Hypoxia and IL-15 Cooperate to Induce Perforin Expression by CD8 T Cells and Promote Damage to the Skin in Murine Cutaneous Leishmaniasis.

Abstract

Cutaneous leishmaniasis is a disease caused by protozoan parasites of the genus Leishmania, and although parasites influence disease severity, cytotoxic CD8 T-cell responses mediate damage to the infected skin. We found that the cytotoxic protein perforin was expressed in CD8 T cells only upon recruitment to Leishmania-infected skin, suggesting that lesional inflammatory cues induced perforin. In this study, using a mouse model of Leishmania major infection, we demonstrated that the expression of perforin was driven by a combination of hypoxia and IL-15, both of which are microenvironmental signals present within Leishmania-infected skin. We also demonstrated that the major sources of Il15 mRNA in cutaneous leishmaniasis lesions are neutrophils and macrophages and that macrophages exposed to hypoxia in vitro produce more Il15. Because perforin is only present in lesions, we reformulated a small-molecule perforin inhibitor for topical application and found that local inhibition of perforin is sufficient to ameliorate disease in established cutaneous leishmaniasis. Thus, topical perforin inhibition may be considered a therapeutic strategy for patients with cutaneous leishmaniasis and other inflammatory skin diseases where cytotoxic CD8 T cells contribute to disease pathogenesis.