Cutting Edge: Vasostatin-1–Derived Peptide ChgA29–42 Is an Antigenic Epitope of Diabetogenic BDC2.5 T Cells in Nonobese Diabetic Mice

Mechanistic and therapeutic insights in autoimmune diabetes would benefit from a more complete identification of relevant autoantigens. BDC2.5 TCR transgenic NOD mice express transgenes for TCR Vα1 and Vβ4 chains from the highly diabetogenic BDC2.5 CD4(+) T cell clone, which recognizes pancreatic β cell membrane Ags presented by NOD I-A(g7) MHC class II molecules. The antigenic epitope of BDC2.5 TCR is absent in β cells that do not express chromogranin A (ChgA) protein. However, characterization of the BDC2.5 epitope in ChgA has given inconclusive results. We have now identified a ChgA29-42 peptide within vasostatin-1, an N-terminal natural derivative of ChgA as the BDC2.5 TCR epitope. Having the necessary motif for binding to I-A(g7), it activates BDC2.5 T cells and induces an IFN-γ response. More importantly, adoptive transfer of naive BDC2.5 splenocytes activated with ChgA29-42 peptide transferred diabetes into NOD/SCID mice

Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice

The cytokine transforming growth factor-β (TGF-β) is an important negative regulator of adaptive immunity1–3. TGF-β is secreted by cells as an inactive precursor that must be activated to exert biological effects4, but the mechanisms that regulate TGF-β activation and function in the immune system are poorly understood. Here we show that conditional loss of the TGF-β-activating integrin α(v)β(8) on leukocytes causes severe inflammatory bowel disease and age-related autoimmunity in mice. This autoimmune phenol-type is largely due to lack of α(v)β(8) on dendritic cells, as mice lacking α(v)β(8) principally on dendritic cells develop identical immunological abnormalities as mice lacking α(v)β(8) on all leukocytes, whereas mice lacking α(v)β(8) on T cells alone are phenotypically normal. We further show that dendritic cells lacking α(v)β(8) fail to induce regulatory T cells (T(R) cells) in vitro, an effect that depends on TGF-β activity. Furthermore, mice lacking α(v)β(8) on dendritic cells have reduced proportions of T(R) cells in colonic tissue. These results suggest that α(v)β(8)-mediated TGF-β activation by dendritic cells is essential for preventing immune dysfunction that results in inflammatory bowel disease and autoimmunity, effects that are due, at least in part, to the ability of α(v)β(8) on dendritic cells to induce and/or maintain tissue T(R) cells