Understanding how immune cells operate within tissues is key to designing better mucosal vaccines and therapies. In this talk, I will discuss how hypoxia-inducible factor 1-alpha (HIF-1α) shapes CD4 T cell fate within lung tertiary lymphoid structures during influenza infection. Using spatial transcriptomics and inducible gene deletion, we uncover a distinct population of HIF-1α+ T cells that orchestrates local immunity—supporting antibody production, innate cell recruitment, and tissue homeostasis.