Tyrosine phosphorylation of both STAT5A and STAT5B is necessary for maximal IL-2 signaling and T cell proliferation

• Published in: Nature communications 2024-08, Vol.15 (1), p.7372-18, Article 7372
• Main Authors: Lin, Jian-Xin, Ge, Meili, Liu, Cheng-yu, Holewinski, Ronald, Andresson, Thorkell, Yu, Zu-Xi, Gebregiorgis, Tesfay, Spolski, Rosanne, Li, Peng, Leonard, Warren J.
• Format: Article
• Language: English
• Subjects: 13/21; 45/91; 631/250/127; 631/250/1619/554; 631/337/458/1733; 631/337/641/1655; 82/58; Animals; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Cell growth; Cell Proliferation; Cyclins; Gene Knock-In Techniques; Humanities and Social Sciences; In vivo methods and tests; Interleukin 2; Interleukin 2 receptors; Interleukin Receptor Common gamma Subunit - genetics; Interleukin Receptor Common gamma Subunit - metabolism; Interleukin-2 - metabolism; Interleukin-2 Receptor beta Subunit - genetics; Interleukin-2 Receptor beta Subunit - metabolism; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; multidisciplinary; Mutants; Myc protein; Phenylalanine; Phosphorylation; Proteomics; S phase; Science; Science (multidisciplinary); Signal Transduction; Stat5 protein; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Transcriptomics; Tyrosine; Tyrosine - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50925-6

Cytokine-mediated STAT5 protein activation is vital for lymphocyte development and function. In vitro tyrosine phosphorylation of a C-terminal tyrosine is critical for activation of STAT5A and STAT5B; however, the importance of STAT5 tyrosine phosphorylation in vivo has not been assessed. Here we generate Stat5a and Stat5b tyrosine-to-phenylalanine mutant knockin mice and find they have greatly reduced CD8 + T-cell numbers and profoundly diminished IL-2-induced proliferation of these cells, and this correlates with reduced induction of Myc, pRB, a range of cyclins and CDKs, and a partial G1→S phase-transition block. These mutant CD8 + T cells also exhibit decreased IL-2-mediated activation of pERK and pAKT, which we attribute in part to diminished expression of IL-2Rβ and IL-2Rγ. Our findings thus demonstrate that tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling. Moreover, our transcriptomic and proteomic analyses elucidate the molecular basis of the IL-2-induced proliferation of CD8 + T cells. The importance of STAT5 tyrosine phosphorylation on T cells has not been investigated in vivo. Here the authors generate STAT5A and STAT5B tyrosine mutant knockin mice and show that Stat5a/b tyrosine is required for maximal IL-2 signaling and CD8 + T cell proliferation.