The preferential ability of B lymphocytes to act as diabetogenic APC in NOD mice depends on expression of self-antigen-specific immunoglobulin receptors

Abstract

B lymphocytes partially contribute to autoimmune type 1 diabetes (T1D) as a subset of APC with a preferential ability to trigger pathogenic CD4 T cells. We hypothesized that this resulted from the unique ability of B lymphocytes to take up pancreatic β cell proteins through Ig mediated capture. T1D was significantly delayed, but not prevented, in a NOD stock in which the B lymphocyte lg repertoire was strongly restricted because of the allelic exclusion induced by transgenic lg molecules specific for the disease irrelevant hen egg lysozyme (HEL) protein (NOD.IgHEL mice). However, introducing the lgμnull mutation to eliminate the small residual numbers of non-transgenic B lymphocytes in the NOD.lgHEL stock strongly suppressed T1D to the same low levels that characterize B lymphocyte deficient NOD.lgμnull mice. In contrast to standard NOD mice, both the NOD.lgHEL.Igμnull and NOD.Igμnull stocks were unable to generate T cell responses against the candidate diabetes autoantigen, glutamic acid decarboxylase. These results indicate that lg-mediated capture of β cell autoantigens accounts for why B lymphocytes have a greater capacity than other APC subtypes to trigger diabetogenic T cells. Hence, defects in B lymphocyte, as well as T lymphocyte, tolerance induction mechanisms may contribute to T1D in NOD mice.