Cytomegalovirus (CMV) infection has long been associated with graft-dysfunction and rejection in transplant-recipients. Nevertheless, precise understanding of underlying molecular mechanisms remains unclear. Here, we investigated the modulatory effects of CMV infection in myeloid cell compartment (central to innate/adaptive immunity) resulting in the abrogation of transplant-tolerance using mouse (M)CMV strain [Delta]m157 in allogeneic pancreatic islets and heart transplant models (Balb/c to C57BL6/J) following acute infection. Donor-specific tolerance was induced by infusions of ethylenecarbodiimide (ECDI)-fixed donor splenocytes (SP) which significantly prolonged graft-survival in these models. This prolonged survival was found to be dependent of the presence of myeloid-derived suppressor cells (MDSC; comprised of CD11b⁺Gr1^hi and CD11b⁺Ly6C^hi) as their depletion using anti-Gr1 Ab acutely precipitated the grafts' rejection within 2-3 weeks. A similar pattern of graft-rejection was manifested following acute MCMV infection in both transplant models suggesting that MCMV alters MDSC generation and/or their function. ECDI-SP tolerized mice showed enhanced differentiation/accumulation of highly immunosuppressive Gr1^hi MDSCs in the periphery. Conversely, MCMV infection inhibited Gr1^hi MDSC generation while promoting the differentiation of Ly6C^hi MDSCs into CD11c⁺ cells in the bone marrow resulting in their accumulation in the periphery including the graft. These cells were highly immunogenic and stimulated the proliferation of allogeneic CD8 T cells in vitro. Post-MCMV infection Ly6C^hi cells expressed RORγt, a transcription factor regulating the Th17 response and its selective inhibition using pharmacologic-inhibitor TMP778 restored the skewed myeloid cell-differentiation. In conclusion, our data demonstrates for the first time that MCMV infection, by modulating the differentiation and functional characteristics of myeloid cells, interferes with the induction of allograft tolerance. Delineating the role of RORγt will have implications in designing anti-CMV therapeutics post-transplantation.

CITATION INFORMATION: Dangi A, Zhang L, Zhang X, Zhang Z, Luo X. Acute Mouse CMV Infection Abrogates Transplant Tolerance by Modulating Myeloid Cell Differentiation and Function: A Possible Role for Transcription Factor RORγt. Am J Transplant. 2017;17 (suppl 3).

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