Influenza infection fortifies local lymph nodes to promote lung-resident heterosubtypic immunity

Influenza infection generates tissue-resident memory T cells (T_RMs) that are maintained in the lung and can mediate protective immunity to heterologous influenza strains, but the precise mechanisms of local T cell–mediated protection are not well understood. In a murine heterosubtypic influenza challenge model, we demonstrate that protective lung T cell responses derive from both in situ activation of T_RMs and the enhanced generation of effector T cells from the local lung draining mediastinal lymph nodes (medLNs). Primary infection fortified the medLNs with an increased number of conventional dendritic cells (cDCs) that mediate enhanced priming of T cells, including those specific for newly encountered epitopes; cDC depletion during the recall response diminished medLN T cell generation and heterosubtypic immunity. Our study shows that during a protective recall response, cDCs in a fortified LN environment enhance the breadth, generation, and tissue migration of effector T cells to augment lung T_RM responses.