Abstract
Previous studies indicate that B-lymphocytes play a key role activating diabetogenic T-lymphocytes during the development of autoimmune diabetes. Recently, two transgenic NOD mouse models were generated: the NOD-PerIg and the 116C-NOD mice. In NOD-PerIg mice, B-lymphocytes acquire an activated proliferative phenotype and support accelerated autoimmune diabetes development. In contrast, in 116C-NOD mice, B-lymphocytes display an anergic-like phenotype delaying autoimmune diabetes onset and decreasing disease incidence. The present study further evaluates the T- and B-lymphocyte phenotype in both models. In islet-infiltrating B-lymphocytes (IIBLs) from 116C-NOD mice, the expression of H2-Kd and H2-Ag7 is decreased, whereas that of BAFF, BAFF-R, and TACI is increased. In contrast, IIBLs from NOD-PerIg show an increase in CD86 and FAS expression. In addition, islet-infiltrating T-lymphocytes (IITLs) from NOD-PerIg mice exhibit an increase in PD-1 expression. Moreover, proliferation assays indicate a high capacity of B-lymphocytes from NOD-PerIg mice to secrete high amounts of cytokines and induce T-lymphocyte activation compared to 116C B-lymphocytes. This functional variability between 116C and PerIg B-lymphocytes ultimately results in differences in the ability to shape T-lymphocyte phenotype. These results support the role of B-lymphocytes as key regulators of T-lymphocytes in autoimmune diabetes and provide essential information on the phenotypic characteristics of the T- and B-lymphocytes involved in the autoimmune response in autoimmune diabetes.
Highlights
CD4+ and CD8+ T-lymphocytes are considered to be the major effectors of ß-cell damage during the development of autoimmune diabetes in both NOD mice and humans
Since B-lymphocytes play an important role in presenting ßcell autoantigens to autoreactive T-lymphocytes in autoimmune diabetes, the present study first analyzed the expression of MHC and CD80, CD86, BAFF, BAFF-R, APRIL, and TACI costimulatory and coinhibitory molecules in spleen and islet infiltrating B-lymphocytes (IIBLs) from 116C-NOD and NODPerIg mice
Since TACI acts as an inhibitor for lymphocyte activation through BAFF/BAFF-R interaction, these results suggest that 116CNOD IIBLs cannot induce activation signals for T cells
Summary
CD4+ and CD8+ T-lymphocytes are considered to be the major effectors of ß-cell damage during the development of autoimmune diabetes in both NOD mice and humans. Further studies indicated that B-lymphocytes promote autoimmune diabetes development through their APC function activating ß-cell-reactive cytotoxic T-lymphocytes (CTLs) [9, 10]. In parallel to this diabetogenic role, a protective effect of some B-lymphocytes on autoimmunity through a potential regulator/suppressor mechanism has been described. Adoptive transfer of LPS-activated splenic B-lymphocytes protects prediabetic NOD female mice from disease development by triggering the apoptosis of ß-cell-reactive CTLs or/and inhibiting APC activity [11]
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