title: Low CD86 expression in the nonobese diabetic mouse results in the impairment of both T cell activation and CTLA-4 up-regulation.
abstract: The nonobese diabetic (NOD) mouse spontaneously develops autoimmune insulin-dependent diabetes mellitus and serves as a model for human type I diabetes. NOD spleen cells proliferate to a lesser extent than those from C57BL/6 and BALB/c mice in response to anti-CD3. To investigate the cause of this reduced T cell proliferation, costimulatory molecule expression was investigated. It was found that NOD macrophages, dendritic cells, and T cells, but not B cells, expressed lower basal levels of CD86, but not CD80, CD28, or CD40, compared with C57BL/6 and BALB/c. This low CD86 expression was not dependent on the MHC haplotype or on diabetes development since the NOD-related, diabetes-free mouse strains NON (H-2nb1) and NOR (H-2g7) exhibited similar low levels of CD86 expression and proliferation. Furthermore, following activation, the relative up-regulation of CTLA-4, as compared with CD28, was more pronounced on C57BL/6 and BALB/c T cells as shown by an increased CTLA-4/CD28 ratio. This activation-induced increase in the CTLA-4/CD28 ratio was markedly reduced on NOD T cells compared with the other two strains. The low CD86 expression in NOD mice may account for the reduced increase in both proliferation and the CTLA-4/CD28 ratio, since reducing CD86 expression in C57BL/6 and BALB/c cultures to NOD levels significantly reduces the proliferation and the CTLA-4/CD28 ratio. Therefore, we propose that a low level of CD86 expression in the NOD mouse contributes to a defective regulation of autoreactive T cells by preventing the full activation of T cells and therefore the up-regulation of CTLA-4.
authors.affiliation: Active Biotech Research AB, Lund, Sweden. eva.dahlen@activebiotech.com
authors.forename: E
authors.initials: E
authors.lastname: Dahlén
authors.forename: G
authors.initials: G
authors.lastname: Hedlund
authors.forename: K
authors.initials: K
authors.lastname: Dawe
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis* / Q000494:pharmacology / Q000502:physiology; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000096:biosynthesis; D017252:CD3 Complex / Q000276:immunology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D005260:Female; D018796:Immunoconjugates; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D051940:B7-2 Antigen; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D000069594:Abatacept