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 5

CosMx and IHC validation of cellular neighborhoods.

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CosMx and IHC validation of cellular neighborhoods. (A–C) Representative...
(A–C) Representative FOVs from the CosMx transcriptomics dataset showing IDO1mye+CD274+mye cells (pink) interacting with CD8+ memory T cells (T CD8 mem; red) (A), Tregs (magenta) (B), and CCL18 macrophages (CCL18_mac; blue) (C). Noninteracting cells are shown with an “oth_” prefix. (D) IHC images showing IDO1, PD-L1, and CD8a protein expression. Scale bars: 20 μm. (E) Proportion of cells coexpressing IDO1 and PD-L1 from D. (F) IHC images showing CD3ɛ, CD8α, and CD8β protein expression. Scale bars: 20 μm. (G) CD3ɛ+CD8α+CD8β+ T cells/mm² as a proportion of total CD8α+ cells (n = 19). (H–J) CD8α proximity to IDO1+PD-L1+ (H, magenta), IDO1+ (I, cyan), and PD-L1+ cells (J, red). Images in H–J show distance masks in shades of gray at 25, 50, and 100 μm diameter. Graphs in H–J show the proportions of CD8+ T cells by distance (Friedman’s test with Dunn’s adjustment, mean ± SD). Scale bars: 20 μm (D and F) and 40 um (H–J). For panels E and H–J, the right panels show data from 23 SL CL patients (see also Supplemental Table 1); other panels represent data from a single patient.