B-LYMPHOCYTES ARE CRITICAL ANTIGEN-PRESENTING CELLS FOR THE INITIATION OF T-CELL-MEDIATED AUTOIMMUNE DIABETES IN NONOBESE DIABETIC MICE

Nonobese diabetic (NOD) mice genetically deficient in B lymphocytes (N OD.Ig mu(null)) are resistant to T cell-mediated autoimmune insulin-de pendent diabetes mellitus (IDDM), Ig infusions From diabetic NOD donor s did not abrogate IDDM resistance in NOD.Ig mu(null) mice, However, T cell responses to the candidate pancreatic beta cell autoantigen glut amic acid decarboxylase (GAD), but not the control Ag keyhole limpet h emocyanin, were eliminated in NOD.Ig mu(null) mice. To initially test whether. they contribute to IDDM as APC, NOD Il lymphocytes were trans ferred into NOD.Ig mu(null) recipients. B lymphocytes transferred irat e unmanipulated NOD.Ig mu(null) recipients were rejected by MHC class I-restricted T cells. Stable T and B lymphocyte repopulation was achie ved in irradiated NOD.Ig mu(null) mice reconstituted with syngeneic bo ne marrow admixed with NOD B lymphocytes. IDDM susceptibility was rest ored in NOD.Ig mu(null) mice reconstituted with syngeneic marrow plus B lymphocytes, but not with syngeneic marrow only. T cell responses to GAD were restored only in NOD.Ig mu(null) mice reconstituted with syn geneic marrow plus B lymphocytes. Hence, B lymphocytes appear to contr ibute to IDDM in NOD mice as APC with a preferential ability to presen t certain beta cell Ags such as GAD to autoreactive T cells.