Insulin-Reactive T Cells Convert Diabetogenic Insulin-Reactive VH125 B Cells Into Tolerogenic Cells by Reducing Germinal Center T:B Cell Interactions in NOD Mice

Abstract

Insulin is a key autoantigen in Type 1 Diabetes (T1D), targeted by both T and B cells. Therefore, understanding insulin-specific T:B cell interactions is important. We have previously reported an insulin-reactive CD4+ T cell, (designated 2H6). Unlike other insulin-reactive T cells, 2H6 cells protect non-obese diabetic (NOD) mice from T1D development, mediated by TGFβ. To investigate insulin-specific T:B cell interactions, we bred 2H6αβ T cell receptor transgenic NOD mice (2H6) with the insulin-reactive B cell receptor transgenic NOD mice (VH125), generating 2H6VH125 NOD mice. Similar to 2H6 mice, 2H6VH125 mice are protected from T1D development. Interestingly, VH125 B cells did not alter the phenotype of 2H6 T cells; however, 2H6 T cells significantly altered the VH125 B cells by reducing the insulin-reactive non-germinal center (GC) and GC B cells, as well as MHC and costimulatory molecule expression on the B cells. Furthermore, the B cells in 2H6VH125 NOD mice exhibited increased non-insulin-specific and a class switched IgG isotype, which can be recapitulated in vivo in Rag-deficient NOD mice by adoptive transfer. In vitro , VH125 B cells from 2H6VH125 mice suppressed the proliferation of 2H6 T cells to insulin antigen but enhanced TGFβ secretion by 2H6 T cells from 2H6VH125 mice compared to 2H6 mice. In summary, our data showed that 2H6 CD4+ T cells alter the phenotype and function of insulin-reactive B cells from pathogenic to tolerogenic cells. In turn, VH125 B cells also modulate the function of the 2H6 T cells. Thus, promoting the interactions between antigen-specific regulatory T cells and B cells may lead to protection from T1D.

Productive Germinal Center Responses Depend on the Nature of Stimuli Received by Anti-Insulin B Cells in Type 1 Diabetes–Prone Mice

“…IgM-restricted anti-insulin B cells in V H 125Tg.NOD mice are able to form spontaneous GCs ( 44 ). We found spontaneous anti-insulin GCs in the pancreatic lymph nodes of 8 of 14 class-switch competent V H 125 SD .NOD mice surveyed in this study ( Fig.…”

“…The 8F10 T cells are diabetogenic T cells that express an anti-insulin TCR and a critical T cell clone that drives T1D development in NOD mice ( 20 , 50 ). However, crossing IgM-restricted V H 125Tg.NOD mice with 2H6 anti-insulin TCR transgenic NOD mice results in a decreased proportion of anti-insulin B cells, as well as decreased anti-insulin B cell expression of costimulatory molecules and differentiation into GC B cells ( 44 ). Thus, the ability of anti-insulin B cells to enter GCs and form Ab may be dependent on both the number of cognate CD4 + T cells and the quality of help received.…”