Human CD1c+ DCs drive the differentiation of CD103+ intraepithelial CD8+ T cells via TGF beta (48.12)

Abstract

Abstract Mucosa is a major site of invasion and replication of pathogens, including influenza virus. However, our understanding of cellular immune responses and their regulation at mucosal sites in the human is limited due to inherent difficulties in assessing cellular interactions using ex vivo systems. Here we analyzed the response of human myeloid dendritic cells (DCs) to live-attenuated influenza virus (LAIV) and the type of CD8+ T cell responses that were generated using human lung tissue samples and humanized mice. Upon LAIV inoculation, the number of CD1c+ (BDCA-1) DCs in the lungs had increased by 16 hours; whereas the number of CD141+ (BDCA-3) remained stable up to three days post inoculation. Both DC subsets acquire flu antigens in vivo and expand specific memory CD8+ T cells ex vivo. However, at an early time point CD141+ DCs are more efficient in expanding CD8+ effector T cells. CD1c+ DCs are able to expand CD8+ T cells at a later time point, and they uniquely expand CD8+ T cells expressing CD103, a receptor for the epithelial cell-specific E-cadherin. CD1c+ DCs induce CD103+CD8+ T cells with the characteristics of cytotoxic intraepithelial T cells owing to the expression of membrane TGF-β. Our results suggest that lung-resident CD141+ DCs launch the effector response early after viral exposure while the role of migratory CD1c+ DCs is to retain the T cells in the epithelium. Thus, myeloid DCs have a major role in the regulation and expansion of memory T cells in mucosa.