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CD5 costimulation induces stable Th17 development by promoting IL-23R expression and sustained STAT3 activation. de Wit Jelle,Souwer Yuri,van Beelen Astrid J,de Groot Rosa,Muller Femke J M,Klaasse Bos Hanny,Jorritsma Tineke,Kapsenberg Martien L,de Jong Esther C,van Ham S Marieke Blood IL-17-producing CD4(+) T helper (Th17) cells are important for immunity against extracellular pathogens and in autoimmune diseases. The factors that drive Th17 development in human remain a matter of debate. Here we show that, compared with classic CD28 costimulation, alternative costimulation via the CD5 or CD6 lymphocyte receptors forms a superior pathway for human Th17-priming. In the presence of the Th17-promoting cytokines IL-1β, IL-6, IL-23, and transforming growth factor-β (TGF-β), CD5 costimulation induces more Th17 cells that produce higher amounts of IL-17, which is preceded by prolonged activation of signal transducer and activator of transcription 3 (STAT3), a key regulator in Th17 differentiation, and enhanced levels of the IL-17-associated transcription factor retinoid-related orphan receptor-γt (ROR-γt). Strikingly, these Th17-promoting signals critically depend on CD5-induced elevation of IL-23 receptor (IL-23R) expression. The present data favor the novel concept that alternative costimulation via CD5, rather than classic costimulation via CD28, primes naive T cells for stable Th17 development through promoting the expression of IL-23R. 10.1182/blood-2011-05-352682
IL-1β promotes Th17 differentiation by inducing alternative splicing of FOXP3. Mailer Reiner K W,Joly Anne-Laure,Liu Sang,Elias Szabolcs,Tegner Jesper,Andersson John Scientific reports CD4(+)FOXP3(+) regulatory T (Treg) cells are essential for maintaining immunological self-tolerance. Treg cell development and function depend on the transcription factor FOXP3, which is present in several distinct isoforms due to alternative splicing. Despite the importance of FOXP3 in the proper maintenance of Treg cells, the regulation and functional consequences of FOXP3 isoform expression remains poorly understood. Here, we show that in human Treg cells IL-1β promotes excision of FOXP3 exon 7. FOXP3 is not only expressed by Treg cells but is also transiently expressed when naïve T cells differentiate into Th17 cells. Forced splicing of FOXP3 into FOXP3Δ2Δ7 strongly favored Th17 differentiation in vitro. We also found that patients with Crohn's disease express increased levels of FOXP3 transcripts lacking exon 7, which correlate with disease severity and IL-17 production. Our results demonstrate that alternative splicing of FOXP3 modulates T cell differentiation. These results highlight the importance of characterizing FOXP3 expression on an isoform basis and suggest that immune responses may be manipulated by modulating the expression of FOXP3 isoforms, which has broad implications for the treatment of autoimmune diseases. 10.1038/srep14674
Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β. Zielinski Christina E,Mele Federico,Aschenbrenner Dominik,Jarrossay David,Ronchi Francesca,Gattorno Marco,Monticelli Silvia,Lanzavecchia Antonio,Sallusto Federica Nature IL-17-producing CD4+ T helper cells (TH17) have been extensively investigated in mouse models of autoimmunity. However, the requirements for differentiation and the properties of pathogen-induced human TH17 cells remain poorly defined. Using an approach that combines the in vitro priming of naive T cells with the ex vivo analysis of memory T cells, we describe here two types of human TH17 cells with distinct effector function and differentiation requirements. Candida albicans-specific TH17 cells produced IL-17 and IFN-γ, but no IL-10, whereas Staphylococcus aureus-specific TH17 cells produced IL-17 and could produce IL-10 upon restimulation. IL-6, IL-23 and IL-1β contributed to TH17 differentiation induced by both pathogens, but IL-1β was essential in C. albicans-induced TH17 differentiation to counteract the inhibitory activity of IL-12 and to prime IL-17/IFN-γ double-producing cells. In addition, IL-1β inhibited IL-10 production in differentiating and in memory TH17 cells, whereas blockade of IL-1β in vivo led to increased IL-10 production by memory TH17 cells. We also show that, after restimulation, TH17 cells transiently downregulated IL-17 production through a mechanism that involved IL-2-induced activation of STAT5 and decreased expression of ROR-γt. Taken together these findings demonstrate that by eliciting different cytokines C. albicans and S. aureus prime TH17 cells that produce either IFN-γ or IL-10, and identify IL-1β and IL-2 as pro- and anti-inflammatory regulators of TH17 cells both at priming and in the effector phase. 10.1038/nature10957
TNFα promotes Th17 cell differentiation through IL-6 and IL-1β produced by monocytes in rheumatoid arthritis. Zheng Yingxia,Sun Lei,Jiang Ting,Zhang Dongqing,He Dongyi,Nie Hong Journal of immunology research TNFα plays an important role in autoimmune pathogenesis and is the main therapeutic target of rheumatoid arthritis. However, its underlying mechanism is not completely understood. In this study, we described that Th17 cells were accumulated in synovial fluid, which was attributable to TNFα aberrantly produced in rheumatoid synovium. Interestingly, TNFα cannot induce IL-17 production of CD4(+) T cells directly, but through the monocytes high levels of IL-1β and IL-6 in a TNFRI and TNFRII dependent manner from the active RA patients are produced. TNFα was shown to enhance the phosphorylation level of STAT3 and the expression level of transcription factor RORC of CD4(+) T cells when cultured with CD14(+) monocytes. Treatment with an approved TNFα blocking antibody showed marked reduction in the levels of IL-6, IL-1β, and IL-17 and the expression level of STAT3 phosphorylation in relation to Th17 cell differentiation in patients with rheumatoid arthritis. The study provides new evidence supporting the critical role of TNFα in the pathogenic Th17 cell differentiation in rheumatoid arthritis. 10.1155/2014/385352
IL-33-matured dendritic cells promote Th17 cell responses via IL-1β and IL-6. Park Su-Ho,Kim Myun Soo,Lim Hui Xuan,Cho Daeho,Kim Tae Sung Cytokine IL-33 is associated with a variety of autoimmune diseases, such as sclerosis, inflammatory bowel disease, and rheumatoid arthritis. Although IL-33 is mainly involved in the induction of Th2 cells, however, the relationship between IL-33 and Th17 cells is still largely unknown. In this study, we investigated the effects of IL-33 on DC-mediated CD4 T cell activation and Th17 cell differentiation because DCs are essential cells for presenting self-antigens to CD4 T cells in autoimmune disease conditions. OT-II mice were injected with IL-33-treated DCs or untreated DCs that were primed by OVA peptide, and their Th17 cell responses were compared. Th17 cell population and IL-17 expression levels were significantly increased in draining lymph nodes of mice injected with IL-33-treated DCs, compared with those in mice injected with untreated DCs. IL-33 treatment maturated DCs to present self-antigens and to increase production of proinflammatory cytokines such as IL-1β and IL-6, which have a crucial role in Th17 cell differentiation. We found that the IL-33-matured DCs enhanced the expression of an early T cell activation marker (CD69) and the Th17 master transcription factor (RORγt), but IL-33 did not directly affect CD4 T cell differentiation or increase Th17 polarization. Notably, neutralizing IL-1β and/or IL-6 significantly decreased IL-17 expression levels and Th17 cell population which were increased by the coculture of CD4 T cells with IL-33-matured DCs, indicating that IL-33 may induce Th17 cell responses via IL-1β and IL-6 derived from IL-33-matured DCs. 10.1016/j.cyto.2017.07.022
Increased Th17 differentiation in aged mice is significantly associated with high IL-1β level and low IL-2 expression. Lim Mi-Ae,Lee Jennifer,Park Jin-Sil,Jhun Joo-Yeon,Moon Young-Mi,Cho Mi-La,Kim Ho-Youn Experimental gerontology OBJECTIVE:Aging has been reported to be associated with changes in immune function. Although frequent infection and the development of malignancy suggest the decline of immune function with aging, changes toward proinflammatory conditions also develop at the same time. Th17 cells are well known CD4(+) T cell subpopulation closely linked to chronic inflammation and autoimmunity. In this study, changes in the Th17 population were investigated to elucidate a possible mechanism for this response with aging. METHODS:Splenocytes were isolated from 2-month-old (young) and 20-month-old (aged) mice. CD4(+)CD44(+) memory T cells and CD4(+)CD62L(+) naïve T cells were isolated and sorted using magnetic beads and flow cytometry. The frequency of IL-17-producing cells was measured using flow cytometry. The expression of IL-17 and Th17-related factors at the mRNA level was measured with RT-PCR. IL-17 and Il-1β expression in spleen tissues was additionally assessed using confocal microscopy. RESULTS:The proportion of IL-17-producing CD4(+) T cells was higher in the splenocytes among the old mice than those of the young mice. When splenocytes were cultured in Th17 polarizing conditions, the proportion of IL-17 producing CD4(+) T cells was higher in aged mice as well. This was consistently observed when naïve and memory cells were isolated and differentiated into Th17 respectively. In addition, the expression of retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt) and other Th17-related factors (AhR, CCR6, and CCL20) increased in the splenocytes of aged mice compared to the young mice. The expression of IL-1β, showing to promote Th17 differentiation, was higher in the aged mice. Likewise, CD4(+) T cell expression of IL-1R was higher in the aged mice, suggesting that the CD4(+) T cells of the aged mice are readily prepared to differentiate into Th17 cells in response to IL-1β. Confocal microscopy showed that cells positive for IL-1R or IL-1β were more frequent in the spleens of the aged mice. When an anti-IL-2 antibody was applied, the proportion of IL-17-producing cells increased more prominently in the young mice. We observed that IL-2 production and IL-2R expression were reduced in the aged mice, respectively, explaining the blunted response to the anti-IL-2 antibody treatment and the consequent minimal change in the Th17 population. CONCLUSION:We demonstrated that the proportion of Th17 cells increased in the aged mice both in naïve and memory cell populations. Elevation of IL-1R and IL-1β expression and the reduction in IL-2 and IL-2R expression in aged mice seemed to promote Th17 differentiation. Our results suggest that enhanced Th17 differentiation in aging may have a pathogenic role in the development of Th17-mediated autoimmune diseases. 10.1016/j.exger.2013.10.006
IL-23 and IL-1β Drive Human Th17 Cell Differentiation and Metabolic Reprogramming in Absence of CD28 Costimulation. Revu Shankar,Wu Jing,Henkel Matthew,Rittenhouse Natalie,Menk Ashley,Delgoffe Greg M,Poholek Amanda C,McGeachy Mandy J Cell reports Th17 cells drive autoimmune disease but also control commensal microbes. A common link among antigens from self-proteins or commensal microbiota is relatively low activation of T cell receptor (TCR) and costimulation signaling. Indeed, strong TCR/CD28 stimulation suppressed Th17 cell differentiation from human naive T cells, but not effector/memory cells. CD28 suppressed the classical Th17 transcriptional program, while inducing known Th17 regulators, and acted through an Akt-dependent mechanism. Th17 cells differentiated without CD28 were not anergic: they showed robust proliferation and maintained Th17 cytokine production following restimulation. Interleukin (IL)-23 and IL-1β promoted glucose uptake and increased glycolysis. Although modestly increased compared to CD28 costimulation, glycolysis was necessary to support Th17 differentiation, indicating that cytokine-mediated metabolic shifts were sufficient to obviate the classical requirement for CD28 in Th17 differentiation. Together, these data propose that, in humans, strength of TCR/CD28/Akt activation serves as a rheostat tuning the magnitude of Th17 development driven by IL-23 and IL-1β. 10.1016/j.celrep.2018.02.044
Transcriptional signature of human pro-inflammatory T17 cells identifies reduced IL10 gene expression in multiple sclerosis. Hu Dan,Notarbartolo Samuele,Croonenborghs Tom,Patel Bonny,Cialic Ron,Yang Tun-Hsiang,Aschenbrenner Dominik,Andersson Karin M,Gattorno Marco,Pham Minh,Kivisakk Pia,Pierre Isabelle V,Lee Youjin,Kiani Karun,Bokarewa Maria,Tjon Emily,Pochet Nathalie,Sallusto Federica,Kuchroo Vijay K,Weiner Howard L Nature communications We have previously reported the molecular signature of murine pathogenic T17 cells that induce experimental autoimmune encephalomyelitis (EAE) in animals. Here we show that human peripheral blood IFN-γIL-17 (T1/17) and IFN-γIL-17 (T17) CD4 T cells display distinct transcriptional profiles in high-throughput transcription analyses. Compared to T17 cells, T1/17 cells have gene signatures with marked similarity to mouse pathogenic T17 cells. Assessing 15 representative signature genes in patients with multiple sclerosis, we find that T1/17 cells have elevated expression of CXCR3 and reduced expression of IFNG, CCL3, CLL4, GZMB, and IL10 compared to healthy controls. Moreover, higher expression of IL10 in T17 cells is found in clinically stable vs. active patients. Our results define the molecular signature of human pro-inflammatory T17 cells, which can be used to both identify pathogenic T17 cells and to measure the effect of treatment on T17 cells in human autoimmune diseases. 10.1038/s41467-017-01571-8
High frequency of intestinal T17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Cosorich Ilaria,Dalla-Costa Gloria,Sorini Chiara,Ferrarese Roberto,Messina Maria Josè,Dolpady Jayashree,Radice Elisa,Mariani Alberto,Testoni Pier Alberto,Canducci Filippo,Comi Giancarlo,Martinelli Vittorio,Falcone Marika Science advances T helper 17 (T17) cells are key players in multiple sclerosis (MS), and studies in animal models demonstrated that effector T17 cells that trigger brain autoimmunity originate in the intestine. We validate in humans the crucial role of the intestinal environment in promoting T17 cell expansion in MS patients. We found that increased frequency of T17 cells correlates with high disease activity and with specific alterations of the gut mucosa-associated microbiota in MS patients. By using 16 ribosomal RNA sequencing, we analyzed the microbiota isolated from small intestinal tissues and found that MS patients with high disease activity and increased intestinal T17 cell frequency showed a higher Firmicutes/Bacteroidetes ratio, increased relative abundance of , and decreased strains compared to healthy controls and MS patients with no disease activity. We demonstrated that the intestinal T17 cell frequency is inversely related to the relative abundance of strains in the human small intestine. Our data demonstrate that brain autoimmunity is associated with specific microbiota modifications and excessive T17 cell expansion in the human intestine. 10.1126/sciadv.1700492