IL-32–producing CD8+ memory T cells define immunoregulatory niches in human cutaneous leishmaniasis
Nidhi S. Dey, Shoumit Dey, Naj Brown, Sujai Senarathne, Luiza Campos Reis, Ritika Sengupta, Jose A.L. Lindoso, Sally R. James, Lesley Gilbert, Dave Boucher, Mitali Chatterjee, Hiro Goto, Shalindra Ranasinghe, Paul M. Kaye
Nidhi S. Dey, Shoumit Dey, Naj Brown, Sujai Senarathne, Luiza Campos Reis, Ritika Sengupta, Jose A.L. Lindoso, Sally R. James, Lesley Gilbert, Dave Boucher, Mitali Chatterjee, Hiro Goto, Shalindra Ranasinghe, Paul M. Kaye
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Research Article Dermatology Immunology Infectious disease

IL-32–producing CD8+ memory T cells define immunoregulatory niches in human cutaneous leishmaniasis

Abstract

Human cutaneous leishmaniasis (CL) is characterized by chronic skin pathology. Experimental and clinical data suggest that immune checkpoints (ICs) play a crucial role in disease outcome, but the cellular and molecular niches that facilitate IC molecule expression during leishmaniasis are ill defined. In Sri Lankan patients with CL, indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death–ligand 1 (PD-L1) were enriched in skin lesions, and reduced PD-L1 expression early after treatment initiation was predictive of a cure rate following antimonial therapy. Here, we used spatial cell interaction mapping to identify IL-32–expressing CD8+ memory T cells and Tregs as key components of the IDO1/PD-L1 niche in Sri Lankan patients with CL and in patients with distinct forms of dermal leishmaniasis in Brazil and India. Furthermore, the abundance of IL-32+ cells and IL-32+CD8+ T cells at treatment initiation was negatively correlated with the rate of cure in Sri Lankan patients. This study provides insights into the spatial mechanisms underpinning IC expression during CL and offers a strategy for identifying additional biomarkers of treatment response.

Authors

Nidhi S. Dey, Shoumit Dey, Naj Brown, Sujai Senarathne, Luiza Campos Reis, Ritika Sengupta, Jose A.L. Lindoso, Sally R. James, Lesley Gilbert, Dave Boucher, Mitali Chatterjee, Hiro Goto, Shalindra Ranasinghe, Paul M. Kaye

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Figure 2

CosMx single-cell transcriptomics imaging of cutaneous lesions from Sri Lankan patients.

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CosMx single-cell transcriptomics imaging of cutaneous lesions from Sri ...
(A–D) Single-cell spatial mapping of CL lesions. (A) H&E-stained image of a lesion from patient P3 showing FOVs analyzed using NanoString CosMx. Scale bar: 500 μm. (B–D) UMAP by patient number (B) and cell type (C), and cell-type–specific top genes heatmap (D). (E) Single-cell map of stitched FOVs of P3 biopsy with magnified regions (boxes a–d). mDC, myeloid DC; pDC, plasmacytoid DC; mem, memory. (F) Gene expression dot plot across myeloid subtypes. (G) UMAP of subclustered myeloid cells. res, resident; infl, inflammatory; cDC2, type 2 conventional DCs. (H and I) Violin plots showing IDO1 (H) and CD274 (I) expression in the top 2 highest-expressing cells, sorted by average cluster expression level. (J) Spatial localization of DC subset: DC3 and monocyte-derived DC subsets moDC2 and moDC3 in P3 with magnified regions. Panels B–D and F–I show data from 4 SL CL patients (P3–P6; Supplemental Table 1); other panels represent data from a single patient.