I-A(g7)-mediated antigen presentation by B lymphocytes is critical in overcoming a checkpoint in T cell tolerance to islet β cells of nonobese diabetic mice

Hooman Noorchashm, Yen K. Lieu, Negin Noorchashm, Susan Y. Rostami, Siri Atma S. Greeley, Alexander Schlachterman, Howard K. Song, Lauren E. Noto, Anthony M. Jevnikar, Clyde F. Barker, Ali Naji

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    175 Scopus citations

    Abstract

    B cell-deficient nonobese diabetic (NOD) mice are protected from the development of spontaneous autoimmune diabetes, suggesting a requisite role for Ag presentation by B lymphocytes for the activation of a diabetogenic T cell repertoire. This study specifically examines the importance of B cell- mediated MHC class II Ag presentation as a regulator of peripheral T cell tolerance to islet β cells. We describe the construction of NOD mice with an I-A(g7) deficiency confined to the B cell compartment. Analysis of these mice, termed NOD B(CHD), revealed the presence of functionally competent non- B cell APCs (macrophages/dendritic cells) with normal I-A(g7) expression and capable of activating Ag-reactive T cells. In addition, the secondary lymphoid organs of these mice harbored phenotypically normal CD4+ and CD8+ T cell compartments. Interestingly, whereas control NOD mice harboring I- A(g7)-sufficient B cells developed diabetes spontaneously, NOD B(CHD) mice were resistant to the development of autoimmune diabetes. Despite their diabetes resistance, histologic examination of pancreata from NOD B(CHD) mice revealed foci of noninvasive peri-insulitis that could be intentionally converted into a destructive process upon treatment with cyclophosphamide. We conclude that I-A(g7)-mediated Ag presentation by B cells serves to overcome a checkpoint in T cell tolerance to islet β cells after their initial targeting has occurred. Overall, this work indicates that the full expression of the autoimmune potential of anti-islet T cells in NOD mice is intimately regulated by B cell-mediated MHC class II Ag presentation.

    Original languageEnglish (US)
    Pages (from-to)743-750
    Number of pages8
    JournalJournal of Immunology
    Volume163
    Issue number2
    StatePublished - Jul 15 1999

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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    Noorchashm, H., Lieu, Y. K., Noorchashm, N., Rostami, S. Y., Greeley, S. A. S., Schlachterman, A., Song, H. K., Noto, L. E., Jevnikar, A. M., Barker, C. F., & Naji, A. (1999). I-A(g7)-mediated antigen presentation by B lymphocytes is critical in overcoming a checkpoint in T cell tolerance to islet β cells of nonobese diabetic mice. Journal of Immunology, 163(2), 743-750.