Neutrophil-mediated hypoxia drives pathogenic CD8 T cell responses 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 found that expression of the cytolytic effecto...

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Bibliographic Details
Published in:The Journal of clinical investigation 2024-07, Vol.134 (14), p.1-14
Main Authors: Fowler, Erin A, Farias Amorim, Camila, Mostacada, Klauss, Yan, Allison, Amorim Sacramento, Laís, Stanco, Rae A, Hales, Emily Ds, Varkey, Aditi, Zong, Wenjing, Wu, Gary D, de Oliveira, Camila I, Collins, Patrick L, Novais, Fernanda O
Format: Article
Language:English
Subjects:
Antigens
CD8 antigen
Cell death
Cell differentiation
Cutaneous leishmaniasis
Cytotoxicity
Effector cells
Hypoxia
Infections
Leishmania
Leukocytes (neutrophilic)
Lymph nodes
Lymphocytes
Lymphocytes T
Neutrophils
Parasites
Parasitic diseases
Pathogenesis
Protozoa
Reactive oxygen species
Skin diseases
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Summary: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 found that expression of the cytolytic effector molecule granzyme B was restricted to lesional CD8 T cells in Leishmania-infected mice, suggesting that local cues within inflamed skin induced cytolytic function. Expression of Blimp-1 (Prdm1), a transcription factor necessary for cytolytic CD8 T cell differentiation, was driven by hypoxia within the inflamed skin. Hypoxia was further enhanced by the recruitment of neutrophils that consumed oxygen to produce reactive oxygen species and ultimately increased the hypoxic state and granzyme B expression in CD8 T cells. Importantly, lesions from cutaneous leishmaniasis patients exhibited hypoxia transcription signatures that correlated 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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI177992