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

H. Noorchashm, D. J. Moore, L. E. Noto, N. Noorchashm, A. J. Reed, A. L. Reed, H. K. Song, R. Mozaffari, A. M. Jevnikar, C. F. Barker, A. Naji

    Research output: Contribution to journalArticle

    52 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)4685-4696
    Number of pages12
    JournalJournal of Immunology
    Volume165
    Issue number8
    DOIs
    StatePublished - Oct 15 2000

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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    Noorchashm, H., Moore, D. J., Noto, L. E., Noorchashm, N., Reed, A. J., Reed, A. L., Song, H. K., Mozaffari, R., Jevnikar, A. M., Barker, C. F., & Naji, A. (2000). Impaired CD4 T cell activation due to reliance upon B cell-mediated costimulation in nonobese diabetic (NOD) mice. Journal of Immunology, 165(8), 4685-4696. https://doi.org/10.4049/jimmunol.165.8.4685