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The hypoxia-inducible factors (HIFs) regulate the main transcriptional pathway of response to hypoxia in T cells and are negatively regulated by vonHippel-Lindau factor (VHL). But the role of HIFs in the regulation of CD4 T cellresponses during infection with M. tuberculosis isn’t well understood. Here weshow that mice lacking VHL in T cells (Vhl cKO) are highly susceptible toinfection with M. tuberculosis, which is associated with a low accumulation ofmycobacteria-specific T cells in the lungs that display reduced proliferation,altered differentiation and enhanced expression of inhibitory receptors. Incontrast, HIF-1 deficiency in T cells is redundant for M. tuberculosis control. VhlcKO mice also show reduced responses to vaccination. Further, VHL promotesproper MYC-activation, cell-growth responses, DNA synthesis, proliferationand survival of CD4 T cells after TCR activation. The VHL-deficient T cellresponses are rescued by the loss of HIF-1α, indicating that the increasedsusceptibility to M. tuberculosis infection and the impaired responses of Vhldeficient T cells are HIF-1-dependent.