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

Ruining Liu, Victoria Muliadi, Wenjun Mou, Hanxiong Li, Juan Yuan, Johan Holmberg, Benedict J. Chambers, Nadeem Ullah, Jakob Wurth, Mohammad Alzrigat, Susanne Schlisio, Berit Carow, Lars Gunnar Larsson and Martin E. Rottenberg ()
Additional contact information
Ruining Liu: Karolinska Institutet
Victoria Muliadi: Karolinska Institutet
Wenjun Mou: Karolinska Institutet
Hanxiong Li: Karolinska Institutet
Juan Yuan: Karolinska Institutet
Johan Holmberg: Karolinska Institutet
Benedict J. Chambers: Karolinska Institutet
Nadeem Ullah: Karolinska Institutet
Jakob Wurth: Karolinska Institutet
Mohammad Alzrigat: Karolinska Institutet
Susanne Schlisio: Karolinska Institutet
Berit Carow: Karolinska Institutet
Lars Gunnar Larsson: Karolinska Institutet
Martin E. Rottenberg: Karolinska Institutet

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32639-9

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