IL21 initiates an alternative pathway to induce proinflammatory TH17 cells (original) (raw)
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Nature, 2006
On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T H ) cells are traditionally thought to differentiate into T H 1 and T H 2 cell subsets. T H 1 cells are necessary to clear intracellular pathogens and T H 2 cells are important for clearing extracellular organisms 1,2 . Recently, a subset of interleukin (IL)-17-producing T (T H 17) cells distinct from T H 1 or T H 2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury 3-5 . In contrast, CD4 1 CD25 1 Foxp3 1 regulatory T (T reg ) cells inhibit autoimmunity and protect against tissue injury 6 . Transforming growth factor-b (TGF-b) is a critical differentiation factor for the generation of T reg cells 7 . Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation 8,9 , completely inhibits the generation of Foxp3 1 T reg cells induced by TGF-b. We also demonstrate that IL-23 is not the differentiation factor for the generation of T H 17 cells. Instead, IL-6 and TGF-b together induce the differentiation of pathogenic T H 17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T H 17) T cells that induce autoimmunity and regulatory (Foxp3 1 ) T cells that inhibit autoimmune tissue injury.
International Immunology, 2008
T helper 17 (T h 17) cells represent a new subset of CD41 effector T cells which have been described in both mice and humans. However, some differences seem to exist between murine and human T h 17 cells with regard to their features, origin and role in immunopathology. Murine T h 17 cells share their developmental origin with Foxp31 Treg cells, indeed naive T-cell precursors can be differentiated to regulatory T (Treg) cells by transforming growth factor-b (TGF-b) alone, whereas the contemporaneous presence of TGF-b and IL-6 gives origin to T h 17 cells. Human T h 17 cells which consistently express the CC chemokine receptor 6 and the equivalent of the murine NK1.1, CD161, appear to exclusively originate in response to IL-1b and IL-23 from a small subset of CD1611CD41 T-cell precursors detectable in the thymus and in umbilical cord blood. These cells constitutively express the T h 17-driving transcription factor retinoic acid-related orphan receptor (ROR)gt and the IL-23R and can also give origin to T h 1 cells or T h 2 cells under the appropriate polarizing conditions. By contrast, human CD161-naive T cells only give rise to T h 1 and T h 2 cells, but not T h 17 cells. TGF-b may not exert a direct critical role in human T h 17 cell differentiation, but indirectly favours their development by inhibiting the development of T h 1 cells, which are much more susceptible than T h 17 cells to its suppressive activity on cell proliferation. Moreover, while murine T h 17 are pathogenic in some murine models of autoimmunity where T h 1 cells seem to play a protective role, both T h 17 and T h 1 certainly contribute to the pathogenesis of human autoimmune and other chronic inflammatory disorders.
Proceedings of the National Academy of Sciences, 2008
antigenic stimulation and the sequential action of the cytokines IL-6, IL-21, and IL-23, along with TGF. Current dogma proposes that IL-6 induces IL-21, which, in a STAT3-dependent manner, amplifies its own transcription, contributes to IL-17 production, and, moreover, promotes the expression of the IL-23 receptor. This, in turn, prepares cells for IL-23-mediated stabilization of the Th17 phenotype. Here we demonstrate that these effects of IL-21 on Th17 differentiation are completely dependent on IFN regulatory factor 4 (IRF4). After culturing in the presence of IL-21 plus TGF, IRF4-deficient (Irf4 ؊/؊ ) Th cells showed a profound intrinsic defect in IL-17 production and in the autocrine IL-21 loop. Likewise, the levels of IL-23 receptor and the lineage-specific orphan nuclear receptors ROR␣ and ROR␥t were diminished, whereas the T regulatory (Treg) transcription factor forkhead box P3 (Foxp3) was strongly up-regulated, consistent with the reciprocal relationship between Th17 and Treg development. Despite this loss of IL-21 functions, IL-21-induced STAT3 activation was unimpaired and induced normal Socs3 expression. Forced expression of Foxp3 in WT cells inhibited IL-21-mediated IL-17 production, suggesting that the increase in Foxp3 contributes to the Irf4 ؊/؊ phenotype. Additionally, the low levels of ROR␣ and ROR␥t are also partially responsible, because simultaneous overexpression of both proteins restored IL-17 production in Irf4 ؊/؊ cells to some extent. These data highlight IRF4 as a decisive factor during the IL-21mediated steps of Th17 development by influencing the balance of Foxp3, ROR␣, and ROR␥t.
Nature Immunology, 2008
Interleukin 17 (IL-17)-producing T helper 17 cells (T(H)-17 cells) have been described as a T helper cell subset distinct from T helper type 1 (T(H)1) and T(H)2 cells, with specific functions in antimicrobial defense and autoimmunity. The factors driving human T(H)-17 differentiation remain controversial. Using a systematic approach combining experimental and computational methods, we show here that transforming growth factor-beta, interleukin 23 (IL-23) and proinflammatory cytokines (IL-1beta and IL-6) were all essential for human T(H)-17 differentiation. However, individual T(H)-17 cell-derived cytokines, such as IL-17, IL-21, IL-22 and IL-6, as well as the global T(H)-17 cytokine profile, were differentially modulated by T(H)-17-promoting cytokines. Transforming growth factor-beta was critical, and its absence induced a shift from a T(H)-17 profile to a T(H)1-like profile. Our results shed new light on the regulation of human T(H)-17 differentiation and provide a framework for the global analysis of T helper responses.