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

Matthew A. Burchill, Jianying Yang, Kieng B. Vang, James J. Moon, H. Hamlet Chu, Chan Wang J. Lio, Amanda L. Vegoe, Chyi Song Hsieh, Marc K. Jenkins, Michael A. Farrar

Research output: Contribution to journalArticlepeer-review

332 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)112-121
Number of pages10
Issue number1
StatePublished - Jan 18 2008

Bibliographical note

Funding Information:
We thank Rachel Agneberg, Jessica Oehrlein, and Jared Liebelt for assistance with animal husbandry; Paul Champoux for assistance with flow cytometry; and Dan Mueller, Laura Ramsey, and Lynn Heltemes-Harris for review of the manuscript. This work was supported by a Pew Scholar Award, a Cancer Investigator Award, a Leukemia and Lymphoma Society Scholar award, and a National Institutes of Health grant (AI061165) to M.A.F.




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