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Tyk2 Signaling in Host Environment Plays an Important Role in Contraction of Antigen-Specific CD8⁺ T Cells following a Microbial Infection¹

Wei Li^*, Hisakata Yamada^*, Toshiki Yajima^*, Ryusuke Nakagawa^*, Kazuya Shimoda, Keiichi Nakayama and Yasunobu Yoshikai^2,*

^* Division of Host Defense and Digital Medicine Initiative, Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, and First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan

Tyrosine kinase 2 (Tyk2), a member of JAK signal transducer family contributes to the signals triggered by IL-12 for IFN- production. To elucidate potential roles of Tyk2 in generation and maintenance of Ag-specific CD8⁺ T cells, we followed the fate of OVA-specific CD8⁺ T cells in Tyk2-deficient (–/–) mice after infection with recombinant Listeria monocytogenes expressing OVA (rLM-OVA). Results showed that the numbers of OVA_257–264/K^b tetramer-positive CD8⁺ T cells in Tyk2^–/– mice were almost the same as those in Tyk2^+/+ mice at the expansion phase on day 7 but were significantly larger in Tyk2^–/– mice than those in Tyk2^+/+ mice at the contraction phase on day 10 and at the memory phase on day 60 after infection. The intracellular expression level of active caspase-3 was significantly decreased in the OVA-specific CD8⁺ T cells of Tyk2^–/– mice on day 7 compared with those of Tyk2^+/+ mice. Adaptive transfer experiments revealed that Tyk2 signaling in other factors rather than CD8⁺ T cells played a regulatory role in CD8⁺ T cell contraction following infection. Administration of exogenous IFN- from day 6 to day 9 restored the CD8⁺ T cell contraction in Tyk2^–/– mice after infection with rLM-OVA. These results suggest that Tyk2 signaling for IFN- production in host environment plays an important role in contraction of effector CD8⁺ T cells following a microbial infection.

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¹ This work was supported in by the Program of Founding Research Centers for Emerging and Reemerging Infectious Diseases was launched as a project commissioned by the Ministry of Education, Culture, Sports, Science and Technology, Japan by a grant-in-aid for Japan Society for Promotion of Science, and grants from the Japanese Ministry of Education, Science and Culture (to Y.Y.).

² Address correspondence and reprint requests to Dr. Yasunobu Yoshikai, Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan. E-mail address: yoshikai{at}bioreg.kyushu-u.ac.jp

³ Abbreviations used in this paper: Tyk2, tyrosine kinase 2; ACAD, activated T cell autonomous cell death; rLM-OVA, recombinant Listeria monocytogenes expressing OVA; PEC, peritoneal exudate cells.

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