Essential Role for STAT5 Signaling in CD25+CD4+ Regulatory T Cell Homeostasis and the Maintenance of Self-Tolerance

• Published in: The Journal of immunology (1950) Vol. 171; no. 7; pp. 3435 - 3441
• Main Authors: Antov, Andrey, Yang, Lili, Vig, Monika, Baltimore, David, Van Parijs, Luk
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.10.2003
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Homeostasis - genetics; Homeostasis - immunology; Interleukin-2 - deficiency; Interleukin-2 - genetics; Interleukin-2 - physiology; Lymphocyte Count; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Milk Proteins; Proto-Oncogene Proteins c-bcl-2 - deficiency; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - physiology; Receptors, Interleukin-2 - biosynthesis; Self Tolerance - genetics; Self Tolerance - immunology; Signal Transduction - genetics; Signal Transduction - immunology; STAT5 Transcription Factor; Trans-Activators - deficiency; Trans-Activators - genetics; Trans-Activators - metabolism; Trans-Activators - physiology; Up-Regulation - genetics; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.7.3435

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.