Donor MHC class II mRNA combined with rapamycin programs Th1-like regulatory T cells and induces donor-specific alloimmune hyporesponsiveness

In this study, we investigated whether donor major histocompatibility complex (MHC) class II could be delivered as an mRNA-encoded alloantigen to modulate donor-reactive T-cell responses. Using the B6.C-H2bm12–C57BL/6 model, mice were treated with donor MHC class II I-Aβ mRNA, rapamycin, or their combination.

Donor MHC mRNA elicited alloimmune responses, whereas combination treatment promoted regulatory T-cell features and donor-specific hyporesponsiveness. Bulk RNA sequencing of splenic CD4+ T cells revealed a mixed effector- and regulatory-associated transcriptional response to donor MHC mRNA, with rapamycin modifying inflammatory transcriptional programs in a context-dependent manner.