A thorough understanding of the generation and function of local immune cells in the tissue is crucial for the development of mucosal vaccines. Currently, there is no mouse model specifically targeting tissue T cells while maintaining the lymphatic system unchanged. We observed that during influenza infection, the regulatory activity of HIF-1α in the lungs is higher than that in CD4+ T cells in the lymph nodes. In CD4+ T cells, the activity of Hif1a begins to be lost at the onset in the lungs, which reduces the tissue-resident T cell compartment but has minimal impact on the surrounding immunity. The HIF-1α activity of CD4+ T cells is located at the boundary of the tertiary lymphoid structure, and they coordinate a spatially co-localized immune cell network dependent on interleukin 21 (IL-21), including macrophages, natural killer cells (NK), and immunoglobulin A-positive (IgA+) B cells. Similar HIF-1α-dependent networks are also involved in the lung adenocarcinoma model, highlighting the broader role of HIF-1α+ CD4+ T cells in integrating protective immunity during infection and cancer. This study was published in the journal Immunity under the title "HIF-1α+ CD4+ T cells coordinate a tissue-resident immune cell network in the lung".
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DOI: 10.1016/j.immuni.2026.01.023