ReseaRch highlights
Nature Reviews Immunology | AOP, published online 11 February 2011; doi:10.1038/nri2942
t CELLS
Plastic TH17 cells
Interleukin‑17 (IL‑17)‑producing
T helper cells (TH17 cells) are a
unique subset of effector CD4+ T cells.
However, TH17 cells that are generated
in vitro have remarkable plasticity and
can produce the TH1 cell‑associated
cytokine interferon‑γ (IFNγ) and/
or may lose the ability to produce
IL‑17. It remains unclear whether
TH17 cell plasticity also exists in vivo.
Using mice in which the fate of cells
that have expressed IL‑17A can be
permanently traced, Stockinger and
colleagues show that TH17 cells are
plastic in vivo and that the functional
fate of these cells is shaped by the
inflammatory environment.
In the fate‑reporter mice gener‑
ated for this study, cells that express
IL‑17A are indelibly marked with
enhanced yellow fluorescence
protein (eYFP). Following the induc‑
tion of experimental autoimmune
encephalomyelitis (EAE; a chronic
inflammatory disease of the central
nervous system) in these mice, the
authors found that the numbers of
eYFP+ TH17 cells in the
STUDIO 8
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draining lymph nodes and spinal cord
increased with disease progression,
as expected. However, about half of
these cells had stopped producing
IL‑17A (referred to as ex‑TH17 cells).
Conversely, the expression of IFNγ
by eYFP+CD4+ T cells increased over
time. In fact, almost all of the IFNγ‑
producing CD4+ T cells in the spinal
cord were ex‑TH17 cells. So, TH17 cells
give rise to both IL‑17+IFNγ– and
IL‑17–IFNγ+ T cells during EAE.
Further analysis revealed that
eYFP+ T cells progressed from
being mainly IL‑17+IFNγ– to being
IL‑17+IFNγ+ and finally to express‑
ing IFNγ alone during the course of
EAE. Moreover, only eYFP+ (and not
eYFP–) T cells produced additional
pro‑inflammatory cytokines (such as
GM‑CSF (granulocyte–macrophage
colony stimulating factor) and TNF
(tumour necrosis factor)). Of note,
IFNγ‑producing ex‑TH17 cells could
be distinguished from eYFP–IFNγ+
TH1 cells by the expression of aryl
hydrocarbon receptor and IL‑1
receptor type 1.
IL‑23 is thought to contribute to
TH17 cell plasticity in vitro, and the
authors found that eYFP+ T cells
isolated from IL‑23p19‑deficient
fate‑reporter mice with EAE lacked
IFNγ expression. Furthermore, loss
of IL‑23p19 prevented the upregula‑
tion of T‑bet (a transcription factor
that is essential for IFNγ produc‑
tion) by eYFP+ T cells. So, IL‑23
is required for the switch in
cytokine production by TH17
cells from IL‑17A to IFNγ during
chronic inflammation.
But does this switch occur during
acute inflammatory responses that
resolve quickly? Cutaneous infection
of fate‑reporter mice with Candida
albicans hyphae, which leads to
an acute infection that is rapidly
cleared, resulted in the accumula‑
tion of IL‑17‑producing TH17 cells
(after an early IL‑17A response
mediated by γδ T cells). IFNγ was
also produced during this acute
infection, but in contrast to the
chronic inflammatory setting, none
of the IFNγ‑expressing CD4+ T cells
were eYFP+. Furthermore, by the
time the pathogen was cleared, most
eYFP+ T cells had stopped produc‑
ing IL‑17A and the absolute number
of T cells in the skin was greatly
reduced. Analysis of local antigen‑
presenting cells showed that they
expressed high levels of the mRNA
encoding the anti‑inflammatory
cytokine IL‑10 and low levels of
Il23 mRNA.
So, the data show that during
chronic inflammation TH17 cells
deviate to express additional pro‑
inflammatory cytokines, whereas
during an acute resolving inflam‑
matory response TH17 cells shut
off IL‑17A production and rapidly
disappear. In addition, IL‑23 seems
to have an important role in driving
the plasticity of TH17 cells during
chronic inflammation.
Olive Leavy
ORIGINAL RESEARCH PAPER Hirota, K. et al.
Fate mapping of IL‑17‑producing T cells in
inflammatory responses. Nature Immunol.
30 Jan 2011 (doi:10.1038/ni.1993)
vOLUME 11 | MARCH 2011