The Th17 plasticity demonstrated in
these two reports comes from cells
generated in canonical culture conditions
in vitro during which they were constantly
exposed to instructive cytokine signals.
In vivo, cells likely receive additional
signals both favoring and opposing Th17
differentiation, and the nature and relative
abundance ofthesesignals, isinconstant.
Thus, an important question is whether
Th17 cells generated in vivo exhibit the
same instability. The evidence at present
isboth limited and conflicting. Bycontrast
to Lee et al. (2009) who purified Th17 cells
based on their expression of an IL-17F-
fied cells from unmanipulated mice based
on their ability to secrete IL-17A directly
ex vivo and found that the fraction of
cells producing IL-17A alone or along
with IFN-g was relatively stable in the
absence of added cytokines for 6 days.
Similarly, when human Th17 cells were
purified from blood based on their ability
to secrete IL-17A directly ex vivo (Streeck
declined and IFN-g increased by 6 weeks
but were considerably more stable than
observed by Lee et al. (2009) whereas An-
nunziato et al. (2007) found that human
Th17 cells cloned directly ex vivo in non-
induced to produce substantial amounts
of IFN-g when activated in the presence
of IL-12. Thus, further study will be
required to reconcile these differences,
to determine whether cells that can
produce IL-17A directly ex vivo represent
a relatively more committed subset of
Th17 cells, and to explore the underlying
In any case, the two reports in this issue
of Immunity indicate that the ability of
CD4+T cell subsets to adopt alternate or
simply by the epigenetic states of cyto-
kine loci but by the epigenetic states of
the entire set of genes associated with
these lineages. Although the data of Wei
et al. (2009) characterized only two
histone modifications, their multilineage
comparison provides hints that global
mapping of histone modifications may
be predictive of lineages that are most
susceptible to deviation and toward
which lineages they are most likely to be
reprogrammed. In the near future, we
can hope to see ever more complete
epigenomic and gene expression profiles
in T helper cell lineages. These profiles
as carried out by Lee et al. (2009) should
help to unravel the many unanswered
question regarding T helper cell lineage
commitment, plasticity, and overlapping
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Interleukin-17A and Interleukin-17F:
A Tale of Two Cytokines
Patricia J. Dubin1and Jay K. Kolls2,*
1Children’s Hospital of Pittsburgh, Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA
2Department of Genetics, LSU Health Sciences Center, CSRB Room 657, New Orleans, LA 70112, USA
In this issue of Immunity, Ishigame et al. (2009) show that interleukin-17A (IL-17A) mediates autoimmunity
whereas both IL-17A and IL-17F are required for mucosal immunity. IL-17A may be more pathologic by
inducing proinflammatory cytokines.
Charles Dickens’s epic tale of Paris and
London begins with ‘‘It was the best of
times, it was the worst of times,’’ empha-
sizing the recent advances in wisdom that
coincided with a time of great ignorance.
In the past 10 years, our understanding of
interleukin-17 (IL-17) in mucosal immunity
and autoimmunity has greatly expanded.
IL-17A, the founding member of the
IL-17 family of cytokines, is produced by
a subset of CD4+T cells termed Th17
cells. IL-17A is potent inducer of antimi-
crobial peptides as well as neutrophil
colony-stimulating factor (G-CSF) and it
Immunity 30, January 16, 2009 ª2009 Elsevier Inc.