Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance.
A population of CD25(+)CD4(+) regulatory T cells (T regs) functions to maintain immunological self tolerance by inhibiting autoreactive T cell responses. CD25(+)CD4(+) T regs are present in low, but steady, numbers in the peripheral lymphoid tissues of healthy mice. Recent studies have shown that IL-2 is an essential growth factor for these cells. How this cytokine functions to regulate CD25(+)CD4(+) T reg homeostasis and prevent autoimmune disease remains unknown. In conventional CD4(+) T cells, IL-2 triggers signaling pathways that promote proliferation and survival by activating the STAT5 transcription factor and by increasing the expression of the antiapoptotic protein, Bcl-2. We show here that bcl-2 deficiency does not affect CD25(+)CD4(+) T reg homeostasis, and that ectopic expression of this molecule fails to rescue CD25(+)CD4(+) T reg numbers or to prevent the development of autoimmunity in IL-2-deficient mice. Furthermore, transient activation of STAT5 is sufficient to increase CD25(+)CD4(+) T reg numbers in IL-2-deficient mice. Our study uncovers an essential role for STAT5 in maintaining CD25(+)CD4(+) T reg homeostasis and self-tolerance.
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D007376:Interleukin-2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008894:Milk Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D050799:STAT5 Transcription Factor; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D015534:Trans-Activators