Journal Article

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

Leonard, Warren J., Lin, Jian-Xin, Ge, Meili, Andresson, Thorkell, Yu, Zu-Xi, Li, Peng, Holewinski, Ronald, Gebregiorgis, Tesfay, Spolski, Rosanne, Liu, Cheng-yu

2024

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 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