title: A regulatory CD4+ T cell subset in the BB rat model of autoimmune diabetes expresses neither CD25 nor Foxp3.
abstract: 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.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Jan-Luuk
authors.initials: JL
authors.lastname: Hillebrands
authors.forename: Barbara
authors.initials: B
authors.lastname: Whalen
authors.forename: Jeroen T J
authors.initials: JT
authors.lastname: Visser
authors.forename: Jasper
authors.initials: J
authors.lastname: Koning
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bishop
authors.forename: Jean
authors.initials: J
authors.lastname: Leif
authors.forename: Jan
authors.initials: J
authors.lastname: Rozing
authors.forename: John P
authors.initials: JP
authors.lastname: Mordes
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.forename: Aldo A
authors.initials: AA
authors.lastname: Rossini
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D051381:Rats; D011913:Rats, Inbred BB; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D053645:Interleukin-2 Receptor alpha Subunit; D017493:Leukocyte Common Antigens; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1