Robin D. Hatton

Transforming growth factor-beta induces development of the T(H)17 lineage.

A new lineage of effector CD4+ T cells characterized by production of interleukin (IL)-17, the T-helper-17 (TH17) lineage, was recently described based on developmental and functional features distinct from those of classical TH1 and TH2 lineages. Like TH1 and TH2, TH17 cells almost certainly evolved to provide adaptive immunity tailored to specific classes of pathogens, such as extracellular bacteria. Aberrant TH17 responses have been implicated in a growing list of autoimmune disorders. TH17 development has been linked to IL-23, an IL-12 cytokine family member that shares with IL-12 a common subunit, IL-12p40 (ref. 8). The IL-23 and IL-12 receptors also share a subunit, IL-12Rβ1, that pairs with unique, inducible components, IL-23R and IL-12Rβ2, to confer receptor responsiveness. Here we identify transforming growth factor-β (TGF-β) as a cytokine critical for commitment to TH17 development. TGF-β acts to upregulate IL-23R expression, thereby conferring responsiveness to IL-23. Although dispensable for the development of IL-17-producing T cells in vitro and in vivo, IL-23 is required for host protection against a bacterial pathogen, Citrobacter rodentium. The action of TGF-β on naive T cells is antagonized by interferon-γ and IL-4, thus providing a mechanism for divergence of the TH1, TH2 and TH17 lineages.

Transforming growth factor-β induces development of the TH17 lineage

A new lineage of effector CD4+ T cells characterized by production of interleukin (IL)-17, the T-helper-17 (TH17) lineage, was recently described based on developmental and functional features distinct from those of classical TH1 and TH2 lineages. Like TH1 and TH2, TH17 cells almost certainly evolved to provide adaptive immunity tailored to specific classes of pathogens, such as extracellular bacteria. Aberrant TH17 responses have been implicated in a growing list of autoimmune disorders. TH17 development has been linked to IL-23, an IL-12 cytokine family member that shares with IL-12 a common subunit, IL-12p40 (ref. 8). The IL-23 and IL-12 receptors also share a subunit, IL-12Rβ1, that pairs with unique, inducible components, IL-23R and IL-12Rβ2, to confer receptor responsiveness. Here we identify transforming growth factor-β (TGF-β) as a cytokine critical for commitment to TH17 development. TGF-β acts to upregulate IL-23R expression, thereby conferring responsiveness to IL-23. Although dispensable for the development of IL-17-producing T cells in vitro and in vivo, IL-23 is required for host protection against a bacterial pathogen, Citrobacter rodentium. The action of TGF-β on naive T cells is antagonized by interferon-γ and IL-4, thus providing a mechanism for divergence of the TH1, TH2 and TH17 lineages.

Reciprocal interactions of the intestinal microbiota and immune system

The emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates the mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defence. These same attributes can put the host at risk of immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how the system integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks to treat and prevent disease.

The AP-1 transcription factor Batf controls TH17 differentiation

Activator protein 1 (AP-1, also known as JUN) transcription factors are dimers of JUN, FOS, MAF and activating transcription factor (ATF) family proteins characterized by basic region and leucine zipper domains. Many AP-1 proteins contain defined transcriptional activation domains, but BATF and the closely related BATF3 (refs 2, 3) contain only a basic region and leucine zipper, and are considered to be inhibitors of AP-1 activity. Here we show that Batf is required for the differentiation of IL17-producing T helper (TH17) cells. TH17 cells comprise a CD4+ T-cell subset that coordinates inflammatory responses in host defence but is pathogenic in autoimmunity. Batf-/- mice have normal TH1 and TH2 differentiation, but show a defect in TH17 differentiation, and are resistant to experimental autoimmune encephalomyelitis. Batf-/- T cells fail to induce known factors required for TH17 differentiation, such as RORγt (encoded by Rorc) and the cytokine IL21 (refs 14–17). Neither the addition of IL21 nor the overexpression of RORγt fully restores IL17 production in Batf-/- T cells. The Il17 promoter is BATF-responsive, and after TH17 differentiation, BATF binds conserved intergenic elements in the Il17a–Il17f locus and to the Il17, Il21 and Il22 (ref. 18) promoters. These results demonstrate that the AP-1 protein BATF has a critical role in TH17 differentiation.

INTERPLAY BETWEEN THE TH17 AND TREG CELL LINEAGES: A (CO-)EVOLUTIONARY PERSPECTIVE

The origins of the adaptive immune system and the basis for its unique association with vertebrate species have been a source of considerable speculation. In light of recent advances in our understanding of the developmental and functional links between the induced regulatory T cell and T helper 17 cell lineages, and their specialized relationship to the gut, we speculate that the co-evolution of these adaptive immune pathways might have given primitive vertebrates a means to benefit from the diversification of their commensal microbiota.

Developmental plasticity of Th17 and Treg cells

The emergence of Th17 cells as a distinct subset of effector CD4 T cells has led to a revised model of the adaptive immune system. Whereas the Th1-Th2 paradigm revolutionized our understanding of adaptive immunity by introducing the concept of alternative developmental pathways for naïve CD4 T cells induced by distinct cytokine cues from microbe-activated innate immune cells, delineation of Th17 cell differentiation has extended this concept and has led to a greater appreciation of the developmental plasticity of CD4 T cells. In contrast to Th1 and Th2 cells, which have been thought to represent terminal products of their respective developmental programs, recent studies suggest that Th17 cells are less rigid. In addition to early developmental links to induced regulatory T cells (Tregs) reflected in the shared requirement for TGF-beta, it is now apparent that there is substantial plasticity late in the Th17 program, which allows committed Th17 cells to transition from effectors that produce predominantly IL-17A and IL-17F, to effectors that produce predominantly IFNgamma. Tregs appear to have similar plasticity. This promises new insights into strategies for balancing antimicrobial defense with restraints on immune-mediated tissue injury, and raises new questions regarding the stability of epigenetic modifications that accompany induction of cytokine gene expression during T cell lineage development.

Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage.

Phenotypic plasticity of T helper 17 (Th17) cells suggests instability of chromatin structure of key genes of this lineage. We identified epigenetic modifications across the clustered Il17a and Il17f and the Ifng loci before and after differential IL-12 or TGF-beta cytokine signaling, which induce divergent fates of Th17 cell precursors. We found that Th17 cell precursors had substantial remodeling of the Ifng locus, but underwent critical additional modifications to enable high expression when stimulated by IL-12. Permissive modifications across the Il17a-Il17f locus were amplified by TGF-beta signaling in Th17 cells, but were rapidly reversed downstream of IL-12-induced silencing of the Rorc gene by the transcription factors STAT4 and T-bet. These findings reveal substantial chromatin instability of key transcription factor and cytokine genes of Th17 cells and support a model of Th17 cell lineage plasticity in which cell-extrinsic factors modulate Th17 cell fates through differential effects on the epigenetic status of Th17 cell lineage factors.

Regulatory T cell suppression and anergy are differentially regulated by proinflammatory cytokines produced by TLR-activated dendritic cells

CD25+CD4+ regulatory T cells (Tregs) are required for the maintenance of peripheral tolerance to certain self Ags. In this study, the requirements for murine Treg-suppressive activity and proliferation were examined in the context of the maturation of myeloid dendritic cells (DCs). We find that the suppressive function of Tregs is critically dependent on immature DCs and is readily reversed by the maturation of DCs induced by GM-CSF, but does not require TLR activation of either DCs or Tregs. In contrast, reversal of Treg anergy is dependent on TLR activation of DCs, and involves the potentiation of Treg responsiveness to IL-2 by cooperative effects of IL-6 and IL-1, both of which are produced by TLR-activated, mature DCs. Thus, proinflammatory cytokines produced by TLR-activated, mature DCs are required for reversal of Treg anergy, but are not required to overcome Treg suppression.

The Th17 family: flexibility follows function

Discovery of the T‐helper 17 (Th17) subset heralded a major shift in T‐cell biology and immune regulation. In addition to defining a new arm of the adaptive immune response, studies of the Th17 pathway have led to a greater appreciation of the developmental flexibility, or plasticity, that is a feature of T‐cell developmental programs. Since the initial finding that differentiation of Th17 cells is promoted by transforming growth factor‐β (TGFβ), it became clear that Th17 cell development overlapped that of induced regulatory T (iTreg) cells. Subsequent findings established that Th17 cells are also unusually flexible in their late developmental programming, demonstrating substantial overlap with conventional Th1 cells through mechanisms that are just beginning to be understood but would appear to have important implications for immunoregulation at homeostasis and in immune‐mediated diseases. Herein we examine the developmental and functional features of Th17 cells in relation to iTreg cells, Th1 cells, and Th22 cells, as a basis for understanding the contributions of this pathway to host defense, immune homeostasis, and immune‐mediated disease.

Transforming growth factor-β induces development of the T H 17 lineage

A new lineage of effector CD4+ T cells characterized by production of interleukin (IL)-17, the T-helper-17 (TH17) lineage, was recently described based on developmental and functional features distinct from those of classical TH1 and TH2 lineages. Like TH1 and TH2, TH17 cells almost certainly evolved to provide adaptive immunity tailored to specific classes of pathogens, such as extracellular bacteria. Aberrant TH17 responses have been implicated in a growing list of autoimmune disorders. TH17 development has been linked to IL-23, an IL-12 cytokine family member that shares with IL-12 a common subunit, IL-12p40 (ref. 8). The IL-23 and IL-12 receptors also share a subunit, IL-12Rβ1, that pairs with unique, inducible components, IL-23R and IL-12Rβ2, to confer receptor responsiveness. Here we identify transforming growth factor-β (TGF-β) as a cytokine critical for commitment to TH17 development. TGF-β acts to upregulate IL-23R expression, thereby conferring responsiveness to IL-23. Although dispensable for the development of IL-17-producing T cells in vitro and in vivo, IL-23 is required for host protection against a bacterial pathogen, Citrobacter rodentium. The action of TGF-β on naive T cells is antagonized by interferon-γ and IL-4, thus providing a mechanism for divergence of the TH1, TH2 and TH17 lineages.