Th17 Cells Changing Colors

Abstract

The transcription factor c-MAF can synergize with IL-27 to transform inflammatory Th17 cells into regulatory IL-10–producing cells that may be beneficial in settings of chronic stimulation. The transcription factor c-MAF can synergize with IL-27 to transform inflammatory Th17 cells into regulatory IL-10–producing cells that may be beneficial in settings of chronic stimulation. CITATION Aschenbrenner D, Foglierini M, Jarrossay D, et al. An immunoregulatory and tissue-residency program modulated by c-MAF in human Th17 cells. Nat Immunol. 2018;19(10):1126-1136. Interleukin (IL)-17A–producing CD4 T (Th17) cells protect hosts against extracellular pathogens and have been linked to transplant rejection and autoimmunity. Some Th17 cells co-express the regulatory cytokine IL-10, which limits their response and may help avoid collateral tissue injury. However, the transcriptional programs underlying IL-10–producing Th17 cells have not been fully explored. The study by Aschenbrenner et al. demonstrates that a subset of human memory Th17 cells acquired anti-inflammatory and immunoregulatory programs upon restimulation, dependent on the transcription factor musculoaponeurotic fibrosarcoma (c-MAF) that largely directed expression of IL-10 and co-inhibitory markers. Aschenbrenner and colleagues isolated CCR6+CCR4+CXCR3– human memory Th17 clones and showed that approximately 25% of these cells upregulated IL-10 and downregulated IL-17A upon restimulation with anti-CD3/CD28. IL-10+ Th17 cells acquired a memory of IL-10 expression associated with permissive H3K4me3 chromatin modifications at the transcriptional start site of the IL-10 locus, and IL-10 production was maintained over several rounds of restimulation. IL-10+ Th17 cells selectively increased expression and binding of the transcriptional co-activator c-MAF to the c-MAF response element (MARE-2) in the IL-10 promoter. This event was not observed in IL-10– Th17 cells, although they expressed basal c-MAF. Collectively, these data suggest a unique epigenetic landscape accompanied by upregulated c-MAF, which results in IL-10 production by Th17 cells. To investigate the global transcriptional profile of Th17 cells, RNA sequencing (RNAseq) was conducted in IL-10+ and IL-10– Th17 subsets. As expected, IL-10+ Th17 cells activated immunoregulatory/tissue homing transcriptional pathways and were enriched in genes encoding regulatory molecules such c-MAF, IL-10, CTLA-4, PD-1, CD69, CCR9 and CXCR6. In contrast, IL-10– Th17 cells exhibited a pro-inflammatory transcriptional profile expressing (IFN)γ, IL-22, IL-1R1, IL-2, IL-23R, and CCR7. Depleting c-MAF using lentivirus-encoding short hairpin RNA reduced expression of IL-10 and of most of the other IL-10+ genes associated with Th17, while a number of pro-inflammatory genes were upregulated. Conversely, ectopic overexpression of c-MAF in IL-10– Th17 cells modestly upregulated IL-10, which was further induced in the presence of IL-27, suggesting synergy between these two pathways. Overall, these data suggest that IL-10+ Th17 cells acquire immunoregulatory and tissue-residency programs, which are in large part defined by c-MAF expression. The IL-10+ and IL-10– Th17 subsets shared considerable plasticity. IL-10– Th17 cells acquired a regulatory phenotype in the presence of IL-27, a cytokine known to induce IL-10, whereas IL-10+ Th17 cells acquired a pro-inflammatory phenotype when restimulated in the presence of IL-1β. Interestingly, IL-27 and IL-1β did not change c-MAF expression levels, such that their effects on IL-10 transcription may depend on altered binding of c-MAF to the IL-10 locus. Functionally, IL-10+ and IL-10– Th17 subsets were able to polarize CD14+ monocytes into anti-inflammatory M2 and pro-inflammatory M1-like macrophages, respectively, in co-culture experiments. Th17 cells are thought to participate in chronic allograft rejection, especially in the setting of lung transplantation. IL-17A is a potent chemoattractant for neutrophils and can induce profibrotic cytokines from allograft epithelial cells and fibroblasts. Therapies targeting IL-17A in select settings of autoimmunity have shown promising results in the clinic. However, IL-17A–targeting in transplant animal models has not resulted in complete attenuation of chronic rejection. The current study suggests that overexpressing c-MAF in T cells or inhibiting its antagonizing pathways, along with IL-27 administration, may help promote regulatory over inflammatory Th17 cells and may improve long-term transplant outcomes. Recent reports demonstrating that c-MAF drives T cell exhaustion and regulates IL-10 in macrophages/Th1 subsets further highlight c-MAF as an attractive therapeutic target. If the proregulatory effects of c-MAF in Th17 cells are conserved in other mammals, it will be exciting to see how targeting T cell–c-MAF influences allograft survival outcomes in preclinical models.