The Role of Senescent CD8⁺T Cells in the Pathogenesis of Disseminated Leishmaniasis

Disseminated leishmaniasis (DL) caused by L. braziliensis is characterized by the presence of 10 to more than 1000 lesions spread on the body. While protection against Leishmania is mediated by macrophages upon activation by IFN-γ produced by CD4⁺T cells, the pathology of disseminated leishmaniasis (DL) could be mediated by macrophages, NK, and CD8⁺T cells. Herein, we evaluate the participation of senescent CD8⁺T cells in the pathogenesis of DL. Methods: Peripheral blood mononuclear cells (PBMCs), biopsies, co-cultures of CD8⁺T cells with uninfected and infected macrophages (MØ), and PBMC cultures stimulated with soluble L. braziliensis antigen (SLA) for 72 h from patients with cutaneous leishmaniasis (CL) and DL were used to characterize senescent CD8⁺T cells. Statistical analysis was performed using the Mann-Whitney and Kruskal-Wallis tests, followed by Dunn's. Results: Patients with DL have an increase in the frequency of circulating CD8⁺T cells that present a memory/senescent phenotype, while lesions from DL patients have an increase in the frequency of infiltrating CD8⁺T cells with a senescent/degranulation phenotype. In addition, after specific stimuli, DL patients' circulating CD8⁺T with memory/senescent profile, showing degranulation characteristics, increased upon SLA stimuli, and those specific CD8⁺T cells from DL patients had an increased degranulation phenotype, causing more apoptosis of infected target cells. Conclusions: DL patients show a higher frequency of cytotoxic senescent CD8⁺T cells compared to CL patients, and that could promote the lysis of infected cells, although without parasite killing, releasing Leishmania to the extracellular compartment, contributing to the spread of parasites.