Foxo proteins cooperatively control the differentiation of Foxp3⁺ regulatory T cells

Ouyang W., et al. 2010. Nat Immunol. 11, 618-27.

Speaker: Wan-Chen Chung (鍾宛臻)                            Time: 13:10~14:00, Nov. 10, 2010

Commentator: Dr. Huan-Yao Lei (黎煥耀 老師)   Place: Room 601

Abstract:

CD4^＋CD25^＋regulatory T cells ( Tregs ) are indispensable in maintaining self tolerance and immune homeostasis. They have been characterized by expression of the forkhead-box transcription factor Foxp3. Deficiencies in Foxp3 result in impaired CD4^＋CD25^＋Treg cells development, causing a fatal lymphoproliferative disorder in scurfy mice and are associated with immunodysregulation, polyendocrinopathy, enteropathy and X-linked  ( IPEX ) syndrome in human patients. Foxo proteins (Foxo1, Foxo3, Foxo4, and Foxo6) are mammalian orthologs of the Caenorhabditiselegans transcription factor DAF-16, which play critical roles in multiple biological processes, including development, metabolism, aging and cancer. Previously studies have shown that Foxo1 not only regulates T-cell trafficking and survival but is also critical for T-cell population of the peripheral lymphoid organs, and Foxo1 deficiency causes a mild autoimmune disease in mice. Foxo3 enforces T cell tolerance and quiescence by inhibiting spontaneous T cell activation. In this report, the authors use T cell-specific Foxo1,Foxo3 deletion mice to investigate the functions of Foxoproteins in immunological tolerance. They found that double Foxo protein deletion developed a lethal systemic inflammatory disease associated with expanding, activated and differentiated CD4^＋T cells in mice. In mixed-bone marrow chimeras experiment, thymic Foxo1^-/-Foxo3^-/- Treg cells differentiation were compromised and lost the suppressive activity in controlling inflammatory disorder caused by cell transfer from scurfy mice. The authors also found that Foxo1 and Foxo3 bound to the Foxp3 promoter and regulate Foxp3 mRNA expression. In conclusion, the authors identified a critical role for Foxo proteins in regulate Foxp3 expression and thymic Treg cell differentiation. Manipulation of the Foxo pathway may provide new therapeutic strategies for Treg cell–regulated immunological disorders.

References:

1.          Ouyang W., et al. An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity.30, 358–371 (2009).

2.          H. Jonsson and S. L. Peng. Forkhead transcription factors in immunology. Cell. Mol. Life Sci. 62, 397–409 (2005).