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CD4 + effector T cells have been categorized into two subsets: T helper type 1 (T H 1) and T H 2. Another subset of T cells that produce interleukin 17 (IL-17; 'T H -17 cells') has been identified that is highly proinflammatory and induces severe autoimmunity. Whereas IL-23 serves to expand previously differentiated T H -17 cell populations, IL-6 and transforming growth factor-β (TGF-β) induce the differentiation of T H -17 cells from naive precursors. These data suggest a dichotomy between CD4 + regulatory T cells positive for the transcription factor Foxp3 and T H -17 cells: TGF-β induces Foxp3 and generates induced regulatory T cells, whereas IL-6 inhibits TGF-β-driven Foxp3 expression and together with TGF-β induces T H -17 cells. Emerging data regarding T H -17 cells suggest a very important function for this T cell subset in immunity and disease.

T helper 17 cells: Induction and effector functions The recently discovered T H 17 cells, the third subset of effector T helper cells, are the subject of intensive research. They produce the cytokine interleukin-17, coordinate defence against specific pathogens and mediate tissue inflammation. Bettelli et al . review this fast-moving field, focusing on the emergence of the balance between pro-inflammatory TH17 cells and inhibitory T reg cells as key factor in many inflammatory and autoimmune diseases. T helper (T H ) cells constitute an important arm of the adaptive immune system because they coordinate defence against specific pathogens, and their unique cytokines and effector functions mediate different types of tissue inflammation. The recently discovered T H 17 cells, the third subset of effector T helper cells, have been the subject of intense research aimed at understanding their role in immunity and disease. Here we review emerging data suggesting that T H 17 cells have an important role in host defence against specific pathogens and are potent inducers of autoimmunity and tissue inflammation. In addition, the differentiation factors responsible for their generation have revealed an interesting reciprocal relationship with regulatory T (T reg ) cells, which prevent tissue inflammation and mediate self-tolerance.

B cells are increasingly recognized as a therapeutic target in autoimmune diseases. B-cell–depleting therapy with the use of rituximab, a monoclonal antibody to CD20, is approved for the treatment of rheumatoid arthritis and antineutrophil cytoplasmic antibody–associated vasculitis and is frequently used off-label to treat lupus nephritis. 1 The rationale for targeting B cells in multiple sclerosis has remained controversial, particularly because major animal models of the disease do not involve B cells. 2 Nevertheless, rituximab and its almost fully humanized successor, ocrelizumab, were tried in patients with multiple sclerosis and appear to be exceedingly potent in suppressing signs of inflammation in the . . .

Korn and colleagues report that Sirpα + dendritic cells trans-present the cytokine IL-6 to T cells through a process that requires its receptor IL-6Rα bound to dendritic cells and that trans-presentation is needed to generate pathogenic cells of the T H 17 subset of helper T cells in vivo . The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the T H 17 subset of helper T cells remain unclear. Here we used a novel strategy for the conditional deletion of distinct IL-6-producing cell types to show that dendritic cells (DCs) positive for the signaling regulator Sirpα were essential for the generation of pathogenic T H 17 cells. Using their IL-6 receptor α-chain (IL-6Rα), Sirpα + DCs trans-presented IL-6 to T cells during the process of cognate interaction. While ambient IL-6 was sufficient to suppress the induction of expression of the transcription factor Foxp3 in T cells, trans-presentation of IL-6 by DC-bound IL-6Rα (called 'IL-6 cluster signaling' here) was needed to prevent premature induction of interferon-γ (IFN-γ) expression in T cells and to generate pathogenic T H 17 cells in vivo . Our findings should guide therapeutic approaches for the treatment of T H 17-cell-mediated autoimmune diseases.

Interleukin-23 (IL-23) is a proinflammatory cytokine mainly produced by myeloid cells that promotes tumor growth in various preclinical cancer models and correlates with adverse outcomes. However, as to how IL-23 fuels tumor growth is unclear. Here, we found tumor-associated macrophages to be the main source of IL-23 in mouse and human tumor microenvironments. Among IL-23-sensing cells, we identified a subset of tumor-infiltrating regulatory T (T reg ) cells that display a highly suppressive phenotype across mouse and human tumors. The use of three preclinical models of solid cancer in combination with genetic ablation of Il23r in T reg cells revealed that they are responsible for the tumor-promoting effect of IL-23. Mechanistically, we found that IL-23 sensing represents a crucial signal driving the maintenance and stabilization of effector T reg cells involving the transcription factor Foxp3. Our data support that targeting the IL-23/IL-23R axis in cancer may represent a means of eliciting antitumor immunity. IL-23 promotes tumor growth in preclinical cancer models and correlates with adverse clinical outcomes. Here, Becher and colleagues find that IL-23 produced by tumor-associated macrophages stabilizes T reg cell identity, promoting immunosuppression and tumor growth.

Regulatory T cells (T reg ) expressing the transcription factor Foxp3 control the autoreactive components of the immune system. The development of T reg cells is reciprocally related to that of pro-inflammatory T cells producing interleukin-17 (T H 17). Although T reg cell dysfunction and/or T H 17 cell dysregulation are thought to contribute to the development of autoimmune disorders, little is known about the physiological pathways that control the generation of these cell lineages. Here we report the identification of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of T reg and T H 17 cell differentiation in mice. AHR activation by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin induced functional T reg cells that suppressed experimental autoimmune encephalomyelitis. On the other hand, AHR activation by 6-formylindolo[3,2-b]carbazole interfered with T reg cell development, boosted T H 17 cell differentiation and increased the severity of experimental autoimmune encephalomyelitis in mice. Thus, AHR regulates both T reg and T H 17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation. Toxins and autoimmunity The aryl hydrocarbon receptor (AHR) is a transcription factor best known for mediating the toxicity of aromatic hydrocarbons such as dioxin: its activation leads to the production of detoxification enzymes. AHR has been intensely studied in relation to toxicology and cancer research, but no mechanistic connection to the immune system was known. Now two groups report a role for AHR in maintaining the balance between two T-lymphocyte populations — the T reg and T H 17 cells — that are part of the immune regulation system dealing with tolerance of self-antigens and pathogen clearance. Both groups also show that AHR affects the severity of experimental autoimmune encephalitis, a mouse model of multiple sclerosis. This work raises the possibility that stimulation of AHR by environmental factors could be involved in the development of autoimmune disease, and point to AHR as a possible drug target for immunomodulation. The aryl hydrocarbon receptor (AHR) is the cellular receptor for a number of environment contaminants. It is shown here to induce regulatory T cells when bound to the ligand TCCD and promote T H 17 differentiation when bound to FICZ.

Single-nucleotide polymorphisms in the gene encoding the cytosolic viral sensor IFIH1 are linked to a variety of autoimmune diseases. Rawlings and colleagues demonstrate that one such common polymorphism results in IFIH1 with more-potent activation and can act synergistically with other genetic backgrounds to manifest autoimmune disease. The single-nucleotide polymorphism rs1990760 in the gene encoding the cytosolic viral sensor IFIH1 results in an amino-acid change (A946T; IFIH1 T946 ) that is associated with multiple autoimmune diseases. The effect of this polymorphism on both viral sensing and autoimmune pathogenesis remains poorly understood. Here we found that human peripheral blood mononuclear cells (PBMCs) and cell lines expressing the risk variant IFIH1 T946 exhibited heightened basal and ligand-triggered production of type I interferons. Consistent with those findings, mice with a knock-in mutation encoding IFIH1 T946 displayed enhanced basal expression of type I interferons, survived a lethal viral challenge and exhibited increased penetrance in autoimmune models, including a combinatorial effect with other risk variants. Furthermore, IFIH1 T946 mice manifested an embryonic survival defect consistent with enhanced responsiveness to RNA self ligands. Together our data support a model wherein the production of type I interferons driven by an autoimmune risk variant and triggered by ligand functions to protect against viral challenge, which probably accounts for its selection within human populations but provides this advantage at the cost of modestly promoting the risk of autoimmunity.

Scurfy mice, which are deficient in a functional Foxp3, exhibit a severe lymphoproliferative disorder and display generalized overproduction of cytokines. Here, we show that, among the Foxp transcriptional factor family, which includes Foxp1, Foxp2, and Foxp3, only Foxp3 has the ability to inhibit IL-2, IL-4, and IFN-γ production by primary T helper cells. We found that Foxp3 physically associates with the Rel family transcription factors, nuclear factor of activated T cells (NFAT) and NF-κB, and blocks their ability to induce the endogenous expression of their target genes, including key cytokine genes. More importantly, T cells derived from scurfy mice have a dramatic increase in nuclear factor of activated T cells (NFAT) and NF-κB transcriptional activity compared with the T cells derived from WT mice. Furthermore, complementation of Foxp3 in scurfy-derived T cells lowers the NFAT and NF-κB transcriptional activity to the physiological level. Finally, we show that myelin proteolipid protein-specific autoreactive T cells transduced with Foxp3 cannot mediate experimental autoimmune encephalomyelitis, providing further support that Foxp3 suppresses the effector function of autoreactive T cells. Foxp3 has already been associated with the generation of CD4+CD25+regulatory T cells; our data additionally demonstrate that Foxp3 suppresses the effector functions of T helper cells by directly inhibiting the activity of two key transcription factors, NFAT and NF-κB, which are essential for cytokine gene expression and T cell functions.

The development of T helper (TH)17 and regulatory T (Treg) cells is reciprocally regulated by cytokines. Transforming growth factor (TGF)-β alone induces FoxP3⁺ Treg cells, but together with IL-6 or IL-21 induces TH17 cells. Here we demonstrate that IL-9 is a key molecule that affects differentiation of TH17 cells and Treg function. IL-9 predominantly produced by TH17 cells, synergizes with TGF-β1 to differentiate naïve CD4⁺ T cells into TH17 cells, while IL-9 secretion by TH17 cells is regulated by IL-23. Interestingly, IL-9 enhances the suppressive functions of FoxP3⁺ CD4⁺ Treg cells in vitro, and absence of IL-9 signaling weakens the suppressive activity of nTregs in vivo, leading to an increase in effector cells and worsening of experimental autoimmune encephalomyelitis. The mechanism of IL-9 effects on TH17 and Tregs is through activation of STAT3 and STAT5 signaling. Our findings highlight a role of IL-9 as a regulator of pathogenic versus protective mechanisms of immune responses.

IL-23 is a key driver of pathogenic Th17 cell responses. It has been suggested that the transcription factor T-bet is required to facilitate IL-23-driven pathogenic effector functions; however, the precise role of T-bet in intestinal T cell responses remains elusive. Here, we show that T-bet expression by T cells is not required for the induction of colitis or the differentiation of pathogenic Th17 cells but modifies qualitative features of the IL-23-driven colitogenic response by negatively regulating IL-23R expression. Consequently, absence of T-bet leads to unrestrained Th17 cell differentiation and activation characterized by high amounts of IL-17A and IL-22. The combined increase in IL-17A/IL-22 results in enhanced epithelial cell activation and inhibition of either IL-17A or IL-22 leads to disease amelioration. Our study identifies T-bet as a key modulator of IL-23-driven colitogenic responses in the intestine and has important implications for understanding of heterogeneity among inflammatory bowel disease patients. How transcription factor T-bet and Th17 cells contribute to colitis remains incompletely understood. Here the authors identify T-bet as a negative regulator of IL-23R pathway activation and show that T-bet deficient T cells drive colitogenic Th17 responses dependent on the cytokines IL-17A and IL-22.