*Purpose: CD154 pathway antagonism has shown to be a promising target for inducing long-time graft survival, in some cases showing efficacy that is superior to anti-CD40. It has recently been shown that CD11b is an alternate receptor for CD154. In recently published work, we showed that a peptide mimetic that specifically blocks the CD154-binding domain of CD11b improved long-term graft survival. However, the impact of CD154:CD11b blockade on protective immunity is not known. The goal of this study was to determine the effects of the CD154:CD11b specific peptide inhibitor on protective immunity to a murine Epstein-Barr virus (EBV) homolog (MHV68).

*Methods: A peptide mimetic that specifically blocks the CD154 binding domain on CD11b (cM7) was used as treatment in a murine model of EBV infection, MHV68. Virus-specific T cell responses were measured using peptide:MHC tetramers containing p56 and p79 viral peptides. In some experiments, response to an ovalbumin-expressing virus, MHV68-OVA, was analyzed using OVA-specific CD8⁺ transgenic OT-I T cells. Viral burden was analyzed using a YFP-expressing virus, MHV68-YFP, in B cells of the spleen and mesenteric lymph nodes (mLNs).

*Results: Mice treated with cM7 had significantly higher numbers and frequencies of total CD8⁺ T cells compared to untreated mice (p=0.0317) at 10 days post-infection in the blood. cM7-treated mice had significantly lower frequencies of short-lived effector cells (p=0.0159) and significantly higher frequencies of memory precursor effector cells (p=0.0159) in the spleen 14 days post-infection. When viral burden was assessed, cM7-treated mice were found to have significantly lower frequencies of CD3^–CD19⁺ B cells in the spleen (P=0.0317) but significantly higher levels in the mLNs (p=0.0079). Importantly, there was no significant difference in the frequency of YFP-expressing virally infected B cells in the spleens and mLNs of cM7-treated mice as compared to PBS-treated controls.

*Conclusions: These data suggest despite its ability to impair CD8⁺ T cell trafficking into allografts, CD154:CD11b blockade does not negatively impact protective immunity to a murine EBV homolog. Targeting this pathway could hold promise for transplant immunosuppression.

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