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Immunology and Cell Biology (2016) 94, 715–716
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NEWS AND COMMENTARY
Vitamin A restrains γδ T cells
Taming pathogenic γδ T cells with vitamin A
Catarina F Almeida and Dale I Godfrey
Immunology and Cell Biology (2016) 94, 715–716; doi:10.1038/icb.2016.54; published online 5 July 2016
γ
δT-cell receptor (TCR)+ T cells (γδ
T cells) are a major histocompatibility
complex (MHC)-unrestricted innate-like
T-cell lineage with a unique and influential
role in many different types of diseases
(reviewed in Godfrey et al.1 and Vantourout
and Hayday2). Although many studies
emphasise a protective role for γδ T cells in
the context of microbial infection and
tumours, they can also have a pathogenic role
in autoimmune disease. In this issue, Raverdeau et al.3 show that interleukin (IL)17 secreting γδ T cells contribute to the
pathogenesis of experimental autoimmune
encephalomyelitis (EAE), an animal model
of multiple sclerosis (MS), and that selective
targeting of these cells with the vitamin A
metabolite, retinoic acid (RA), inhibits IL-17
production and is sufficient to ameliorate this
disease. This highlights the central role that γδ
T cells have in this disease model and suggests
that they may be important therapeutic targets
for MS and other autoimmune diseases.
MS is an autoimmune disease where T cells
target and degrade the myelin sheath
surrounding nerves in the central nervous
system (Figure 1). The mouse model for this
disease, EAE, has been used extensively to
understand the immunological mechanisms
that contribute to MS. IL-17A, a T-cellderived cytokine, is known to be a key
mediator of pathogenesis in EAE4. Furthermore, γδ T cells, which produce IL-17A in
response to IL-1β and IL-23 stimulation,
contribute to the severity of this disease by
inhibiting the activity of FoxP3+ regulatory
T cells (Treg) and enhancing the expansion of
CF Almeida and DI Godfrey are at Department of
Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of
Melbourne, Melbourne, Victoria, Australia; and the
Australian Research Council Centre of Excellence in
Advanced Molecular Imaging, The University of Melbourne, Melbourne, Victoria, Australia
E-mail: [email protected] or godfrey@
unimelb.edu.au
pathogenic IL–17–producing Th17 CD4+
T cells5,6. The active metabolite of vitamin
A, RA, inhibits IL-17 production by CD4
T cells and promotes Treg generation7, and it
has long been appreciated that RA can
ameliorate EAE (reviewed in Raverdeau and
Mills.8). Given that the balance between Tregs
and Th17 CD4+ T cells tightly correlates with
the manifestation, severity and relapse/remit
episodes in EAE (reviewed in Fletcher et al.9)
and in patients with MS,10 it is important to
properly understand the mechanisms and
therapeutic potential of RA in this disease.
Raverdeau et al.3 demonstrate that RA can
suppress IL-17A and IL-17F production by γδ
T cells in vitro and in vivo, and furthermore,
that this activity on γδ T cells is important
for the therapeutic activity of RA in
EAE. Myelin oligodendrocyte glycoprotein
(MOG)-primed T cells, cultured in the
presence of IL-1 and IL-23 (Th17-priming
conditions), elicit EAE upon transfer to naïve
recipient mice. The disease transferring
potential of these MOG-primed T cells is
ameliorated by inclusion of RA in these
cultures, or by depletion of γδ T cells before
culture. Moreover when γδ T cells and
γδ-depleted T cells were separated and only
the γδ T cells were cultured with RA, before
recombining these cells in the presence of
MOG/IL-1β/IL-23, the recombined cells also
lost much of their disease-inducing capacity.
The authors of this study3 demonstrated
that Vγ4+ γδ T cells were responsible for RA
mediated disease inhibition and that although
IL-17 production was inhibited, it had no
effect on IFNγ production by γδ T cells. This
selectivity likely correlates with the much
higher levels of RA nuclear receptor α
(RARα) in IL-17-producing (CD27−) γδ
T cells compared with their IFNγ+ (CD27+)
counterparts3. They also provide evidence
that RA leads to a partial reduction in the
cell surface level of IL-1R and IL-23R, and a
corresponding decrease in phosphorylated
STAT3 in response to these cytokines. Given
that IL-17 production depends on STAT3
phosphorylation,11 the authors propose that
this represents the underlying mechanism of
how RA reduces IL-17 production by these γδ
T cells3. Because the role for γδ T cells in this
disease was not absolute, this raises the
question of whether other IL–17–producing
innate-like cell types might also contribute
to pathogenesis. Candidates worthy of
further
investigation
include
IL-17producing mucosal-associated invariant
T (MAIT) cells, which have also been implicated in EAE, Natural Killer T (NKT)-17 cells
(reviewed in Godfrey et al.1) or Innate
lymphoid cells type 3 (ILC3) cells (reviewed
in Sonnenberg and Artis12).
Previous studies have shown that the
timing of administration of RARα agonists
can be critical in the disease outcome of EAE.
Thus, while administration of these agonists
during the disease induction phase can inhibit
disease (reviewed in Raverdeau and Mills8),
administration at later stages of disease can
hamper the generation of immunosuppressive populations involved in the recovery
phase, such as myeloid-derived suppressor
cells.13 Considering that MS and other autoimmune diseases are generally only detected
in patients following disease manifestation,
this may limit the therapeutic potential of
RAR agonists in the clinic. However, with
rapid advances in human genetic profiling
and disease prediction, it will be increasingly
possible to intervene before the onset of
disease symptoms. Another possible caveat
associated with translation of the work in the
study by Raverdeau et al.3 is that mouse and
human γδ T cells are very distinct in terms of
their TCR specificity, cytokine production
and function (reviewed in Godfrey et al.1
and Vantourout and Hayday2). As γδ
T cells tend to accumulate in lesions of
patients with MS,14 it will be important to
determine if these cells produce IL-17 and
News and Commentary
716
Neuron
Retinoic acid
+
Th17 CD4 T cells
Vγ4+ γδT cells
CD8+ T cell
Myelin sheath
IL-17
Axon
Vγ4+ γδT cell
Pro-inflammatory and
cytotoxic molecules
Stat3
Macrophage
Lesions
pStat3
RARα
IL-1Rβ
Activated microglia
IL-23R
Figure 1 Proposed model for RA modulation of pathogenic IL-17-secreting Vγ4+ γδ T cells in EAE. IL-17 is a driver of pathogenesis of EAE, associated with
the demyelination and lesions of neurons. Vγ4+ γδ T cells produce IL-17 in response to IL-1 and IL-23 activation in a TCR–independent manner and this
promotes differentiation and expansion of pathogenic Th17 CD4+ T cells. RA interferes with this process at multiple levels. It impairs the differentiation of
Th17 CD4+ T cells, prevents DC maturation and antigen presentation and inhibits IL-17 production by Vγ4+ γδ T cells. RA binds the (RARα) expressed in
Vγ4+ γδ T cells, reducing their response to IL-1 and IL-23 signalling and inhibiting STAT3 phosphorylation, which is required for Th17 production.
modulate autoimmunity in a similar manner
to mouse γδ T cells, and moreover, if this
activity can also be modulated by RA treatment. Furthermore, as IL–17–producing
Vγ4+ γδ T cells have been reported to
promote tumour growth,15 the potential to
manipulate these cells in other diseases such
as cancer deserves further investigation.
In summary, the study by Raverdeau et al. 3
shows that RA can modulate the pathogenic
activity of γδ T cells in EAE, the mouse model
of MS, and that this is a key mechanism
underlying RA-mediated inhibition of EAE. It
highlights the unique role that γδ T cells have
in the immune system and the therapeutic
potential of targeting these cells. If this also
applies to MS in humans, this work opens up
new therapeutic possibilities for treating this
devastating autoimmune disease. Additionally,
the possibility that a similar mechanism might
underpin other IL-17-mediated diseases, such
as psoriasis, colitis and even cancer, suggests
even broader immunotherapeutic potential
that will be important to investigate in future
studies.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
Immunology and Cell Biology
ACKNOWLEDGEMENTS
The authors of this commentary are supported by
research grants from the National Health and
Medical Research Council of Australia (NHMRC)
and the Australian Research Council (ARC).
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