Distinct inflammatory Th17 subsets emerge in autoimmunity and infection.

Th17 cells play a critical role in both tissue homeostasis and inflammation during clearance of infections as well as autoimmune and inflammatory disorders. Despite numerous efforts to distinguish the homeostatic and inflammatory roles of Th17 cells, the mechanism underlying the divergent functions of inflammatory Th17 cells remains poorly understood. In this study, we demonstrate that the inflammatory Th17 cells involved in autoimmune colitis and those activated during colitogenic infection are distinguishable populations characterized by their differential responses to the pharmacological molecule, clofazimine (CLF). Unlike existing Th17 inhibitors, CLF selectively inhibits proautoimmune Th17 cells while preserving the functional state of infection-elicited Th17 cells partially by reducing the enzyme ALDH1L2. Overall, our study identifies two distinct subsets within the inflammatory Th17 compartment with distinct regulatory mechanisms. Furthermore, we highlight the feasibility to develop disease-promoting Th17 selective inhibitor for treating autoimmune diseases.

USP19 Suppresses Th17-Driven Pathogenesis in Autoimmunity.

Th17 cells have emerged as a chief pathogenic cell type in murine models of autoimmunity and human autoimmune diseases. Th17 cells are markedly plastic in their pathogenic potential, as they can adopt pro- or anti-inflammatory programming under distinct conditions. The specific mechanism underlying the plasticity of Th17 pathogenesis remains elusive. In this study, we found that Th17 lineage-specific transcription factor RORγt directly bound to the promoters of genes engaged in the ubiquitination pathway and thus upregulated their expression in pathogenic Th17 cells. We observed that ubiquitination activity correlated with Th17-related pathology in the context of autoimmunity. Consistent with this finding, the deubiquitinase USP19 was shown to suppress pathogenic Th17 differentiation in vitro and Th17-mediated pathogenesis in vivo. Mechanistically, USP19 removed the K63-linked ubiquitin chain from RORγt lysine 313, which is essential for recruiting the coactivator SRC3. Collectively, our findings indicate that USP19 selectively suppresses the pathogenic potential of Th17 cells and offer novel strategies for treating autoimmune diseases.