Linked T Cell Receptor and Cytokine Signaling Govern the Development of the Regulatory T Cell Repertoire

• Published in: Immunity (Cambridge, Mass.) Mass.), 2008-01, Vol.28 (1), p.112-121
• Main Authors: Burchill, Matthew A., Yang, Jianying, Vang, Kieng B., Moon, James J., Chu, H. Hamlet, Lio, Chan-Wang J., Vegoe, Amanda L., Hsieh, Chyi-Song, Jenkins, Marc K., Farrar, Michael A.
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Blotting, Western; CD28 Antigens - immunology; CD28 Antigens - metabolism; Cell Differentiation - immunology; Cell Lineage - immunology; CELLIMMUNO; Cytokines - biosynthesis; Flow Cytometry; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Immune system; Infrared imaging systems; Lymphocytes; Mice; Mice, Transgenic; MOLIMMUNO; Phosphorylation; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Rodents; Self Tolerance - immunology; Sequence Analysis; Signal Transduction - immunology; STAT5 Transcription Factor - immunology; STAT5 Transcription Factor - metabolism; T cell receptors; T-Lymphocytes, Regulatory - cytology; Transcription factors
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2007.11.022

Appropriate development of regulatory T (Treg) cells is necessary to prevent autoimmunity. Neonatal mice, unlike adults, lack factors required for Treg cell development. It is unclear what these missing factors are. However, signals emanating from the T cell receptor (TCR), the costimulatory receptor CD28, and the family of γc-dependent cytokine receptors are required for Treg cell development. Herein we demonstrate that expression of a constitutively active Stat5b transgene ( Stat5b-CA) allowed for Treg cell development in neonatal mice and restored Treg cell numbers in Cd28 −/− mice. Sequence analysis of TCR genes in Stat5b-CA Treg cells indicated that ectopic STAT5 activation resulted in a TCR repertoire that more closely resembled that of naive T cells. Using MHCII tetramers to identify antigen-specific T cells, we showed that STAT5 signals diverted thymocytes normally destined to become naive T cells into the Treg cell lineage. Our data support a two-step model of Treg cell differentiation in which TCR and CD28 signals induce cytokine responsiveness and STAT5-inducing cytokines then complete the program of Treg cell differentiation.