title: Dendritic cell-directed CTLA-4 engagement during pancreatic beta cell antigen presentation delays type 1 diabetes.
abstract: The levels of expression of alternatively spliced variants of CTLA-4 and insufficient CTLA-4 signaling have been implicated in type 1 diabetes. Hence, we hypothesized that increasing CTLA-4-specific ligand strength on autoantigen-presenting dendritic cells (DCs) can enhance ligation of CTLA-4 on T cells and lead to modulation of autoreactive T cell response. In this study, we show that DC-directed enhanced CTLA-4 engagement upon pancreatic beta cell Ag presentation results in the suppression of autoreactive T cell response in NOD mice. The T cells from prediabetic NOD mice treated with an agonistic anti-CTLA-4 Ab-coated DC (anti-CTLA-4-Ab DC) showed significantly less proliferative response and enhanced IL-10 and TGF-beta1 production upon exposure to beta cell Ags. Furthermore, these mice showed increased frequency of Foxp3+ and IL-10+ T cells, less severe insulitis, and a significant delay in the onset of hyperglycemia compared with mice treated with control Ab-coated DCs. Further analyses showed that diabetogenic T cell function was modulated primarily through the induction of Foxp3 and IL-10 expression upon Ag presentation by anti-CTLA-4-Ab DCs. The induction of Foxp3 and IL-10 expression appeared to be a consequence of increased TGF-beta1 production by T cells activated using anti-CTLA-4-Ab DCs, and this effect could be enhanced by the addition of exogenous IL-2 or TGF-beta1. Collectively, this study demonstrates the potential of a DC-directed CTLA-4 engagement approach not only in treating autoimmunity in type 1 diabetes, but also in altering diabetogenic T cell function ex vivo for therapy.
authors.affiliation: Department of Surgery, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Subha
authors.initials: S
authors.lastname: Karumuthil-Melethil
authors.forename: Nicolas
authors.initials: N
authors.lastname: Perez
authors.forename: Ruobing
authors.initials: R
authors.lastname: Li
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Holterman
authors.forename: Chenthamarakshan
authors.initials: C
authors.lastname: Vasu
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines