Immunomodulation of T cell-mediated alloimmunity by proximity to endothelial cells under the mammalian target of rapamycin blockade.

Endothelial cells (ECs) are an initial barrier between vascularized organ allografts and the host immune system and are thus well positioned to initiate and influence alloimmune rejection. The mammalian target of rapamycin inhibitor rapamycin is known to inhibit T cell activation and attenuate acute allograft rejection. It also has numerous effects on ECs. We hypothesized that A mammalian target of rapamycin blockade might directly alter EC alloimmunogenicity and reduce alloimmune responses independent of its effects on T cell function. Here we report that rapamycin treatment modulates EC coinhibitory ligand expression and alters cytokine/chemokine production. It alters the EC transcriptome broadly associated with negative regulation of immune responses. Rapamycin-treated ECs suppress EC-specific T cell proliferation independent of programmed cell death 1/programmed death-ligand interaction and inhibit T cells responding to adjacent allogeneic cells in a contact-independent manner via secreted inhibitory mediators above 10 kDa. The T cell hyporesponsiveness induced by rapamycin-pretreated ECs was rescued by exogenous interleukin 2. Preexposing donor hearts to rapamycin improves the effect of B7 costimulation blockade in prolonging heart allograft survival in a major histocompatibility complex-mismatched mouse model. Our results indicate that rapamycin-treated ECs have reduced alloimmunogenicity and created a local, contact-independent environment that limits T cell alloreactivity via anergy induction and improves the efficacy of B7 costimulation blockade.