Impaired CD4 T cell activation due to reliance upon B cell-mediated costimulation in nonobese diabetic (NOD) mice.

Noorchashm H, Moore DJ, Noto LE, Noorchashm N, Reed AJ, Reed AL, Song HK, Mozaffari R, Jevnikar AM, Barker CF, Naji A
J Immunol. 2000 165 (8): 4685-96

PMID: 11035112 · DOI:10.4049/jimmunol.165.8.4685

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.

MeSH Terms (20)

Animals Antigen-Presenting Cells B-Lymphocytes CD4-Positive T-Lymphocytes Cell Communication Cell Death Cell Division Cells, Cultured Clonal Deletion Diabetes Mellitus, Type 1 Histocompatibility Antigens Class II Ligands Lymphocyte Activation Lymphocyte Depletion Mice Mice, Congenic Mice, Inbred BALB C Mice, Inbred C57BL Mice, Inbred NOD Mice, Knockout

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