B Lymphocytes Are Critical Antigen-Presenting Cells for the Initiation of T Cell-Mediated Autoimmune Diabetes in Nonobese Diabetic Mice

Abstract

AbstractNonobese diabetic (NOD) mice genetically deficient in B lymphocytes (NOD.Igμnull) are resistant to T cell-mediated autoimmune insulin-dependent diabetes mellitus (IDDM). Ig infusions from diabetic NOD donors did not abrogate IDDM resistance in NOD.Igμnull mice. However, T cell responses to the candidate pancreatic β cell autoantigen glutamic acid decarboxylase (GAD), but not the control Ag keyhole limpet hemocyanin, were eliminated in NOD.Igμnull mice. To initially test whether they contribute to IDDM as APC, NOD B lymphocytes were transferred into NOD.Igμnull recipients. B lymphocytes transferred into unmanipulated NOD.Igμnull recipients were rejected by MHC class I-restricted T cells. Stable T and B lymphocyte repopulation was achieved in irradiated NOD.Igμnull mice reconstituted with syngeneic bone marrow admixed with NOD B lymphocytes. IDDM susceptibility was restored in NOD.Igμnull mice reconstituted with syngeneic marrow plus B lymphocytes, but not with syngeneic marrow only. T cell responses to GAD were restored only in NOD.Igμnull mice reconstituted with syngeneic marrow plus B lymphocytes. Hence, B lymphocytes appear to contribute to IDDM in NOD mice as APC with a preferential ability to present certain β cell Ags such as GAD to autoreactive T cells.