Sacramento Laís Amorim, Amorim Camila Farias, Lombana Claudia G, Beiting Daniel, Novais Fernanda, Carvalho Lucas P, Carvalho Edgar M, Scott Phillip
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, PA 19104-4539, USA.
Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH, USA.
bioRxiv. 2023 Oct 13:2023.10.10.561700. doi: 10.1101/2023.10.10.561700.
Cytolytic CD8 T cells mediate immunopathology in cutaneous leishmaniasis without controlling parasites. Here, we identify factors involved in CD8 T cell migration to the lesion that could be targeted to ameliorate disease severity. CCR5 was the most highly expressed chemokine receptor in patient lesions, and the high expression of CCL3 and CCL4, CCR5 ligands, was associated with delayed healing of lesions. To test the requirement for CCR5, infected Rag1 mice were reconstituted with CCR5 CD8 T cells. We found that these mice developed smaller lesions accompanied by a reduction in CD8 T cell numbers compared to controls. We confirmed these findings by showing that the inhibition of CCR5 with maraviroc, a selective inhibitor of CCR5, reduced lesion development without affecting the parasite burden. Together, these results reveal that CD8 T cells migrate to leishmanial lesions in a CCR5-dependent manner and that blocking CCR5 prevents CD8 T cell-mediated pathology.
细胞溶解性CD8 T细胞在皮肤利什曼病中介导免疫病理反应，但无法控制寄生虫。在此，我们确定了参与CD8 T细胞迁移至病灶的因素，这些因素可作为靶点以减轻疾病严重程度。CCR5是患者病灶中表达最高的趋化因子受体，CCR5配体CCL3和CCL4的高表达与病灶愈合延迟相关。为了测试对CCR5的需求，用CCR5缺陷的CD8 T细胞重建感染的Rag1小鼠。我们发现，与对照组相比，这些小鼠的病灶较小，同时CD8 T细胞数量减少。我们通过使用CCR5的选择性抑制剂马拉维若抑制CCR5来证实这些发现，结果显示这可减少病灶发展，而不影响寄生虫负荷。总之，这些结果表明，CD8 T细胞以CCR5依赖的方式迁移至利什曼病灶，阻断CCR5可预防CD8 T细胞介导的病理反应。
