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Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function.

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.

Pubmed ID: 22520852

Authors

  • Lin JX
  • Li P
  • Liu D
  • Jin HT
  • He J
  • Ata Ur Rasheed M
  • Rochman Y
  • Wang L
  • Cui K
  • Liu C
  • Kelsall BL
  • Ahmed R
  • Leonard WJ

Journal

Immunity

Publication Data

April 20, 2012

Associated Grants

  • Agency: Intramural NIH HHS, Id: Z99 HL999999

Mesh Terms

  • Animals
  • Binding Sites
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Cell Proliferation
  • Cell Survival
  • Colitis
  • Cytokines
  • DNA-Binding Proteins
  • Gene Knock-In Techniques
  • Interleukin-2 Receptor alpha Subunit
  • Killer Cells, Natural
  • Lymphocyte Activation
  • Lymphocytic choriomeningitis virus
  • Mice
  • Mice, Transgenic
  • Protein Multimerization
  • STAT5 Transcription Factor
  • Signal Transduction