Deciphering T and B lymphocyte cross-talk in Type 1 Diabetes

Background: Two transgenic NOD mouse models, the NOD-PerIg and the 116C-NOD, were generated and characterized to better understand the role of B cells in the development of T1D. The NOD-PerIg model expresses an immunoglobulin of naturally occurring islet-infiltrating B-lymphocyte (IIBLs) in NOD mice that recognize the neuronal antigen peripherin; and the 116C-NOD model wears an immunoglobulin expressed by a few IIBLs, from the insulitis prone but diabetes resistant 8.3-(NODxNOR)F1 mice, that recognize a ß-cell autoantigen that has not been defined yet. Methods: B and T cell phenotype from mechanically disrupted mononuclear-infiltrated pancreatic islets and spleens of 6 weeks old NOD, 116C-NOD and NOD-PerIg mice were analyzed by flow cytometry. Proliferation and cytokine release assays were also performed on splenic B and T cells. Results: In NOD-PerIg mice, B-lymphocytes show an activated phenotype that drives to an accelerated T1D development. In contrast, in 116C-NOD mice, B lymphocytes display an anergic-like phenotype, that delays the onset of T1D and decreases the incidence of the disease. The expression of FAS, CD86,H-2Kd and H-2Ag7 in IIBLs was decreased in 116C-NOD, but increased in NOD-PerIg mice. In addition, expression of BAFF, BAFF-R, and TACI was increased in IIBLs and islet-infiltrating T-lymphocytes (IITLs) in 116C-NOD mice. CD4+ IITLs from NOD-PerIg mice showed an increase in PD-1 with almost no PD-L1 expression. Moreover, proliferation assays indicated that the capacity to induce T cell activation was higher in NOD-PerIg mice B cells when compared to 116C-NOD B cells. These results support the role of B-lymphocytes as key regulators of T-lymphocytes in T1D, and provide essential information on the phenotypic characteristics of T- and B-lymphocytes involved in T1D.