CCR5 promotes the migration of pathological 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. Author summary: Cutaneous leishmaniasis remains a serious disease in many parts of the world, and the current treatment is often ineffective. The increased pathology observed in some patients results from pathologic CD8+ T cells, which promote the lysis of infected cells, leading to tissue destruction without controlling the parasites. Our objective is to develop host-directed therapies that could augment disease resolution. Here, we identify factors involved in CD8+ T cell migration to cutaneous leishmaniasis lesions to reveal additional targets that could be used as host-directed therapies in patients. We found that CD8+ T cells migrate to leishmanial lesions in a CCR5-dependent manner, and by blocking CD8+ T cell migration with maraviroc, an FDA-approved selective inhibitor of CCR5, we decreased disease severity. Thus, we suggest that inhibiting CCR5 by maraviroc may be a useful approach to lessen disease in cutaneous leishmaniasis and other diseases where CD8+ T cell mediates pathology. [ABSTRACT FROM AUTHOR]

Copyright of PLoS Pathogens is the property of Public Library of Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)