Regulatory maturation of lung cDC1 is required for resolution of Influenza infection

Abstract

Abstract Pulmonary infection with Influenza A virus (IAV) is responsible for 20,000–30,000 deaths in the US yearly. During the acute stage of infection, pattern recognition receptors (PRRs)-dependent recognition of the virus leads to DC maturation and subsequent expansion of virus-specific effector T cells in the lung-draining lymph node. Recruitment of cytotoxic T cells into the lungs is crucial for the control of IAV infection, however unchecked effector T cell activation often leads to lung immunopathology even after the virus has been cleared. Reducing the availability of IL-2 by CD25+ regulatory T cells is thought to be the principal mechanism limiting the expansion and differentiation of effector CD8 T cells. Recently, efferocytotic maturation of cDC1 (mregDC) has been implicated in impairing CD8 T cells responses, however mregDC has not been studied in the context of IAV infection. Here we described expression of maturation markers, CCR7, PD-L1, and CD40 of lung cDC subsets. PD-L1+ CCR7+ CD40+ cDC1 differentiates in the lungs several days after the virus has been cleared (12–16 days post-infection, dpi). The accumulation of mature cDC1 coincides with increased frequency of Caspase 3+ cells and recovery of disease. At 8dpi, mature cDC1 produce IL-12p70 and induce IFNg+ CD8 T cells, in contrast, at 16dpi mature cDC1 only produce IL-12p40 and fail to induce IFNg+ CD8 T cells. In conclusion, our data suggest that mature DC1 play a role in limiting CD8 T cells mediated immunopathology after IAV infection.