in the follicles.
7,34
We and others have shown that the tran-
scription repressor Bcl6 directs Tfh differentiation and suppresses the
differentiation programme to other Th lineages.
6,7,35
Bcl6 decreases
production of IFN-c, IL-4 and IL-17 probably through the direct
repression of the transcription factors T-box 21, GATA-binding
protein 3 and retinoic acid receptor-related orphan receptor gamma,
thymus-specific isoform.
6,7,35
Of interest, there is a striking negative correlation between express-
ion of CXCR5 and IL-17 in tonsil CD4
1
T cells, which are typically rich
in Th1, Th2, Th17 and Tfh cells.
7
This suggests that Th17 cells are
excluded from follicular entry and unlikely to provide help to germinal
centre B cells. Several lines of experimental evidence support this
notion. First, a pathogenic role of IL-17 in dysregulated antibody
responses and autoimmunity has been recently reported. SLE patients
display increased levels of both IL-17 and B cell-activating factor.
Strikingly, IL-17 alone or in combination with B cell-activating factor
that enhances human B-cell survival, promotes B-cell proliferation
and differentiation into antibody-secreting cells ex vivo.
36
This sug-
gests that exclusion of Th17 cells from B cell follicles would be import-
ant to prevent them from providing non-cognate survival and
differentiation signals to autoreactive germinal centre B cells and
lower the threshold for B-cell selection.
A second line of evidence supporting the idea IL-17 may subvert
tolerance mechanisms in germinal centres leading to autoimmunity
comes from studies of BDX2 mice. BDX2 mice were generated by
inbreeding the intercross progeny of C57BL/6J and DBA/2J mice for
more than 20 generations.
37
These mice show rising titres of autoan-
tibodies and circulating immune complexes and progressively develop
glomerulonephritis and erosive arthritis with age.
38
The pathogenic
autoantibodies developed in BDX2 mice are largely dependent on T-
cell help and are likely to be the products of germinal centres.
39
The
important, yet surprising observation is the accumulation of Th17
cells in BDX2 mice and the fact many of these Th17 cells localise within
germinal centres.
40
Introduction of two null alleles of IL-17R amelio-
rated the spontaneous formation of germinal centres in BDX2 mice,
whereas administration of exogenous IL-17 induced germinal centre
formation in wild-type mice and exaggerated spontaneous germinal
centre formation and autoantibody production in BDX2 mice.
40
It has
been suggested that excessive IL-17 upregulates the expression of regu-
lator of G-protein signalling 13 and/or 16 of B cells and causes reten-
tion of B cells in germinal centres, allowing them to undergo repeated
rounds of somatic hypermutation.
40
This together with a lower selec-
tion threshold due to the abundance of T cells and provision of
non-cognate survival signals would lead to an environment where
self-reactive B cells are aberrantly selected.
EXCESSIVE HELPER SIGNALS TO B CELLS
Tfh-derived helper signals such as CD40L and IL-21 not only sustain
germinal centres but also are critical to select mutant B cells and enable
them to terminally differentiate into long-lived high affinity memory
or plasma cells.
8
The question is: Do varying amounts of these helper
signals control germinal centre events and determine the threshold for
selection? There is indirect evidence to suggest that this is the case. In
humans, overexpression of CD40L
41,42
and IL-21
43
has been reported
in SLE patients, suggesting a link between excessive B helper signals
and autoimmunity. However, this does not necessarily mean that an
excess of these signals exclusively corrupts germinal centre selection,
since both CD40L and IL-21 play important roles in extrafollicular
antibody responses (see discussion below).
Overexpression of CD40L on T cells enhances thymocyte apoptosis,
which causes thymic atrophy and precludes investigating the func-
tional consequences of excessive expression of CD40L in the peri-
phery.
44
To circumvent this problem, CD40L was overexpressed on
B cells, and shown to provide autocrine helper signals that resulted in a
lupus-like autoimmune disease in mice with spontaneous production
Tfh cells in autoimmunity
D Yu and CG Vinuesa
200
Cellular & Molecular Immunology
of autoantibodies and development of glomerulonephritis with
immune-complex deposition.
45
IL-21 transgenic mice showed a dramatic increase in the number of
post-switch plasma cells and the titres of IgM and IgG1 in sera com-
pared to wild-type littermates.
46
Higher serum levels of IL-21 were
also detected in BSXB-Yaa mice, a mouse model of SLE with the
characteristic lymphadenopathy, splenomegaly, leukocytosis, hyper-
gammaglobulinemia and severe immune complex-mediated glomer-
ulonephritis.
46
Genetic depletion of IL-21R in these mice abrogated
the hypergammaglobulinemia, autoantibody production, renal dis-
ease and premature morbidity in these mice,
47
suggesting an essential
role of IL-21/IL-21R pathway in the pathogenesis of the autoimmune
disorder. It appears that both follicular and extrafollicular T cells are
important producers of IL-21 in these mice.
As mentioned above, the excessive B helper signals contributing to
autoimmunity do not act exclusively in germinal centres, but also
perturb extrafollicular B-cell responses. Arguably, the best example
is the demonstration of the pathogenic role of IL-21 in the MRL/
MpJ-Fas
lpr
(MRL
lpr
) mouse model of SLE, in which mutated auto-
reactive plasmablasts grow in extrafollicualr foci. In these mice, IL-21
contributes to the production of pathogenic autoantibodies.
48
An
extrafollicular population of ICOS
high
P-selectin glycoprotein ligand
1
low
CD4
1
helper T cells appears to be the primary source of CD40L
and IL-21 helper signals supporting extrafollicular development of
IgG plasmablasts.
49
The relationship between these extrafollicular
helper T cells and Tfh cells is still not fully resolved.
CONTROLLING THE LIFESPAN OF TFH CELLS
Most Tfh cells appear to be short-lived effectors with limited prolif-
erative potential once they enter germinal centres, probably due to
decreased expression of antiapoptotic Bcl2 and Bcl
xL
and increased
expression of other proapoptotic Bcl2 family members including
Bcl2-antagonist/killer 1, BH3 interacting domain death agonist and
Bcl2-associated agonist of cell death. Tfh cells also express high
amounts of the tumour-necrosis factor receptor superfamily, member
6 (Fas), and are more sensitive to cell death after TCR stimulation than
naı
¨ve or memory helper T cells.
50,51
Histological staining reveals that,
unlike interfollicular T cells, human tonsillar Tfh cells do not express
Bcl2,
52
which is consistent with the reported role for the Tfh-directing
transcription factor Bcl6 in repressing Bcl2 expression.
53
Over-
expression of Bcl2 in the entire hematopoietic compartment (Bcl2
transgene controlled by Vav gene regulatory sequences) instead of
selectively in B cells (Bcl2 transgene controlled by an IgH enhancer),
results in spontaneous germinal centre formation.
54
The germinal
centre hyperplasia was abrogated by CD4
1
T-cell depletion, suggest-
ing that excessive CD4
1
T cell longevity was the cause of this pheno-
type.
54
Although the entire peripheral T-cell compartment was
expanded in this mice by about five-fold,
54
it is likely that defective
Tfh cell apoptosis is a major contributor to the abnormal formation of
germinal centres.
TREG-MEDIATED SUPPRESSION OF TFH CELLS
Treg cells represent a small but bona fide population of T cells in
germinal centres.
55,56
These Treg cells are capable of suppressing the
effects of Tfh cells and may play a role in repressing Tfh function,
including IL-17 expression by Tfh cells, thus moderating the provi-
sion of help that Tfh cells can provide to B cells within the germinal
centres.
55,57
Of particular interest is the observation that Treg cells, an immu-
nosuppressive population, can differentiate into Tfh cells in the gut of
lymphopenic mice.
58
This conversion appears to only take place in
Peyer’s patches but not in spleen or lymph nodes of the same mice,
demonstrating the need of a unique microenvironment to foster Tfh-
cell differentiation from Treg cells.
58
However, it is possible that cer-
tain conditions or proinflammatory environments may promote Treg
to Tfh-cell conversion in secondary and tertiary lymphoid organs.
Figure 1 Cellular checkpoints that keep Tfh cells under control to maintain tolerance. Individual checkpoints are shown by numbered red crosses: (1) deletionof
immature T cells with high-affinity self-reactive T-cell receptors; (2) limiting extrinsic stimuli and intrinsic signals that promote Tfh differentiation; (3) exclusion of non-
Tfh effector populations from the follicles; (4) maintenance of the threshold for germinal centre B-cell selection; (5) short lifespan and proapoptotic nature of Tfh cells;
(6) suppression of Tfh cells by Treg cells. Tfh, follicular helper T; Treg, regulatory T.
Tfh cells in autoimmunity
D Yu and CG Vinuesa
201
Cellular & Molecular Immunology
Ectopic germinal centres are detected in 30–50% of joints from
patients with rheumatoid arthritis and the salivary glands from
patients with Sjo
¨gren’s syndrome.
59
Whether Treg to Tfh conversion
occurs at those sites or the reasons why it may fail to occur are still not
clear and will be an interesting subject of investigation.
CONCLUDING REMARKS
Tfh cells have recently acquired their own identity in the big Th cell
family. Growing evidence of their important role in maintaining ger-
minal centre tolerance and demonstration that autoimmunity can
arise when they are dysregulated have placed Tfh cells in the limelight
of the pathogenesis of autoantibody-driven autoimmune diseases
(Figure 1). There are still many unanswered questions regarding
Tfh-cell ontogeny, tolerisation, mechanism of action, factors that con-
trol their growth and survival, and their relationship with other helper
and regulatory subsets. The answers to these questions will hold the
key to unravelling how tolerance is maintained during the process of
negative and positive selection in germinal centres. Much of the
information available to date illuminating the checkpoints that pre-
vent autoimmunity of Tfh/germinal centre origin has been obtained
from autoimmune mouse models. The challenge ahead is to translate
these findings into information that is valuable to improve the dia-
gnosis and therapy of patients with autoimmune diseases. This will
need a much better understanding of human Tfh biology in health and
disease.
ACKNOWLEDGEMENTS
We wish to acknowledge constructive discussion with Nina Chevalier, Charles
R. Mackay, Jing He and Zhanguo Li. CGV is supported by a Viertel Senior
Medical Research Fellowship and NHMRC project and programme grants. DY
is supported by a Cancer Institute New South Wales Fellowship, an NHMRC
Fellowships and an NHMRC programme grant to CRM.
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