TGF-β converts apoptotic stimuli into the signal for Th9 differentiation

• Published in: The Journal of immunology (1950) Vol. 188; no. 9; pp. 4369 - 4375
• Main Authors: Takami, Mariko, Love, Robert B, Iwashima, Makio
• Format: Journal Article
• Language: English
• Published: United States 01.05.2012
• Subjects: Animals; Apoptosis - genetics; Apoptosis - immunology; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - immunology; Bcl-2-Like Protein 11; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Survival - genetics; Cell Survival - immunology; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Interleukin-6 - genetics; Interleukin-6 - immunology; Interleukin-9 - genetics; Interleukin-9 - immunology; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Mice, Transgenic; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - immunology; Signal Transduction - genetics; Signal Transduction - immunology; T-Lymphocytes, Helper-Inducer - immunology; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1102698

Naturally arising CD4(+)CD25(+)FoxP3(+) regulatory T cells (nTregs) have an essential role in maintenance of immune homeostasis and peripheral tolerance. Previously, we reported that conventional CD4(+) and CD8(+) T cells undergo p53-induced CD28-dependent apoptosis (PICA) when stimulated with a combination of immobilized anti-CD3 and anti-CD28 Abs, whereas nTregs expand robustly under the same conditions, suggesting that there is a differential survival mechanism against PICA between conventional T cells and nTregs. In this study, we demonstrate that TGF-β signaling is required for nTregs to survive PICA. Conversely, when an active form of exogenous TGF-β is present, conventional T cells become resistant to PICA and undergo robust expansion instead of apoptosis, with reduction of the proapoptotic protein Bim and FoxO3a. A substantial fraction of PICA-resistant T cells expressed IL-9 (T(H)9 cells). Moreover, the presence of IL-6 along with TGF-β led to the generation of T(H)17 cells from conventional T cells. Together, the data demonstrate a novel role for TGF-β in the homeostasis of regulatory T cells and effector T cell differentiation and expansion.