A regulatory CD4+ T cell subset in the BB rat model of autoimmune diabetes expresses neither CD25 nor Foxp3
Department of Medicine, Division of Diabetes; Program in Molecular Medicine; Program in Immunology and Virology
Adoptive Transfer; Animals; Antigens, CD45; Autoimmune Diseases; Cell Proliferation; Diabetes Mellitus, Type 1; Flow Cytometry; Forkhead Transcription Factors; Interleukin-2 Receptor alpha Subunit; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Rats, Inbred BB; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory
Life Sciences | Medicine and Health Sciences
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-beta 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.
DOI of Published Version
J Immunol. 2006 Dec 1;177(11):7820-32.
Journal of immunology (Baltimore, Md. : 1950)
Hillebrands, Jan-Luuk; Whalen, Barbara J.; Visser, Jeroen T. J.; Koning, Jasper; Bishop, Kenneth D.; Leif, Jean; Rozing, Jan; Mordes, John P.; Greiner, Dale L.; and Rossini, Aldo A., "A regulatory CD4+ T cell subset in the BB rat model of autoimmune diabetes expresses neither CD25 nor Foxp3" (2006). Open Access Articles. 1080.