HIF-1 stabilization in T cells hampers the control of Mycobacterium tuberculosis infection

• Published in: Nature communications Vol. 13; no. 1; p. 5093
• Main Authors: Liu, Ruining, Muliadi, Victoria, Mou, Wenjun, Li, Hanxiong, Yuan, Juan, Holmberg, Johan, Chambers, Benedict J., Ullah, Nadeem, Wurth, Jakob, Alzrigat, Mohammad, Schlisio, Susanne, Carow, Berit, Larsson, Lars Gunnar, Rottenberg, Martin E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 38; 38/91; 631/250/1619/554/1898/1272; 631/250/2152/1566/1618; 631/250/255/1856; 64; 64/60; CD4 antigen; Cell activation; Cell proliferation; DNA biosynthesis; Flow cytometry; Humanities and Social Sciences; Hypoxia; Hypoxia-inducible factor 1a; Hypoxia-inducible factors; Immune response; Infections; Lymphocytes; Lymphocytes T; Medicin och hälsovetenskap; multidisciplinary; Myc protein; Science; Science (multidisciplinary); T cell receptors; Transcriptomics; Tuberculosis; Vaccination; VHL protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-32639-9

The hypoxia-inducible factors (HIFs) regulate the main transcriptional pathway of response to hypoxia in T cells and are negatively regulated by von Hippel-Lindau factor (VHL). But the role of HIFs in the regulation of CD4 T cell responses during infection with M. tuberculosis isn’t well understood. Here we show that mice lacking VHL in T cells ( Vhl cKO ) are highly susceptible to infection with M. tuberculosis , which is associated with a low accumulation of mycobacteria-specific T cells in the lungs that display reduced proliferation, altered differentiation and enhanced expression of inhibitory receptors. In contrast, HIF-1 deficiency in T cells is redundant for M. tuberculosis control. Vhl cKO mice also show reduced responses to vaccination. Further, VHL promotes proper MYC-activation, cell-growth responses, DNA synthesis, proliferation and survival of CD4 T cells after TCR activation. The VHL-deficient T cell responses are rescued by the loss of HIF-1α, indicating that the increased susceptibility to M. tuberculosis infection and the impaired responses of Vhl -deficient T cells are HIF-1-dependent. The role of hypoxia inducible factors in infection and immune response is unclear. Here, the authors study their impact on the regulation of T cells responses during Mycobacteria tuberculosis infection using transcriptomics, flow cytometry and in vivo infection.