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T Cell Dysfunction in Cutaneous Leishmaniasis at Single-Cell Resolution

Avila, J. P.; Singh, Y.; de Souza, F. M.; de Assuncao, S. F.; Damasceno, S.; Guedes, H. L. d. S.; Cunha, T. M.; Fillho, R. B.; da Silva, J. S.; Nakaya, H. I.

2025-02-25 infectious diseases
10.1101/2025.02.21.25322565 medRxiv
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BackgroundCutaneous leishmaniasis (CL) is characterized by immune dysregulation that facilitates chronic infection. ObjectiveTo investigate the role of T cells in the immunopathology of CL by characterizing the immune landscape of skin lesions using single-cell RNA sequencing (scRNA-seq). MethodsWe performed scRNA-seq to profile T cells from PBMC and skin lesions of CL patients. ResultsWe analyzed the transcriptional profile of distinct populations of CD4+ and CD8+ migratory T cells in CL lesions. CD8+ resident T cells displayed expression of exhaustion markers and were categorized into progenitor, transitional, and terminal stages, with HAVCR2 (TIM-3) identified as a potential driver of dysfunction. Compared to psoriasis and healthy skin, CL lesions showed a reduced frequency of regulatory T cells (Tregs), potentially linked to oxidative stress, DNA damage, and increased apoptosis. We also detected double-negative (DN) {gamma}{delta} T cells, suggesting their potential role in antigen presentation via MHC class II through TGF-{beta} signaling. ConclusionThis study provides novel insights into immune evasion mechanisms in CL, identifying TIM-3, Treg modulation, and the functional role of DN {gamma}{delta} T cells as distinct potential targets for future immunotherapies.

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