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 6

CosMx analysis of cellular sources and targets of cytokines in IDO1+ and CD274+ microenvironments.

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CosMx analysis of cellular sources and targets of cytokines in IDO1+ and...
(A–F) Expression of IL32 (A), CXCL9 (B), CCL18 (C), IL24 (D), IFNGR2 (E) and IL1B (F) in the top 5 neighbors from Figure 4G. Data are presented as follows: mean = +, median = vertical line; Kruskal-Wallis with Dunn’s correction. (G and H) Expression of CCL18, IL24, IL1B, IFNGR2, CXCL9, IL32, TNFSF14, and FASLG in the top 5 neighbors of IDO1mye+ and CD274mye+ cells. (I) Heatmap showing the phenotype of neighboring CD8+ memory T cells and Tregs. Scale shows Gini coefficient z scores. Data shown in A–I are from 4 SL CL patients (see also Supplemental Table 1). (J) IL32 isoform (α, β, γ, and δ) fold change versus GAPDH and healthy skin (n = 3) in L. donovani (L. don) CL patients (n = 2) and L. (V.) braziliensis (L. b) CL patients (n = 3). Data indicate the mean ± SD.