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

Jean de Lima; Nivedya Swarnalekha; Claire E. Depew; Ewelina Magdalena Bartoszek; Ludivine C. Litzler; Mara Esposito; Maike Erber; Tiphaine Camarasa; Lorenzo Iseppi; Marco Künzli; Anukul T. Shenoy; Inés Lammens; Stijn Vanhee; Bart N. Lambrecht; Ananda W. Goldrath; Jie Sun; David Schreiner; Carolyn G. King

doi:10.1016/j.immuni.2026.01.023

ImmunologyImmunityMar 7, 2026

Peer-reviewed journal article

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

Jean de Lima, Nivedya Swarnalekha iD, Claire E. Depew iD, Ewelina Magdalena Bartoszek iD, Ludivine C. Litzler iD, Mara Esposito iD, Maike Erber, Tiphaine Camarasa iD, Lorenzo Iseppi, Marco Künzli iD, Anukul T. Shenoy iD, Inés Lammens iD, Stijn Vanhee iD, Bart N. Lambrecht iD, Ananda W. Goldrath iD, Jie Sun iD, David Schreiner iD, Carolyn G. King iD

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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-1 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-1-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-1-dependent network is engaged in a lung adenocarcinoma model, highlighting a broader role for HIF-1+ CD4 T cells in integrating protective immunity during infection and cancer.