SummaryLymphoid cells that produce IL-17 cytokines protect barrier tissues from pathogenic microbes, but are also prominent effectors of inflammation and autoimmune disease. T-helper (TH17) cells, defined by RORγt-dependent production of IL-17A and IL-17F, exert homeostatic functions in the gut upon microbiota-directed differentiation from naïve CD4+ T cells. In the non-pathogenic setting, their cytokine production is regulated by serum amyloid A proteins (SAA1 and SAA2) secreted by adjacent intestinal epithelial cells. However, TH17 cell behaviors vary markedly according to their environment. Here we show that SAAs additionally direct a pathogenic pro-inflammatory TH17 cell differentiation program, acting directly on T cells in collaboration with STAT3-activating cytokines. Using loss- and gain-of-function mouse models, we show that SAA1, SAA2, and SAA3 have distinct systemic and local functions in promoting TH17-mediated inflammatory diseases. These studies suggest that T cell signaling pathways modulated by the SAAs may be attractive targets for anti-inflammatory therapies.
Serum amyloid A inhibits dendritic cell apoptosis to induce glucocorticoid resistance in CD4+ T cells