THE RESOLUTION OF LESIONS INDUCED BY LEISHMANIA-MAJOR IN MICE REQUIRES A FUNCTIONAL FAS (APO-1, CD95) PATHWAY OF CYTOTOXICITY

Normal or perforin-deficient C57BL/6 mice are able to heal spontaneous ly cutaneous lesions induced by Leishmania major. In this report, we s how that syngeneic gld and lpr mice, lacking a functional Fas system, fail to heal their lesions. This inability to control infection could not be attributed either to a failure to mount a protective CD4(+) Th1 response or to an unresponsiveness of their macrophages to the activa ting signals of IFN-gamma. The observation showing that administration of exogenous recombinant Fas ligand (Fast) to FasL-deficient mice res ulted in the resolution of cutaneous lesions demonstrates the importan ce of the Fas-FasL pathway in the elimination of parasites. Furthermor e, macrophages infected with L. major in vitro up-regulate their surfa ce expression of Fas in response to IFN-gamma and as a result become s usceptible to CD4(+) T cell-induced apoptotic death. These results sug gest that the CD4(+) T cell-induced apoptotic death of MHC class II-ex pressing antigen-presenting cells, observed in vitro and operating thr ough the Fas (Apo-1/CD95) pathway, is relevant in vivo.