{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:35:05Z","timestamp":1786116905806,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,4]]},"group-title":"Immunology","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["R01AI162711"],"award-info":[{"award-number":["R01AI162711"]}]},{"name":"NIH","award":["T32 AI165391"],"award-info":[{"award-number":["T32 AI165391"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Cutaneous leishmaniasis is characterized by chronic inflammatory skin lesions in which CD8\u25a1 T cells exhibit paradoxical functions. While IFN-\u03b3-producing CD8\u25a1 T cells contribute to the development of protective immunity in the draining lymph node, CD8\u25a1 T cells recruited to the infected skin lose their ability to produce IFN-\u03b3 and instead acquire cytotoxic functions that exacerbate tissue damage. We previously demonstrated that the hypoxic microenvironment of leishmanial lesions promotes CD8\u25a1 T cell cytotoxicity through induction of Blimp-1. Whether hypoxia also suppresses protective CD8\u25a1 T cell functions, however, is unknown. Here, we show that hypoxia simultaneously suppresses production of the protective cytokines IFN-\u03b3 and TNF-\u03b1 while enhancing expression of granzyme B and perforin in activated CD8\u25a1 T cells. In vitro, HIF-1\u03b1, but not HIF-2\u03b1, was required for hypoxia-induced expression of granzyme B, perforin, and Blimp-1, whereas suppression of IFN-\u03b3 and TNF-\u03b1 occurred independently of HIF signaling, indicating that distinct oxygen-related pathways regulate pathogenic and protective CD8\u25a1 T cell functions. Hypoxia also increased expression of multiple inhibitory receptors on CD8\u25a1 T cells, although lesional CD8\u25a1 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\u03b1 and HIF-2\u03b1 expression in CD8\u25a1 T cells contributed to immunopathology during cutaneous leishmaniasis. Together, these findings identify hypoxia as a key regulator that functionally reprograms CD8\u25a1 T cells by promoting pathogenic cytotoxicity while suppressing protective cytokine production within lesions.<\/jats:p>","DOI":"10.64898\/2026.07.30.741849","type":"posted-content","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T02:05:19Z","timestamp":1785895519000},"source":"Crossref","is-referenced-by-count":0,"title":["Hypoxia induces cytotoxicity and suppresses cytokine production by CD8\u25a1 T cells in cutaneous leishmaniasis"],"prefix":"10.64898","author":[{"given":"Erin A.","family":"Fowler","sequence":"first","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia L.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faaiza","family":"Saif","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9491-0384","authenticated-orcid":false,"given":"Fernanda O.","family":"Novais","sequence":"additional","affiliation":[{"name":"Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080605501247000_2026.07.30.741849v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.72"},{"key":"2026080605501247000_2026.07.30.741849v1.2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003504"},{"key":"2026080605501247000_2026.07.30.741849v1.3","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701597"},{"key":"2026080605501247000_2026.07.30.741849v1.4","first-page":"e03537","article-title":"Step-by-step: the CD8 T cell journey in leishmaniasis","volume":"16","year":"2025","journal-title":"mBio"},{"key":"2026080605501247000_2026.07.30.741849v1.5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/s41577-024-01087-5","article-title":"How oxygenation shapes immune responses: emerging roles for physioxia and pathological hypoxia","volume":"25","year":"2025","journal-title":"Nat Rev Immunol"},{"key":"2026080605501247000_2026.07.30.741849v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0227-y"},{"key":"2026080605501247000_2026.07.30.741849v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2014.121"},{"key":"2026080605501247000_2026.07.30.741849v1.8","doi-asserted-by":"crossref","unstructured":"Fowler, E. 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