Flightless-1 promotes lung CD103+ cDC phagocytosis and migration

Abstract

Abstract Dendritic cells are specialized antigen-presenting cells integral for bridging the innate and adaptive immune responses. Critical to dendritic cell function is the need for a dynamic actin cytoskeleton. Flightless-1 is an actin capping protein linked to processes vital for dendritic cell immune functions including cell extension formation, phagocytosis, cell migration, and cell adhesion. Consistent with an important role in actin dynamics, whole body Flightless-1 knockouts are embryonic lethal. To enable further study of Flightless-1 in the immune response, we made mice with dendritic cell Flightless-1 deficiency using the CD11c-CRE driver. Homeostatic cDC1 and cDC2 populations in the spleen and lymph nodes were unchanged in DC-Flightless-1 knockouts relative to control animals. However, DC-Flightless-1 ablation led to a developmental disadvantage when in competition with WT DCs in mixed bone marrow chimeras. Upon LPS challenge in the airways, the Flightless-deficient cDC1 population showed reduced phagocytosis and migration to the lung draining lymph nodes. The DC migratory defect in the absence of Flightless-1 was supported by decreased CCR7 expression in both cDC1 and cDC2 populations. We hypothesize that the observed defects in phagocytosis and migration in Flightless-1-deficient dendritic cells are due to an altered actin cytoskeleton, which may also affect other actin-based immune structures. Current experiments are testing this hypothesis, and investigating the ability of Flightless-deficient DC to prime T cell responses.