Activating CD8 T cell clones via the T cell receptor complex in the absence and presence of cyclosporine A. Mus musculus

Comparison of a cyclosporine-resistant murine CD8 T cell clone to a cyclosporine-sensitive murine T cell clone during activation (CSA = Cyclosporine A) Chronic allograft rejection is the leading cause of morbidity/mortality in solid organ and bone marrow transplant patients. It occurs in the setting of potent calcineurin and mTOR inhibitor therapies, implying that T cells mediating chronic rejection can function with compromised calcineurin-NFAT or IL-2 receptor signaling pathways. In murine models the T cells mediating allograft rejection in the setting of calcineurin inhibitor therapy are CD8 T cells making IFN-gamma without a requirement for perforin. It is not known whether these pathologic T cells are a unique subset or how they function. In parallel other animal model research has shown that alloepthelial cells residing in the donor organ are critical targets for rejection. While investigating T cell-alloepithelial cell interactions, we discovered an unusual alloreactive CD8 T cell population that recognized MHC class II I-Abm12. A CD8 T cell clone derived from that population was intrinsically-resistant to cyclosporine and rapamycin without prior exposure to either in vivo or in vitro. Microarray analysis comparing the novel CD8 T cell clone to a conventional CD8 CTL clone specific for MHC class I Kbm1 suggested that the TCR signaling pathway responsible for cyclosporine-resistance utilized the Aryl Hydrocarbon Receptor (AHR). Overall design: Two T cell clones x 2 experimental conditions x 4 replicates