Human CCR6+CXCR3+ “Th1/17” cells are polyfunctional and can develop from Th17 cells under the influence of IL-1β and IL-12 (P4122)

Abstract

Abstract In humans, memory CD4+ T cells co-expressing the chemokine receptors CCR6 and CXCR3, and producing both IL-17 and IFN-γ, have been proposed to be highly pathogenic in several autoimmune disorders. However, their developmental pathways, relationship with “classic” Th17 and Th1 cells and physiological role in normal immune responses are not well understood. Here, we examined CCR6+CXCR3+ T cells from healthy individuals, and found that ex vivo those cells expressed higher levels of IL12Rβ2 and IL23R compared to Th17 and Th1 cells and displayed an enhanced response to IL-12 and IL-23. Interestingly, Th17 cells cultured in the presence of IL-1β upregulated IL-12Rβ2, and IL-1β together with IL-12 induced IL-17+ IFN-γ+ cells and strongly increased the expression of T-bet, IL-12Rβ2 and IL-23R without inhibiting RORγt. CCR6+CXCR3+ T cells shared antigen specificities with Th17 and Th1 cells, and T cells specific for extracellular bacteria such as S. pneumoniae, E. coli and L. rhamnosus were highly enriched in this subset. Furthermore, a significant proportion of CCR6+CXCR3+ T cells expressed the gut-homing molecule α4β7. Thus, CCR6+CXCR3+ CD4+ T cells are a functionally distinct population of T cells with broad antigen specificity and migratory potential that can develop from “classic” Th17 cells under the influence of IL-1β and IL-12. Further characterization of these cells will reveal new insights into CD4+ T cell differentiation and function in infection and autoimmunity.