A defect in bone marrow derived dendritic cell maturation in the nonobesediabetic mouse

The pathogenesis of diabetes in the nonobese diabetic (NOD) mouse is charac terized by a selective destruction of the insulin-producing beta -cells in the islets of Langerhans mediated by autoreactive T cells. The function of T cells is controlled by dendritic cells (DC), which are not only the most potent activators of naive T cells, but also contribute significantly to th e establishment of central and peripheral tolerance. In this study, we demo nstrate that the NOD mouse (H2: K-d, A(g7), E degrees, D-b) shows selective phenotypic and functional abnormalities in DC derived from bone marrow pro geny cells in response to GM-CSF (DCNOD). NOD DC, in contrast to CBA DC, ha ve very low levels of intracellular I-A molecules and cell surface expressi on of MHC class II, CD80, CD86 and CD40 but normal beta2-microglobulin expr ession. Incubation with the strong inflammatory stimulus of LPS and IFN-gam ma does not increase class II MHC, CD80 or CD86, but upregulates the level of CD40. The genetic defect observed in the DCNOD does not map to the MHC, because the DC from the MHC congenic NOD.H2(h4) mouse (H2: K-k, A(k), E-k, D-k) shares the cell surface phenotype of the DCNOD. DC from these NOD.H2(h 4) also fail to present HEL or the appropriate HEL-peptide to an antigen-sp ecific T cell hybridoma. However all the DC irrespective of origin were abl e to produce TNF-alpha, IL-6, low levels of IL-12(p70) and NO in response t o LPS plus IFN-gamma. A gene or genes specific to the NOD strain, but outsi de the MHC region, therefore must regulate the differentiation of DC in res ponse to GM-CSF. This defect may contribute to the complex genetic aetiolog y of the multifactorial autoimmune phenotype of the NOD strain.