Type 1 regulatory T (TR1) cells are Foxp3− interleukin-10 (IL-10)–producing CD4+ T cells with potent immunosuppressive properties, but their requirements for lineage development have remained elusive. We show that TR1 cells constitute the most abundant regulatory population after allogeneic bone marrow transplantation (BMT), express the transcription factor Eomesodermin (Eomes), and are critical for the prevention of graft-versus-host disease. We demonstrate that Eomes is required for TR1 cell differentiation, during which it acts in concert with the transcription factor B lymphocyte–induced maturation protein-1 (Blimp-1) by transcriptionally activating IL-10 expression and repressing differentiation into other T helper cell lineages. We further show that Eomes induction in TR1 cells requires T-bet and donor macrophage–derived IL-27. Thus, we define the cellular and transcriptional control of TR1 cell differentiation during BMT, opening new avenues to therapeutic manipulation.
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We thank P. Hall, M. Rist, and G. Chojnowski for expert cell sorting and the animal facilities of QIMR Berghofer Medical Research Institute and M. Flynn for expert graphical work. This work was supported by research grants held by G.R.H. from the National Health and Medical Research Council (NHMRC; Australia). B.R.B. is supported by funds from the NIH (R01 AI34495, R01 HL56067, and AI 11879). C.R.E. is an NHMRC Senior Research Fellow. G.T.B. is an Australian Research Council Future Fellow. A.K. is a fellow of the Sylvia and Charles Viertel Foundation. M.A.D.-E. is an NHMRC Principal Research Fellow. G.R.H. is an NHMRC Senior Principal Research Fellow and a Queensland Health Senior Clinical Research Fellow.