Nonobese diabetic (NOD) mice genetically deficient in B lymphocytes (NOD. Igμ null) 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. Igμ null 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. Igμ null mice. To initially test whether they contribute to IDDM as APC, NOD B lymphocytes were transferred into NOD. Igμ null recipients. B lymphocytes transferred into unmanipulated NOD. Igμ null recipients were rejected by MHC class I-restricted T cells. Stable T and B lymphocyte repopulation was achieved in irradiated NOD. Igμ null mice reconstituted with syngeneic bone marrow admixed with NOD B lymphocytes. IDDM susceptibility was restored in NOD. Igμ 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. Igμ null 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.