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* Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655;
Department of Cell Biology, Section Immunology, University of Groningen Medical Center, University of Groningen, Groningen, The Netherlands; and
Program in Immunology and Virology, and
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655
Biobreeding (BB) rats model type 1 autoimmune diabetes (T1D). BB diabetes-prone (BBDP) rats develop T1D spontaneously. BB diabetes-resistant (BBDR) rats develop T1D after immunological perturbations that include regulatory T cell (Treg) depletion plus administration of low doses of a TLR ligand, polyinosinic-polycytidylic acid. Using both models, we analyzed CD4+CD25+ and CD4+CD45RC– candidate rat Treg populations. In BBDR and control Wistar Furth rats, CD25+ T cells comprised 5–8% of CD4+ T cells. In vitro, rat CD4+CD25+ T cells were hyporesponsive and suppressed T cell proliferation in the absence of TGF-
and IL-10, suggesting that they are natural Tregs. In contrast, CD4+CD45RC– T cells proliferated in vitro in response to mitogen and were not suppressive. Adoptive transfer of purified CD4+CD25+ BBDR T cells to prediabetic BBDP rats prevented diabetes in 80% of recipients. Surprisingly, CD4+CD45RC–CD25– T cells were equally protective. Quantitative studies in an adoptive cotransfer model confirmed the protective capability of both cell populations, but the latter was less potent on a per cell basis. The disease-suppressing CD4+CD45RC–CD25– population expressed PD-1 but not Foxp3, which was confined to CD4+CD25+ cells. We conclude that CD4+CD25+ cells in the BBDR rat act in vitro and in vivo as natural Tregs. In addition, another population that is CD4+CD45RC–CD25– also participates in the regulation of autoimmune diabetes.
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1 This work was supported in part by National Institutes of Health Grants DK49106, DK36024, DK25306, and a Diabetes Endocrinology Center Research Grant DK32520 to the University of Massachusetts Medical School from the National Institutes of Health. J.-L.H. was supported by the Ter Meulen Fund, Royal Netherlands Academy of Arts and Sciences (project no. 6419) and the Dutch Diabetes Foundation (project no. 2001.05.003). J.T.J.V. was supported by the Dutch Diabetes Foundation (project no. 2005.00.024). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
2 Current address: Department of Cell Biology, Section Immunology, University Medical Center Groningen, University of Groningen, NL9713AV Groningen, The Netherlands.
3 Address correspondence and reprint requests to Dr. Dale L. Greiner, Diabetes Division, University of Massachusetts Medical School, 373 Plantation Street, Suite 218, Worcester, MA 01605. E-mail address: dale.greiner{at}umassmed.edu
4 Abbreviations used in this paper: BB, biobreeding; BBDP, BB diabetes prone; BBDR, BB diabetes resistant; WF; Wistar Furth; T1D, type 1 diabetes; Treg, regulatory T cell; poly(I:C), polyinosinic:polycytidylic acid; GITR, glucocorticoid-induced TNF receptor; LN, lymph node; MLN, mesenteric LN; CLN, cervical LN; PLN, pancreatic LN; Egr-2, early growth response 2; PD-1, programmed death-1; HPRT, hypoxanthine phosphoribosyltransferase; int, intermediate.
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