A regulatory CD4+ T cell subset in the BB rat model of autoimmune diabetes expresses neither CD25 nor Foxp3

Jan Luuk Hillebrands, Barbara Whalen, Jeroen T.J. Visser, Jasper Koning, Kenneth D. Bishop, Jean Leif, Jan Rozing, John P. Mordes, Dale L. Greiner, Aldo A. Rossini

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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-β 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.

Original languageEnglish
Pages (from-to)7820-7832
Number of pages13
JournalJournal of Immunology
Issue number11
Publication statusPublished - 1 Dec 2006
Externally publishedYes

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