Hypoxia induces cytotoxicity and suppresses cytokine production by CD8□ T cells in cutaneous leishmaniasis.

Cutaneous leishmaniasis is characterized by chronic inflammatory skin lesions in which CD8□ T cells exhibit paradoxical functions. While IFN-γ-producing CD8□ T cells contribute to the development of protective immunity in the draining lymph node, CD8□ T cells recruited to the infected skin lose their ability to produce IFN-γ and instead acquire cytotoxic functions that exacerbate tissue damage. We previously demonstrated that the hypoxic microenvironment of leishmanial lesions promotes CD8□ T cell cytotoxicity through induction of Blimp-1. Whether hypoxia also suppresses protective CD8□ T cell functions, however, is unknown. Here, we show that hypoxia simultaneously suppresses production of the protective cytokines IFN-γ and TNF-α while enhancing expression of granzyme B and perforin in activated CD8□ T cells. In vitro, HIF-1α, but not HIF-2α, was required for hypoxia-induced expression of granzyme B, perforin, and Blimp-1, whereas suppression of IFN-γ and TNF-α occurred independently of HIF signaling, indicating that distinct oxygen-related pathways regulate pathogenic and protective CD8□ T cell functions. Hypoxia also increased expression of multiple inhibitory receptors on CD8□ T cells, although lesional CD8□ T cells lacked expression of the terminal exhaustion-associated transcription factor TOX, suggesting that hypoxia promotes an inhibitory phenotype distinct from terminal exhaustion. Finally, adoptive transfer studies demonstrated that in vivo both HIF-1α and HIF-2α expression in CD8□ T cells contributed to immunopathology during cutaneous leishmaniasis. Together, these findings identify hypoxia as a key regulator that functionally reprograms CD8□ T cells by promoting pathogenic cytotoxicity while suppressing protective cytokine production within lesions.