Critical Role of STAT5 Transcription Factor Tetramerization for Cytokine Responses and Normal Immune Function

• Type of Material: Article
• Authors: Jian-Xin Lin, National Institutes of Health; Peng Li, National Institutes of Health; Hyun Tak Jin, Emory University; Jianping He, National Institutes of Health; Mohammed Rasheed, Emory University; Yrina Rochman, National Institutes of Health; Lu Wang, National Institutes of Health; Kairong Cui, National Institutes of Health; Chengyu Liu, Emory University; Brian L. Kelsall, National Institutes of Health; Rafi Ahmed, Emory University; Warren J. Leonard, National Institutes of Health
• Language: English
• Date: 2012-04-20
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.immuni.2012.02.017
• Title of Journal or Parent Work: Immunity
• ISSN: 1074-7613
• Volume: 36
• Issue: 4
• Start Page: 586
• End Page: 599
• Grant/Funding Information: This work was supported in part by the Division of Intramural Research, NHLBI, NIH, Bethesda, MD.
• Keywords: IL-2 RECEPTOR; DIMERS; T-CELLS; DIFFERENTIATION; Life Sciences & Biomedicine; Immunology; ALPHA; PROMOTER; DNA-BINDING; SEQUENCE; PROLIFERATION; GENE-EXPRESSION; Science & Technology
• Research Categories: Statistics; Health Sciences, Pathology; Health Sciences, Immunology

Abstract

Cytokine-activated STAT proteins dimerize and bind to high-affinity motifs, and N-terminal domain-mediated oligomerization of dimers allows tetramer formation and binding to low-affinity tandem motifs, but the functions of dimers versus tetramers are unknown. We generated Stat5a-Stat5b double knockin (DKI) N-domain mutant mice in which STAT5 proteins form dimers but not tetramers, identified cytokine-regulated genes whose expression required STAT5 tetramers, and defined dimer versus tetramer consensus motifs. Whereas Stat5-deficient mice exhibited perinatal lethality, DKI mice were viable; thus, STAT5 dimers were sufficient for survival. Nevertheless, STAT5 DKI mice had fewer CD4+CD25+T cells, NK cells, and CD8+T cells, with impaired cytokine-induced and homeostatic proliferation of CD8+T cells. Moreover, DKI CD8+T cell proliferation after viral infection was diminished and DKI Treg cells did not efficiently control colitis. Thus, tetramerization of STAT5 is critical for cytokine responses and normal immune function, establishing a critical role for STAT5 tetramerization in vivo.