Hypoxia Inducible Factor Signaling Limits Cytotoxic T-cell Exhaustion

Chronic exposure to viral or tumor antigens dampens the function of CD8⁺ cytotoxic T lymphocytes (CTL), presumably as an evolved mechanism to limit immune system–mediated destructive and potentially lethal tissue damage. The transcription factors hypoxia-inducible factor (HIF) 1α and HIF2α, which are activated in response to hypoxia and other stimuli such as T-cell receptor signaling, have been implicated in innate immunity and the function of specific T-cell subsets; however, the role of HIF signaling in CD8⁺ CTL responses to persistent antigen stimulation is unclear. Doedens and colleagues found that T-cell–specific deletion of von Hippel-Lindau (Vhl), which encodes a tumor suppressor that negatively regulates HIF activity, resulted in increased immunopathology and mortality in response to chronic but not acute viral infection. This sustained immune response was mediated by CD8⁺ T-cells and was dependent on enhanced HIF expression in the absence of Vhl. Increased HIF activity stimulated expression of glycolytic pathway genes and suppressed oxidative phosphorylation, consistent with HIF activity in other cell types. Unexpectedly, HIFs limited terminal differentiation of CD8⁺ T cells, and HIFα stabilization in Vhl-deficient CTLs or in response to hypoxia or cytokines induced the expression of genes encoding both T-cell activating and inhibitory receptors, transcription factors that regulate CD8⁺ T-cell differentiation, and essential CTL effector molecules including multiple granzymes and cytokines such as TNF. HIF-driven maintenance of this CTL effector signature was dependent in part on increased glycolytic flux in activated CTLs. Furthermore, Vhl deficiency also enhanced the ability of CTLs to suppress the growth of established melanoma tumors, supporting the idea that elevated HIF signaling limits T-cell exhaustion and loss of CTL responsiveness following persistent antigen exposure. These results suggest that therapeutic enhancement of HIF activity in CTLs may improve antiviral and antitumor responses.

Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, et al. Hypoxia-inducible factors enhance the effector responses of CD8⁺ T cells to persistent antigen. Nat Immunol 2013 Sept 29 [Epub ahead of print].