*Purpose: Costimulation blockade (CoB) is a promising new strategy that provides a more targeted therapy with fewer side effects compared to traditional transplant immunosuppressants, leading to improved long-term graft and patient outcomes. However, acute costimulation independent rejection is a concern for a subset of treated patients. Type I interferons (IFNs), which signal through the type I IFN receptor (IFNAR), are produced in response to innate immune signals and may prime the adaptive immune system for acute rejection. We have previously demonstrated that blockade of IFNAR signaling significantly prolongs graft survival. Here we sought to investigate the role of IFNAR signaling on myeloid cells during costimulation blockade resistant rejection.

*Methods: In order to assess the contribution of IFNAR signaling on myeloid cells we generated LysM-Cre IFNAR^fl/fl mice that do not express IFNAR on monocytes, macrophages, or neutrophils. We confirmed their phenotype by stimulating neutrophils overnight with 1000IU of IFN-α, which induced the upregulation of MHC-I on neutrophils from wildtype C57BL/6 mice but not IFNAR-/- or LysM-Cre IFNAR^fl/fl mice (left). LysM-Cre IFNAR^fl/fl neutrophils expressed minimal IFNAR, equivalent to neutrophils from IFNAR-/- mice, compared to wildtype cells. Statistical differences were determined by one-way ANOVA using Tukey’s multiple correction test. *** = p<0.0005. **** = p<0.0001.

*Results: We then assessed the survival of fully MHC mismatched BALB/cJ skin grafted onto C56BL/6 wildtype, IFNAR-/-, or LysM-Cre IFNAR^fl/fl mice treated with CoB (CTLA4-Ig + anti-CD154) with or without anti-IFNAR. We found that LysM-Cre IFNAR^fl/fl recipient mice show no survival benefit compared to IFNAR-/- recipients treated with CoB or wildtype mice treated with CoB + anti-IFNAR, compared to wildtype mice treated with CoB alone.

*Conclusions: The results from this experiment suggest that IFNAR signaling on myeloid cells does not contribute to costimulation blockade independent rejection. Future experiments are underway to evaluate the contribution of IFNAR signaling on other cell types in this setting, specifically T cells.

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