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 7

Visium spatial transcriptomics of IDO1 and CD274 niches in different dermal variants of leishmaniasis.

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Visium spatial transcriptomics of IDO1 and CD274 niches in different der...
(A) CL lesion caused by L. braziliensis in P1 from Brazil. (B) H&E image from A. (C) Polymorphic PKDL lesion caused by L. donovani in P1 from India. (D) H&E image from C. (E and F) IDO1 and CD274 spatial expression in L. braziliensis CL P1 (E) and L. donovani PKDL P1 (F). (G and H) CD274 and IDO1 expression scatter plots from all spots from L. braziliensis–infected CL skin lesions (n = 4) (see also Supplemental Table 2; thresholds: x = 0.5, y = 0.2) (G) and L. donovani PKDL P1 and P2 (H) (see also Supplemental Table 3; thresholds: x,y = 0.2). (I and J) Spatial plot of IDO1 and PD-L1 expression classes for L. braziliensis CL P1 (I) and L. donovani PKDL P1 (J). (K and L) Differential expression of cytokines, chemokines, ILs, and TNF- and IFN-related and checkpoint markers between IDO1 and CD274 classes in L. braziliensis CL (K) (n = 4) and PKDL (L) (n = 2). (M) Top 50 IDO1- and CD274-correlated genes overlap across SL CL (n = 6), L. braziliensis CL (n = 4), and L. donovani PKDL (n = 2). (See also Supplemental Tables 1–3). Original magnification, ×20 (B, E, and I) and ×21 (D, F, and J).