Institute for Frontier Life and Medical Sciences, Kyoto University

Competition between STAT5 and phosphatidylinositol 3-kinase under IL-7 receptor signaling modulates T cell development and homeostasis

Guangwei Cui1, Akihiro Shimba1,2, Guangyong Ma3, Kazuhiko Takahara4, Shizue Tani-ichi1,2, Yuanbo Zhu1,2, Takuma Asahi1,2, Akifumi Abe1, Hitoshi Miyachi5, Satsuki Kitano5, Takahiro Hara1, Jun-ichirou Yasunaga3,6, Hirotsugu Suwanai7, Hisakata Yamada8, Masao Matsuoka3,6, Kohjiro Ueki9, Yasunobu Yoshikai8, and Koichi Ikuta1

(1Laboratory of Immune Regulation, Institute for Frontier Life and Medical Sciences, Kyoto University; 2Graduate School of Medicine, Kyoto University; 3Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University; 4Graduate School of Biostudies, Kyoto University; 5Reproductive Engineering Team, Institute for Frontier Life and Medical Sciences, Kyoto University; 6Faculty of Life Sciences, Kumamoto University; 7Tokyo Medical University Hospital; 8Medical Institute of Bioregulation, Kyushu University; 9National Center for Global Health and Medicine)

“IL-7R-dependent phosphatidylinositol 3-kinase competes with the STAT5 signal to modulate T cell development and homeostasis”

Journal of Immunology (2020) 204: 844-857. doi: 10.4049/jimmunol.1900456

Abstract

IL-7 is a cytokine essential for immune development and homeostasis. STAT5 and PI3K are two major signal molecules of the IL-7 receptor (IL-7R) involved in these processes. The tyrosine residue Y449 of IL-7Rα is essential for interaction and activation of both STAT5 and PI3K, while the methionine residue M452 is additionally required for PI3K recruitment. Nevertheless, how STAT5 and PI3K signals are precisely contributed under the IL-7R has not been well understood. To characterize the differential roles of these signals in vivo, we established two lines of IL-7Rα mutant mice, IL7R-Y449F and IL7R-M452L. Interestingly, the levels of phosphorylated STAT5 were downregulated in Y449F mice but significantly upregulated in M452L mice, whereas the levels of phosphorylated Akt were reduced in both Y449F and M452L mice. The Y449F mice showed markedly decreased T cells in thymus and periphery because of the poor survival and proliferative dysfunction. In contrast, only early T progenitors (ETP) and DN2 thymocytes were reduced in the M452L mice, due to the reduction of TCF-1 expression. In addition, development of Th17 cells and memory CD8 T cell was impaired in M452L mice. Thus, our study suggests that the competition between STAT5 and PI3K for the Y449 of IL-7Rα is important for the development and homeostasis of T cells in vivo.

 

Figure. IL-7R-dependent phosphatidylinositol 3-kinase competes with the STAT5 signal to modulate T cell development and homeostasis