title: Impaired CD4 T cell activation due to reliance upon B cell-mediated costimulation in nonobese diabetic (NOD) mice.
abstract: Diabetes in nonobese diabetic (NOD) mice results from the activation of I-A(g7)-restricted, islet-reactive T cells. This study delineates several characteristics of NOD CD4 T cell activation, which, independent of I-A(g7), are likely to promote a dysregulated state of peripheral T cell tolerance. NOD CD4 T cell activation was found to be resistant to antigenic stimulation via the TCR complex, using the progression of cell division as a measure. The extent of NOD CD4 T cell division was highly sensitive to changes in Ag ligand density. Moreover, even upon maximal TCR complex-mediated stimulation, NOD CD4 T cell division prematurely terminated. Maximally stimulated NOD CD4 T cells failed to achieve the threshold number of division cycles required for optimal susceptibility to activation-induced death, a critical mechanism for the regulation of peripheral T cell tolerance. Importantly, these aberrant activation characteristics were not T cell-intrinsic but resulted from reliance on B cell costimulatory function in NOD mice. Costimulation delivered by nonautoimmune strain APCs normalized NOD CD4 T cell division and the extent of activation-induced death. Thus, by disrupting the progression of CD4 T cell division, polarization of APC costimulatory function to the B cell compartment could allow the persistence and activation of diabetogenic cells in NOD mice.
authors.affiliation: Department of Surgery, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
authors.forename: H
authors.initials: H
authors.lastname: Noorchashm
authors.forename: D J
authors.initials: DJ
authors.lastname: Moore
authors.forename: L E
authors.initials: LE
authors.lastname: Noto
authors.forename: N
authors.initials: N
authors.lastname: Noorchashm
authors.forename: A J
authors.initials: AJ
authors.lastname: Reed
authors.forename: A L
authors.initials: AL
authors.lastname: Reed
authors.forename: H K
authors.initials: HK
authors.lastname: Song
authors.forename: R
authors.initials: R
authors.lastname: Mozaffari
authors.forename: A M
authors.initials: AM
authors.lastname: Jevnikar
authors.forename: C F
authors.initials: CF
authors.lastname: Barker
authors.forename: A
authors.initials: A
authors.lastname: Naji
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D017637:Clonal Deletion; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout
chemical_list: D000949:Histocompatibility Antigens Class II; D008024:Ligands