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

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. 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-1 alpha, indicating that the increased susceptibility to M. tuberculosis infection and the impaired responses of Vhl-deficient T cells are HIF-1-dependent.

Automated summary

In this study, the researchers investigated the role of hypoxia-inducible factors (HIFs) in the regulation of T cell responses during Mycobacteria tuberculosis infection. They found that mice lacking von Hippel-Lindau factor (VHL) in T cells were more susceptible to M. tuberculosis infection and exhibited reduced accumulation and impaired function of mycobacteria-specific T cells. Interestingly, deficiency in HIF-1 in T cells did not have an impact on M. tuberculosis control. These findings suggest that VHL plays an important role in T cell responses during M. tuberculosis infection, which is dependent on HIF-1.