CD8 +T cells require CCR5 expression to mediate immunopathology in cutaneous leishmaniasis

Abstract

Abstract Cytolytic CD8 +T cells mediate immunopathology in cutaneous leishmaniasis by a mechanism dependent on degranulation and lysis of Leishmania-infected cells, culminating in NLRP3 activation and IL-1b release. Here, we sought to identify chemokine receptors involved in CD8 +T cell migration to the lesion that could be employed as a treatment target to ameliorate disease severity. A transcriptional study identified the profile of chemokine receptors that predicts treatment failure in Leishmania braziliensispatients and identifies possible targets that may be involved in CD8 +T cell migration. Using murine models of cutaneous leishmaniasis, we found that around 20% of CD8 +T-cells express CCR5 in lesions at the peak of the disease. In previous studies, we found that CD8 +T cells transferred to Rag1 −/−mice mediated increased NLRP3 and IL-1b dependent disease. Therefore, to test if CCR5 expression on CD8 +T cells was involved in their migration to lesions, we transferred wild-type or CCR5 −/−CD8 +T cells to L. braziliensisinfected Rag1 −/−mice. While infected Rag1 −/−mice reconstituted with wild-type CD8 +T cells developed severe pathology, Rag1 −/−mice that received CCR5 −/−CD8 +T cells developed smaller lesions accompanied by a significant reduction in the number of CD8 +T cells in the lesions. To test whether CCR5 blockade would control disease severity, we used maraviroc (MVC), a selective inhibitor of CCR5 approved by the FDA. MVC treatment significantly reduced lesion development without affecting parasite number in our murine models. Collectively, these results demonstrate that cytolytic CD8 +T cells migrate to leishmania lesions in a CCR5-dependent manner, and MVC treatment efficiently prevents CD8 +T-cell mediated pathology. R01 AI106842 and U01 AI08865006