Tyk2-signaling plays an important role in host defense against Escherichia coli through IL-23-induced IL-17 production by gammadelta 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 gammadelta 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 gammadelta T cells using Tyk2 deficient (-/-) mice. Gammadelta 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, gammadelta T cells in Tyk2(-/-) mice produced less amount of IL-17 in response to IL-23 in vitro than those in Tyk2(+/+) mice. Similarly, gammadelta 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 neutrophils and severely impaired bacterial clearance after Escherichia coli infection. These results indicate that Tyk2-signaling is critical for IL-23-induced IL-17 production by gammadelta T cells, which is involved in the first line of host defense by controlling neutrophil-mediated immune responses.
Nakamura
Risa
R
Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Shibata
Kensuke
K
Yamada
Hisakata
H
Shimoda
Kazuya
K
Nakayama
Keiichi
K
Yoshikai
Yasunobu
Y
D000818:Animals; D004926:Escherichia coli / Q000276:immunology*; D004927:Escherichia coli Infections / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D053759:Interleukin-23 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010529:Peritoneal Cavity; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D053634:TYK2 Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D020381:Interleukin-17; D053759:Interleukin-23; D016692:Receptors, Antigen, T-Cell, gamma-delta; D053634:TYK2 Kinase