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Abstract：
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.
摘要：
由巴西乳杆菌引起的播散性利什曼病（DL）的特征是存在10至1000多个散布在身体上的病变。虽然对抗利什曼原虫的保护是由CD4+T细胞产生的IFN-γ激活后的巨噬细胞介导的，播散性利什曼病（DL）的病理可由巨噬细胞介导，NK,和CD8+T细胞。在这里，我们评估了衰老CD8+T细胞在DL发病机制中的参与。方法：外周血单核细胞（PBMC），活检,CD8+T细胞与未感染和感染的巨噬细胞（MØ）的共培养，和来自皮肤利什曼病（CL）和DL患者的可溶性巴西乳杆菌抗原（SLA）刺激72小时的PBMC培养物用于表征衰老的CD8T细胞。使用Mann-Whitney和Kruskal-Wallis检验进行统计分析，其次是邓恩。结果：DL患者循环CD8+T细胞的频率增加，呈现记忆/衰老表型，而来自DL患者的病变具有衰老/脱颗粒表型的浸润CD8+T细胞的频率增加。此外,经过特定的刺激，DL患者循环CD8+T具有记忆/衰老特征，显示脱粒特征，在SLA刺激下增加，那些来自DL患者的特异性CD8+T细胞的脱颗粒表型增加，导致更多的受感染的靶细胞凋亡。结论：与CL患者相比，DL患者表现出更高的细胞毒性衰老CD8+T细胞频率，这可以促进被感染细胞的裂解，虽然没有寄生虫杀死，利什曼原虫释放到细胞外室，有助于寄生虫的传播。
