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* Department of Surgery and
Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, IL 60612
Costimulatory ligands CD80 and CD86 have different binding preferences and affinities to their receptors, CD28 and CTLA-4. Earlier, we demonstrated that CD80 binds to CTLA-4 with higher affinity and has a role in suppressing T cell response. The current study demonstrates that not only did blockade of CD86 upon Ag presentation by bone marrow-derived dendritic cells (DC) to OVA-specific T cells result in induction of hyporesponsive T cells but also that these T cells could suppress the proliferative response of effector T cells. These T cells showed TGF-β1 on their surface and secreted TGF-β1 and IL-10 upon restimulation. Although blockade of CTLA-4 and neutralization of IL-10 profoundly inhibited the induction of these TGF-β1+ T cells, their ability to suppress the effector T cell proliferation was abrogated by neutralization of TGF-β1 alone. Induction of TGF-β1+ and IL-10+ T cells was found to be independent of natural CD4+CD25+ regulatory T cells, demonstrating that preferential ligation of CTLA-4 by CD80 induced IL-10 production by effector T cells, which in turn promoted the secretion of TGF-β1. Treatment of prediabetic NOD mice with islet β cell Ag-pulsed CD86–/– DCs, but not CD80–/– DCs, resulted in the induction of TGF-β1- and IL-10-producing cells, significant suppression of insulitis, and delay of the onset of hyperglycemia. These observations demonstrate not only that CD80 preferentially binds to CTLA-4 but also that interaction during Ag presentation can result in IL-10-dependent TGF-β1+ regulatory T cell induction, reinstating the potential of approaches to preferentially engage CTLA-4 through CD80 during self-Ag presentation in suppressing autoimmunity.
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1 This work was supported by National Institutes of Health Grant R21 AI069848 and Juvenile Diabetes Research Foundation Regular Grant 1-2005-27 (to C.V.), National Institutes of Health Grant KO8 AI001821 (to M.J.H.), and National Institutes of Health Grant RO1 AI058190 (to B.S.P.).
2 Address correspondence and reprint requests to Dr. Chenthamarakshan Vasu, Department of Surgery, University of Illinois, 909 South Wolcott, College of Medical Research Building Room 7113 MC 790, Chicago, IL 60612. E-mail address: chenta{at}uic.edu
3 Abbreviations used in this paper: Treg, regulatory T cell; DC, dendritic cell; BM, bone marrow; BMDC, BM-derived DC; T1D, type 1 diabetes; TCR-Tg, TCR transgenic; PD-L1, programmed death-1 ligand 1.
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