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

Authors

Fowler, E. A., Schneider, O. L., Saif, F., Novais, F. O.

Abstract

Cutaneous leishmaniasis is characterized by chronic inflammatory skin lesions in which CD8 T cells exhibit paradoxical functions. While IFN-{gamma}-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-{gamma} 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-{gamma} and TNF- while enhancing expression of granzyme B and perforin in activated CD8 T cells. In vitro, HIF-1, but not HIF-2, was required for hypoxia-induced expression of granzyme B, perforin, and Blimp-1, whereas suppression of IFN-{gamma} and TNF- 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-1 and HIF-2 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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Aug 2026.

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