Biology subjects

Fowler, E. A.

Publications and source records attributed to Fowler, E. A..

3 recordsLinked to original sources

bioRxiv2026

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{square} T cells exhibit paradoxical functions. While IFN-{gamma}-producing CD8{square} T cells contribute to the development of protective immunity in the draining lymph node, CD8{square} 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{square} T cell cytotoxicity through induction of Blimp-1. Whether hypoxia also suppresses protective CD8{square} 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{square} 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{square} T cell functions. Hypoxia also increased expression of multiple inhibitory receptors on CD8{square} T cells, although lesional CD8{square} 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{square} T cells contributed to immunopathology during cutaneous leishmaniasis. Together, these findings identify hypoxia as a key regulator that functionally reprograms CD8{square} T cells by promoting pathogenic cytotoxicity while suppressing protective cytokine production within lesions.

immunology↗

bioRxiv2026

Acriflavine treatment attenuates inflammatory pathology in cutaneous leishmaniasis independently of parasite control

Cutaneous leishmaniasis is a parasitic skin disease for which current treatments often fail, highlighting the need for new therapeutic approaches. While high parasite burdens are associated with delayed healing, excessive protective immune responses, including elevated IFN-{gamma} production, have also been linked to worse clinical outcomes, indicating that immunopathology contributes significantly to disease progression. Acriflavine is an antimicrobial compound with reported anti-leishmanial activity and the ability to inhibit hypoxia-driven responses. Because Leishmania-infected skin is hypoxic in both mice and humans, and hypoxia has been implicated in disease pathogenesis, we investigated whether acriflavine alters the course of cutaneous leishmaniasis by affecting parasite control and/or host immune responses. We found that acriflavine treatment significantly reduced lesion size in Leishmania major-infected mice. Unexpectedly, this improvement occurred without changes in parasite burden. Instead, acriflavine treatment reduced the frequency of dendritic cells within lesions and decreased their expression of MHC class II, which correlated with fewer IFN-{gamma}-producing CD4 T cells at the site of infection. These findings indicate that acriflavine ameliorates disease by limiting dendritic cell activation and subsequent IFN-{gamma}-driven immunopathology rather than enhancing parasite clearance. Together, our results identify acriflavine as a potential host-directed therapeutic strategy for cutaneous leishmaniasis and support targeting hypoxia-associated pathways to reduce tissue damage driven by excessive inflammatory responses.

immunology↗

bioRxiv2023

Pathogenic CD8 T cell responses are driven by neutrophil-mediated hypoxia in cutaneous leishmaniasis.

Cutaneous leishmaniasis caused by Leishmania parasites exhibits a wide range of clinical manifestations. Although parasites influence disease severity, cytolytic CD8 T cell responses mediate disease. While these responses originate in the lymph node, we find that expression of the cytolytic effector molecule granzyme B is restricted to lesional CD8 T cells in Leishmania- infected mice, suggesting that local cues within inflamed skin induce cytolytic function. Expression of Blimp-1 (Prdm1), a transcription factor necessary for cytolytic CD8 T cell differentiation, is driven by hypoxia within the inflamed skin. Hypoxia is further enhanced by the recruitment of neutrophils that consume oxygen to produce reactive oxygen species, ultimately increasing granzyme B expression in CD8 T cells. Importantly, lesions from cutaneous leishmaniasis patients exhibit hypoxia transcription signatures that correlate with the presence of neutrophils. Thus, targeting hypoxia-driven signals that support local differentiation of cytolytic CD8 T cells may improve the prognosis for patients with cutaneous leishmaniasis, as well as other inflammatory skin diseases where cytolytic CD8 T cells contribute to pathogenesis.

immunology↗