Biology Reference
In-Depth Information
IL-12 family. IL-12 is important in driving naïve CD4
+
T-cell differentiation
into the Th1 pathway
[7]
and is composed of two subunits, termed p35 and
p40. Oppmann and colleagues in 2000
[8]
reported a new cytokine, IL-23, in
which the p40 subunit previously assumed to be exclusive to IL-12 paired
with a new p19 subunit to form a heterodimeric cytokine. Thus, IL-12 and
IL-23 share the common p40 subunit, but they also have unique subunits,
p35 for IL-12 and p19 for IL-23. The subsequent investigation into the role
of IL-23 led to the seminal studies performed by Cua and colleagues
[9]
that
showed that mice deficient in the IL-23 p19 subunit were highly resistant
to the development of autoimmunity, whereas those mice deficient only
in the IL-12 p35 subunit were highly susceptible to experimental autoim-
mune encephalomyelitis (EAE) induction. Moreover, IL-23 gene transfer
vectors delivered into the central nervous system (CNS) reconstituted EAE
in both p19- and p40-deficient mice, while IL-12 gene transfer into the CNS
did not facilitate disease in p40-deficient animals. Thus, IL-12 and Th1 cells
were not required for induction of EAE, and IL-23 was shown to be a crucial
cytokine for the development of CNS autoimmune inflammation
[9]
. These
observations revealed IL-23 as a critical driver of autoimmune inflamma-
tion and suggested that T cells that differentiate under the influence of IL-23
are key players in the induction of autoimmunity. A link between IL-23 and
IL-17 was then established by studies showing that IL-23 could promote
the secretion of IL-17 by activated T cells
[10]
and that IL-23 enhanced
the expansion of CD4
+
IL-17-secreting T cells in various murine models of
autoimmunity
[11-13]
. These investigations also demonstrated a unique
cytokine and gene expression profile for these cells that distinguished them
from both Th1 and Th2 cells
[12]
. Finally, elegant work identified that Th17
cells expressed a transcription factor termed retinoic acid-related orphan
receptor γt (ROR-γt)
[14]
, which distinguished them from Th1 and Th2 cells
and clearly demarcated these cells as a unique T-helper population.
272
Differentiation and actions of Th17 cells
The differentiation of helper T cells requires coordinated cytokine signal-
ing that induces the activation of specific transcription factors to promote
lineage-specific CD4
+
T-cell differentiation. While T-box-containing pro-
tein expressed in T cells (T-bet) is activated by IL-12 and IFN-γ and is exclu-
sively expressed during Th1 cell differentiation
[15]
, GATA-binding protein
3 is required for Th2 cell polarization
[16]
. Th17 cells have a specialized
developmental pathway that is distinct from that of Th1 or Th2. It has been
shown that Th17 cell differentiation does not depend on signal transducer
and activator of transcription 1 (STAT1), STAT4, and/or STAT6, and they
do not express any conventional transcriptional factors involved in Th1
and Th2 differentiation
[17,18]
. Initially, it was reported that IL-23 was an
important factor for the development of Th17 cells
[10,19]
. However, naïve
murine T cells do not express the IL-23 receptor and do not differentiate
into Th17 cells in the presence of IL-23
in vitro
[20]
. Therefore, IL-23 is not
required for the initial differentiation of Th17 cells from naïve CD4 T-cell
precursors, although it appears to have a role in the maintenance of effec-
tor function once these cells are induced
[21]
. Three independent groups
made the observation that a combination of transforming growth factor
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