HIF-1a+ CD4 T cells coordinate a tissue resident immune cell network in the lung [scRNA-seq]
Pulmonary infection leads to the development of CD4+ T resident helper (TRH) cells in the lung. TRH cells generated after influenza infection support local humoral responses and exhibit differentiation plasticity following infectious challenge. A subset of TRH cells is enriched for expression of the transcription factor HIF-1a which has unknown function in the lung. Here we find that inducible deletion of HIF-1a in CD4 T cells leads to decreased numbers of CXCR6+ tissue resident T cells with minimal impact on peripheral lymphoid responses. At the same time, HIF-1a deletion impairs the replenishment of tissue resident macrophages and NK cells, as well as influenza specific IgA titers. These seemingly disparate responses converge upon a requirement for IL-21 produced by HIF-1a+ CD4 T cells. A similar HIF-1a dependent network is engaged in a lung adenocarcinoma model, highlighting novel roles for HIF-1a+ CD4 T cells in coordinating protective immunity during infection and cancer. Overall design: Following influenza infection control (Hif1a wt/wt CD4 ert2 ki wt ROSA ki wt) and Hif1a KO mice (Hif1a fl/fl CD4 ert2 ki wt ROSA ki wt) were treated with tamoxifen to delete Hif1a in CD4 T cells.  Individual mice were hashtagged, and CD45+ cells were sorted from lungs at d45 p.i. and submitted for library preparation.