The migration of pathogenic T cells to the pancreas, and their subsequent activation and proliferation, are important steps in the pathogenesis of type I diabetes. CD98 is a heterodimeric transmembrane protein that functions in amino acid transport and integrin signaling. Integrin expression and function are important for autoimmune diabetes in the NOD mouse model, and proliferation of T cells in pancreatic draining lymph nodes is a hallmark of disease. Therefore we have begun investigating CD98 as a potential target in type I diabetes. Our preliminary data shows that T cells in which CD98 has been targeted are unable to transfer disease, while transfer of control T cells causes beta cell destruction and overt diabetes. Our overall hypothesis is that CD98 controls migration or proliferation of diabetogenic T cells, and thus is a potential target for disease intervention. The research proposed in this application will Investigate the cellular and biochemical mechanisms by which CD98 deletion protects from type I diabetes, and to study potential side effects of CD98 targeting on normal immune responses.
Blocking the autoimmune attack mediated by lymphocytes in type I diabetes is a high priority, both to prevent the disease, and to stop its recurrence after islet cell transplant. We found that deleting CD98 on T lymphocyte immune cells makes them unable to cause experimental type I diabetes. We are proposing to investigate the mechanism of this protection, and to test what CD98 targeting might do to normal immune responses.
|Abplanalp, Wesley T; Conklin, Daniel J; Cantor, Joseph M et al. (2016) Enhanced Integrin Î±4Î²1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes. Diabetes :|
|Ablack, Jailal N G; Metz, Patrick J; Chang, John T et al. (2015) Ubiquitylation of CD98 limits cell proliferation and clonal expansion. J Cell Sci 128:4273-8|
|Cantor, Joseph M; Rose, David M; Slepak, Marina et al. (2015) Fine-tuning Tumor Immunity with Integrin Trans-regulation. Cancer Immunol Res 3:661-7|
|Cantor, Joseph M (2014) CD98 is a potential target for ablating B cell clonal expansion and autoantibody in multiple sclerosis. J Neuroimmunol 274:230-3|
|Cantor, Joseph M; Ginsberg, Mark H (2012) CD98 at the crossroads of adaptive immunity and cancer. J Cell Sci 125:1373-82|
|Cantor, Joseph; Slepak, Marina; Ege, Nil et al. (2011) Loss of T cell CD98 H chain specifically ablates T cell clonal expansion and protects from autoimmunity. J Immunol 187:851-60|