B and T cell interactions that drive type 1 diabetes

In summary, the aim of my PhD study was to better understand the interactions between B and T cells that lead to beta cell destruction in the NOD model of type 1 diabetes (T1D). We were particularly interested in understanding the role of different B cell subsets in T cell activation, the timing of when B cells provide help T cells, and the T cell subtypes that B cells interact with. These questions provided the underlying framework for this thesis study. My work demonstrates that marginal zone B cells (MZB), as well as follicular B (FoB) cells may important players in the development of T1D. MZB aberrantly migrate to the pancreas and pancreatic lymph nodes, where they undergo expansion in association with increased activated CD4+ T cells. These events are coincident with diabetes development. Both MZB cells and FoB cells were able to present autoantigens, i.e. insulin peptide, to effectively activate self-reactive T cells and drive their proliferation. These data demonstrate for the first time that multiple B cell subtypes may play distinct roles in diabetes pathogenesis. To study when B cells contribute to the development of diabetes, we reduced B cells in female NOD mice by specifically targeting the BAFF/APRIL system with BCMA-Fc from 9-15 weeks of age. B cell depletion during that time period protected NOD mice from diabetes and restored islet-tolerance through a mechanism dependent upon regulatory T cells. These data show that B cells are necessary for the transition from insulitis to frank diabetes that occurs from ~12 weeks of age in NOD mice. The reason B cells are important at this stage is that they are necessary for the expansion of self-reactive CD8+ T cells. We demonstrate that B cells can activate self-reactive CD8+ T cells directly via presentation of MHC class I/peptide complexes. Also, B cells can activate CD8+ T cells indirectly via providing help to CD4+ T cells, stimulating the expression of helper cytokines like IL-21. The present PhD study has contributed to the pool of knowledge on the mechanisms by which B cells may contribute to the development of type 1 diabetes