Monocytes distinguish between self and allogeneic non-self and contribute to allograft rejection by generating mature, IL-12+, DCs. The initial trigger of monocyte differentiation to DCs is the binding of SIRPa, a polymorphic marker of non-self on donor cells, to CD47 on recipient monocytes. Here, we show that monocytes primed in vivo with allogeneic cells via the SIRPa-CD47 pathway acquire allospecific memory. First, they mount an anamnestic recall response (measured by enhanced DC generation) to grafts from the same but not third-party donors. Second, removal of the MHC-disparity between the donor and recipient at the time of recall abrogates the response, indicating that memory specificity is to the allogeneic MHC. Third, the recall response can be elicited up to 4-7 weeks after initial priming – a duration that is significantly longer than the very short lifespan of a monocyte (1-3 days). Fourth, acquisition and recall of memory occurs in the complete absence lymphoid cells, indicating the innate nature of monocyte memory. We provide direct evidence that memory is preceded by monocyte proliferation (measured by EdU uptake) and is associated with transcriptional changes in monocytes (measured by RNAseq analysis). Using blocking antibodies to paired immunoglobulin receptor (PIR) molecules present on monocytes, we show that MHC specificity of memory is mediated by PIR-A receptors that preferentially bind allogeneic MHC molecules. Therefore, the innate alloresponse triggered in monocytes by non-self SIRPa rapidly evolves into an enhanced memory response specific to non-self MHC. This novel form of innate memory could have profound effects on allogeneic transplantation by continually generating mature DCs that promote rejection and prevent tolerance.

CITATION INFORMATION: Dai H., Lan P., Friday A., Williams A., Oberbarnscheidt M., Li X., Lakkis F. Specific Monocyte Memory to Allogeneic MHC Mediated by Paired Immunoglobulin Receptors (PIR) Am J Transplant. 2017;17 (suppl 3).

« Back to 2018 American Transplant Congress