Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity

Abstract

R e v i e w S e R i e S : A u t o i m m u n i t y2 2 1 2 jci.org Volume 125 Number 6 June 2015Murine Th17 differentiation can also be induced in the absence of TGF-β1 signaling, via the combination either of IL-1β, IL-6, and IL-23 or of 42). These TGF-β1-independent Th17 cells can efficiently induce autoimmune tissue inflammation upon adoptive transfer, a trait that led to them being termed "pathogenic" Th17 cells. Additionally, they possess a gene expression profile distinct from that of "nonpathogenic" Th17 cells, which are differentiated with TGF-β1 and IL-6. These observations have led to two competing hypotheses. The first posits that IL-23 cements Th17 lineage commitment such that Th17 cells induced with TGF-β1 and IL-6 are insufficiently committed to the lineage and cannot induce autoimmune tissue inflammation. The second suggests that there are distinct subtypes of Th17 cells whose differentiation is dependent on distinct combinations of cytokines. The latter hypothesis is supported by the finding that pathogenic Th17 cells express higher levels of several Th1 lineage-associated transcripts, such as the transcription factor T-bet and IFN-γ, and have been shown to be derived from IL-17 single producers by fate mapping experiments (43,44). Similarly, an important feature of human Th17 cells, as well as those isolated from inflamed tissues in mouse models of Th17-mediated disease, is that they coproduce IL-17 with other cytokines, leading to distinct functional roles (45)(46)(47). For instance, human Th17 cells that produce both IL-10 and IL-17 preferentially respond to Staphylococcus aureus, while those that produce both IL-17 and IFN-γ recognize Candida albicans, suggesting that distinct pathogens induce distinct subtypes of Th17 cells (40). IL-17/IFN-γ coproducers have been ascribed pathogenic functions in the CNS during EAE; however, it has been difficult to reliably differentiate such cells in vitro. Repeated rounds of in vitro culture in the presence of either Th1-inducing cytokines or IL-23 can induce IL-17/IFN-γ coproducers, albeit at moderate percentages. The transcription factors T-bet, RUNX1, and RUNX3 appear to be important in the acquisition of this phenotype (48,49).Large-scale transcriptional analysis of Th17 differentiation at very high temporal resolution has begun to elucidate the molecular networks that control this process, and is a promising approach to the identification of novel regulatory molecules that control pathogenic Th17 differentiation (50, 51). In fact, Th17 development is controlled induction of this lineage. The combination of TGF-β1 and IL-6 efficiently induces IL-17-producing murine T cells in vitro and highlights the reciprocal relationship between induced Tregs, which are generated by TGF-β1 alone, and Th17 cells (19,20). A series of studies demonstrated that IL-21, a γ c -dependent cytokine, could promote the differentiation of Th17 cells (21-23). In combination with TGF-β, IL-21 induces IL-17 production from naive Th cells and promotes the expression of both RORγt, th...

CD4 T Cells in IBD: Crossing the Line?

“…T cells in the intestinal mucosa which blur conventional lines by which T cell subsets have been defined. This study expands upon existing reports by the authors [5] and others [6] showing that IBD patients more than healthy subjects harbor T cells that express the Treg marker FOXP3, and yet are able to produce IL-17 upon activation, or express the nuclear transcription factor RORct, similar to Th17 cells [2]. Similar to prior studies [5,6], the group reported a trend towards these Treg/Th17 crossover cells being more prevalent in IBD subjects with higher clinical activity scores.…”

“…T cell function, such as the receptor for interleukin (IL)-23 [1], a cytokine essential for the survival of the Th17 subset of CD4? T cells, which is implicated in the pathogenesis of several animal models of autoimmunity [2]. Similarly, clinical efficacy has been conclusively demonstrated in large clinical trials of drugs targeting proteins important for CD4?…”

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…By examining clonal populations of CD4 + T cells, they found that different clones expressed selected patterns of cytokines -principally interleukin-4 (IL-4) in T H 2 cells or interferon-γ (IFNγ) in T H 1 cells -thus delineating CD4 + T cells into specialized subsets on the basis of the cytokines they produced and providing a central paradigm for how CD4 + T cells could be linked to different pathologies or associated with the control of different types of infection 3 . Since that time, the breadth of CD4 + T cell subsets has broadened, from the longstudied T H 1 and T H 2 cell subsets, to a more expansive collection, including T H 17, T H 9 and T follicular helper (T FH ) cells, as well as thymically derived and peripherally induced regulatory T cells (tT Reg cells and pT Reg cells, respectively) [4][5][6][7] . Each T cell subset can be characterized by its ability to sense different inductive cytokines, programme the expression of distinct transcription factors and function by producing select cytokines and chemokine receptors to best control specific pathogens or prevent immune pathology (FIG.…”

IL‐23R Deficiency Does Not Impact Atherosclerotic Plaque Development in Mice

“…5, 6, 7 IL‐23 signals through the IL‐23 receptor to stabilize and promote production of IL‐17 and IFN‐γ in Th17 cells 5. Furthermore, IL‐23 is required for the generation of “pathogenic” IL‐17 + IFN‐γ + double‐producing helper T cells that mediate tissue damage in models of autoimmune disease 8, 9. In this study, we investigated the role of IL‐23/IL‐23R signaling in atherosclerosis using IL‐23R reporter mice and IL‐23‐deficient mice 10…”