HIF-1α⁺ CD4⁺ T cells coordinate a tissue-resident immune cell network in the lung

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 with 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 interleukin 21 (IL-21)-dependent network of spatially colocalized immune cells including macrophages, natural killer (NK) cells, and immunoglobulin A-positive (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.