Effect of CD154:CD11b blockade on antigen-specific CD8 T cell response to murine Epstein-Barr virus infection

CD154 is a promising target for immunosuppression in transplantation, autoimmunity, and inflammatory diseases. We previously identified CD11b as a novel alternate receptor for CD154 during alloimmunity. However, the impact of specific CD154:CD11b blockade on immune responses to infection has not been well characterized. Here, we have shown that in contrast to its immunosuppressive effect on graft-specific CD8+ T cells, CD154:CD11b blockade unexpectedly improved both the quantity and quality of murine herpesvirus-68 (MHV)-specific CD8+ T cells as measured by an increase in tetramer-positive KLRG1loCD127hi memory precursor effector cells (MPECs). RNAseq of antigen-specific CD8+ T cells identified using an MHV68-specific MHC tetramer reveals specific pathways altered following cM7 treatment during MHV68 infection, including transcripts associated with T cell activation and survival. The differential effect of CD154:CD11b blockade on graft-vs. virus-specific CD8+ T cells was underpinned by differences in phospho-S6 downstream of mTORC1, however differential expression of key transcription factors Eomes and TCF-1 was dictated by the type of antigen stimulus. These data demonstrate that priming conditions play an important role in determining the outcome of immunotherapy and suggest that specific inhibition of CD154:CD11b interactions could be effective for suppressing alloimmune responses while maintaining protective immunity to minimize infectious complications following transplantation.