Neutrophil-mediated hypoxia drives pathogenic CD8+ T cell responses in cutaneous leishmaniasis
Erin A. Fowler, … , Patrick L. Collins, Fernanda O. Novais
Erin A. Fowler, … , Patrick L. Collins, Fernanda O. Novais
Published June 4, 2024
Citation Information: J Clin Invest. 2024;134(14):e177992. https://doi.org/10.1172/JCI177992.
View: Text | PDF
Research Article Infectious disease Inflammation

Neutrophil-mediated hypoxia drives pathogenic CD8+ T cell responses in cutaneous leishmaniasis

Abstract

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. Although 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 ROS and ultimately increased the hypoxic state and granzyme B expression in CD8+ T cells. Importantly, lesions from patients with cutaneous leishmaniasis 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 for other inflammatory skin diseases in which cytolytic CD8+ T cells contribute to pathogenesis.

Authors

Erin A. Fowler, Camila Farias Amorim, Klauss Mostacada, Allison Yan, Laís Amorim Sacramento, Rae A. Stanco, Emily D.S. Hales, Aditi Varkey, Wenjing Zong, Gary D. Wu, Camila I. de Oliveira, Patrick L. Collins, Fernanda O. Novais

×

Figure 1

CD8+ T cell function is tissue specific.

Options: View larger image (or click on image) Download as PowerPoint
CD8+ T cell function is tissue specific. (A) GzmB expression in CD8+ T c...
(A) GzmB expression in CD8+ T cells from dLNs and lesions from C57BL/6 mice in week 2 after infection with L. major. Data are representative of more than 3 experiments with at least 4 mice per experiment. (B) GzmB expression in CD8+ T cells from dLNs and lesions from L. major–infected C57BL/6 mice treated with FTY720 or vehicle daily for 10 days, 12 days after infection. Data are from 2 independent experiments with 5 mice per group. (C) Schematic representation of the transfer of purified CD8+ T cells from dLNs of CD45.2 mice into the lesions of CD45.1 recipients, both infected for 3 weeks. Flow cytometric plot shows GzmB expression in donor CD8+ T cells from dLNs and lesions from recipient mice 48 hours after transfer. Data were combined from 2 independent experiments. (D–H) RNA-Seq analyses of antigen-experienced (CD44hi) CD8+ T cells purified from dLNs and lesions of L. major–infected mice in week 5. (D) PCA showing PC1 and PC2. (E) Volcano plot highlighting the top 5 DEGs. The orange line indicates an adjusted P value of 0.05. (F) Heatmap showing the expression of genes encoding transcription factors (TFs) associated with effector-like T cell functions and the FC between lesional and dLN CD8+ T cells. (G) GSEA (Biocarta) showing pathways enriched in dLNs (green) and lesions (purple). NES, normalized enrichment score. (H) Heatmap of hypoxia-related pathways enriched in lesional and dLN CD8+ T cells. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001, by 2-tailed Student’s t test (A , C, and F) and 1-way ANOVA (B).