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

SummaryCytokine-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.

► Spacing between nonconsensus GAS motifs is critical for STAT5 tetrameric binding ► STAT5 tetramers regulate the expression of a subset of cytokine-induced genes ► Cytokine-induced and homeostatic CD8 T cell proliferation require STAT tetramers ► STAT5 tetramers are critical for normal Treg cell function in vivo