IL-1β Promotes the Differentiation of Polyfunctional Human CCR6+CXCR3+ Th1/17 Cells That Are Specific for Pathogenic and Commensal Microbes

In humans, Th1/17 cells, identified by coexpression of the chemokine receptors CCR6 and CXCR3, are proposed to be highly pathogenic in several autoimmune disorders due in part to their expression of the proinflammatory cytokines IL-17, IFN-gamma, and GM-CSF. However, their developmental requirements, relationship with classic Th17 and Th1 cells and physiological role in normal immune responses are not well understood. In this study, we examined CCR6(+)CXCR3(+) Th1/17 cells from healthy individuals and found that ex vivo these cells produced the effector cytokines IL-17, IL-22, and IFN-gamma in all possible combinations and were highly responsive to both IL-12 and IL-23. Moreover, although the Ag specificity of CCR6(+)CXCR3(+) Th1/17 cells showed substantial overlap with that of Th1 and Th17 cells, this population was enriched in cells recognizing certain extracellular bacteria and expressing the intestinal homing receptor integrin beta(7). Finally, we identified IL-1 beta as a key cytokine that renders Th17 cells sensitive to IL-12, and both cytokines together potently induced the differentiation of cells that produce IL-17, IFN-gamma, and GMCSF. Therefore, interfering with IL-1 beta and IL-12 signaling in Th17 cells during inflammation may be a promising therapeutic approach to reduce their differentiation into pathogenic CCR6(+)CXCR3(+) Th1/17 cells in patients with autoimmune diseases.