Inflammation-induced development and migration of a novel monocyte-like dendritic cell population that regulates antiviral CD8 T cell immunity.

Abstract

Abstract We recently discovered a CD11c+MHC-II+CD103+CD11b+ monocyte-like dendritic cell (moDC) population that colocalizes with CD8 T cells in the draining lymph node (dLN) early after respiratory infection. Importantly, depletion of these cells enhances the formation of CD8+ tissue resident memory T cells (T RM) in the lung. Given the importance of T RMafter respiratory challenge, we aimed to understand the origin and migration of these moDCs. To this end, we intranasally (i.n.) infected C57Bl/6 mice with influenza virus A HK-×31 (×31) or with vesicular stomatitis virus (VSV), the latter which allows us to compare with identical systemic infection. moDCs were detected in the bone marrow (BM) ~2 days post infection, one day prior to their peak recovery from the dLN. BM moDCs phenotypically resembled dLN moDCs, including expression of the inflammatory monocyte-associated markers CCR2 and Ly6C. Adoptive transfer of BM Ly6C+ monocytes into congenically mismatched recipients showed a meaningful percentage of moDCs were monocyte-donor derived. Additionally, type I IFNs, which can induce monocyte differentiation and are crucial in early antiviral immunity, were required for moDC development. We showed that moDCs are decreased in the BM, and consequently the dLN of Ifnar1−/− mice compared to WT mice following respiratory infection. Lastly, moDCs were detected in the BM after intravenous (i.v.) VSV but not in the dLN. This could be attributed to the increased expression of CCL2, MIP-1β, and IL-12p40 in the dLN of i.n. VSV or ×31 infected mice compared to naïve or i.v. VSV infected mice, where inflammation is dispersed. Overall, we provide potential targets in the moDC development and migration process that could enhance antiviral CD8 T cell immunity. Supported by grant from NIH (R21 AI131093)