Abstract
A deeper understanding of how tissue localized immune cells arise and function is critical for developing mucosal vaccines. Currently, there are no murine models that specifically target tissue T cells while leaving their lymphoid counterparts untouched. Here we leverage the observation that during influenza infection, HIF-1α regulatory activity is higher in the lung compared to lymph node CD4 T cells. Inducible deletion of Hif1a in CD4 T cells, at the onset of its activity in the lung, reduces the tissue resident T cell compartment with minimal impact on peripheral immunity. HIF-1α-active CD4 T cells occupy the border of tertiary lymphoid structures, where they coordinate an IL-21-dependent network of spatially co-localized immune cells including macrophages, NK cells and IgA+ B cells. A similar HIF-1α-dependent network is engaged in a lung adenocarcinoma model, highlighting a broader role for HIF-1α+ CD4 T cells in integrating protective immunity during infection and cancer.