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A Central Role for Induced Regulatory T Cells in Tolerance Induction in Experimental Colitis¹

Dipica Haribhai^2,*, Wen Lin^2,, Brandon Edwards^*, Jennifer Ziegelbauer^*, Nita H. Salzman, Marc R. Carlson^¶, Shun-Hwa Li, Pippa M. Simpson, Talal A. Chatila^3, and Calvin B. Williams^3,*

^* Section of Rheumatology, Department of Pediatrics, Section of Gastroenterology, Department of Pediatrics, and Section of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226; Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and ^¶ Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

In addition to thymus-derived or natural T regulatory (nT_reg) cells, a second subset of induced T regulatory (iT_reg) cells arises de novo from conventional CD4⁺ T cells in the periphery. The function of iT_reg cells in tolerance was examined in a CD45RB^highCD4⁺ T cell transfer model of colitis. In situ-generated iT_reg cells were similar to nT_reg cells in their capacity to suppress T cell proliferation in vitro and their absence in vivo accelerated bowel disease. Treatment with nT_reg cells resolved the colitis, but only when iT_reg cells were also present. Although iT_reg cells required Foxp3 for suppressive activity and phenotypic stability, their gene expression profile was distinct from the established nT_reg "genetic signature," indicative of developmental and possibly mechanistic differences. These results identified a functional role for iT_reg cells in vivo and demonstrated that both iT_reg and nT_reg cells can act in concert to maintain tolerance.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI47154 (to C.B.W.) and AI080002 (to T.A.C.), the D.B. and Marjorie Reinhart, Nickolett, and Montgomery Family Foundations (to C.B.W.), the Children’s Hospital of Wisconsin (to C.B.W.), and American Heart Association Grant 0525142Y (to W.L.).

² D.H. and W.L. are first co-authors.

³ Address correspondence and reprint requests to Dr. Calvin B. Williams, Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226 and Dr. Talal A. Chatila, Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, The David Geffen School of Medicine, University of California, Los Angeles, MDCC 12-430, 10833 Le Conte Avenue, Los Angeles, CA 90095-1752. E-mail addresses: cwilliam{at}mcw.edu and tchatila{at}mednet.ucla.edu

⁴ Abbreviations used in this paper: T_conv, conventional T; T_reg, regulatory T; iT_reg, induced T_reg; nT_reg, natural Treg; EGFP, enhanced GFP; RORt, retinoic acid-related orphan receptor t.

⁵ The online version of this article contains supplemental material.

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