BMT procedure alters the functions of dendritic cells and subsequently causes pathogenic Th responses to gammaherpesvirus infection

Abstract

Abstract Hematopoietic stem cell transplantation is a standard of care for many patients with genetic disorders, autoimmune diseases and malignancies. However, stem cell recipients are often more susceptible to microbial infections even after full hematopoietic reconstitution. We have previously demonstrated that syngeneic bone marrow transplantation (syn-BMT) in mice causes increased Th17 response and decreased Th1 response to murine gamma herpesvirus MHV-68 infection leading to pulmonary fibrosis. In this study, we found that Notch2-dependent conventional dendritic cells (DCs), i.e., a set of CD11b+ DCs, are required for the Th17 response to MHV-68 infection in BMT mice, while Batf3-dependent CD103+ DCs suppress the Th17 response. Furthermore, CD11b+ DCs in BMT lungs are hyper-activated with high expression of CD80 and CD86. When co-cultured with CD4+ T cells, DCs from BMT lungs promote higher productions of both IL-17A and IFN-γ than DCs from non-BMT mice, and addition of antibodies against CD80 and CD86 abolish the productions of both IL-17 and IFN-γ. Although the DCs in the BMT lungs are potent in inducing both Th1 and Th17 responses ex vivo, they are impaired in migrating into the lung draining lymph nodes (dLNs). Surprisingly, migration of DCs into the dLNs is not required for Th17 priming, since transplanting CCR7−/− bone marrow, which gives rise to non-migrating DCs in the recipient mice, does not prevent the Th17 response, but does abolish the Th1 response, suggesting a role for peripheral priming of the Th17 response in the lung post-BMT. In summary, syn-BMT causes a hyper-activated phenotype of CD11b+ DCs that promotes a pathogenic Th17 response and also causes dysfunction in DC trafficking that is required for a maximum Th1 response.