Tyk2-signaling plays an important role in host defense against Escherichia coli through IL-23-induced IL-17 production by γδ T cells

Tyrosine kinase 2 (Tyk2), a member of the JAK-signal transducer family, is involved in intracellular signaling triggered by various cytokines, including IL-23. We have recently reported that resident gamma delta T cells in the peritoneal cavity of naive mice produced IL-17 in response to IL-23. In this study, we examined importance of Tyk2-mediated signaling in the IL-17 production by gamma delta T cells using Tyk2 deficient (-/-) mice. gamma delta T cells in the peritoneal cavity of Tyk2(-/-) mice displayed effecter/memory phenotypes and TCR V repertoire similar to those in Tyk2(+/+) mice and produced comparable level of IL-17 to those in Tyk2(+/+) mice in response to PMA and ionomycin, indicating normal differentiation to IL-17-producing effectors in the absence of Tyk2-signaling. However, gamma delta T cells in Tyk2(-/-) mice produced less amount of IL-17 in response to IL-23 in vitro than those in Tyk2(+/+) mice. Similarly, gamma delta T cells in the peritoneal cavity of Tyk2(-/-) mice showed severely impaired IL-17 production after an i.p. infection with E. coli despite comparable level of IL-23 production to Tyk2(+/+) mice. As a consequence, Tyk2(-/-) mice showed a reduced infiltration of nentrophils and severely impaired bacteria] clearance after Escherichia coli infection. These results indicate that Tyk2-signaling is critical for IL-23-induced IL-17 production by gamma delta T cells, which is involved in the first line of host defense by controlling neutrophil-mediated immune responses.