CCR5 promotes the migration of CD8+ T cells to the leishmanial lesions

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, Leishmania-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. Rag1-/- mice were infected withL. braziliensis(strain MHOM/BR/01/BA788) and subsequently reconstituted with CD8+ T cells alone or CD8+ and CD4+ T cells or did not receive any T cells. 5 weeks post-infection, mice were euthanized, and ears were collected in RNAlater

溶细胞性CD8+ T细胞（cytolytic CD8+ T cells）在皮肤利什曼病中介导免疫病理损伤，却无法控制寄生虫增殖。本研究旨在鉴定参与CD8+ T细胞向皮损部位迁移的潜在靶点，以改善疾病严重程度。患者皮损中表达量最高的趋化因子受体为CCR5，而CCR5的配体CCL3与CCL4的高表达与皮损愈合延迟相关。为验证CCR5的必要性，我们将CCR5敲除的CD8+ T细胞过继转移至利什曼原虫（Leishmania）感染的Rag1基因敲除（Rag1-/-）小鼠体内。结果显示，与对照组相比，该组小鼠的皮损体积更小，且皮损内CD8+ T细胞数量减少。我们进一步使用CCR5选择性抑制剂马拉韦罗（maraviroc）阻断CCR5功能，结果证实该处理可抑制皮损进展，但不影响寄生虫载量，从而验证了上述发现。综上，本研究结果表明CD8+ T细胞向利什曼原虫感染皮损的迁移依赖CCR5通路，而阻断CCR5可抑制CD8+ T细胞介导的免疫病理损伤。我们将Rag1基因敲除小鼠感染巴西利什曼原虫（L. braziliensis，菌株MHOM/BR/01/BA788），随后分别过继转移单独的CD8+ T细胞、CD8+与CD4+ T细胞，或不进行T细胞过继移植。感染5周后处死小鼠，将耳部组织置于RNAlater试剂中保存。