CCR5 promotes the migration of CD8+ T cells to the leishmanial lesions (S2W)
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. Overall design: C57BL/6 mice were topically colonized with 10^8 S. epidermidis every day for a total of five applications and then intradermally infected with 2 x 10^6 L. major parasites. Staphylococcus epidermidis strain Tu3298 expressing a fluorescent protein mCherry (S2W) was a gift of Dr. Tiffany Scharschmidt (UCSF). Mice were colonized once per week for the duration of the experiment. At 5 weeks post-infection, lesions were obtained for bulk RNA-seq.