Subsets against Influenza A Virus Infection Protection of Human Myeloid Dendritic Cell

The proinflammatory microenvironment in the respiratory airway induces maturation of both resident and infiltrating dendritic cells (DCs) upon influenza A virus (IAV) infection. This results in upregulation of antiviral pathways as well as modulation of endo-cytic processes, which affect the susceptibility of DCs to IAV infection. Therefore, it is highly relevant to understand how IAV interacts with and infects mature DCs. To investigate how different subsets of human myeloid DCs (MDCs) involved in tissue inflammation are affected by inflammatory stimulation during IAV infection, we stimulated primary blood MDCs and inflammatory monocyte-derived DCs (MDDCs) with TLR ligands, resulting in maturation. Interestingly, MDDCs but not MDCs were protected against IAV infection after LPS (TLR4) stimulation. In contrast, stimulation with TLR7/8 ligand protected MDCs but not MDDCs from IAV infection. The reduced susceptibility to IAV infection correlated with induction of type I IFNs. We found that differential expression of TLR4, TRIF, and MyD88 in the two MDC subsets regulated the ability of the cells to enter an antiviral state upon maturation. This difference was functionally confirmed using small interfering RNA and inhibitors. Our data show that different human MDC subsets may play distinct roles during IAV infection, as their capacity to induce type I IFNs is dependent on TLR-specific maturation, resulting in differential susceptibility to IAV infection. D endritic cells (DCs) are rare, highly specialized innate immune cells that line body surfaces and circulate in blood (1). Owing to their location, expression of pathogen recognition receptors such as TLRs, and their ability to secrete cytokines and chemokines in response to recognition of foreign Ag, DCs are crucial for our first line of defense against invading pathogens, including viruses such as influenza A virus (IAV) (2). Additionally, DCs have the unique capacity to activate naive T cells and play a pivotal role in initiating adaptive immune responses to IAV, necessary for control and clearance of the virus (3). IAV causes an acute infection in the lungs associated with tissue inflammation, mediated by excessive induction of cytokines (4–6). Upon IAV infection, immature DCs in the respiratory tract sense and capture the virus and undergo maturation that includes induction of proinflammatory cytokine and chemokine production (7). Thus, DCs contribute to the " cytokine storm " associated with IAV immunopathology, which is also critical for the recruitment of immune cells to the site of infection. The proinflammatory milieu in the lung during IAV infection suggests that both …