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 spontaneously cutaneous lesions induced by Leishmania major. In this report, we show 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 activating signals of IFN-gamma. The observation showing that administration of exogenous recombinant Fas ligand (FasL) to FasL-deficient mice resulted in the resolution of cutaneous lesions demonstrates the importance of the Fas-FasL pathway in the elimination of parasites. Furthermore, macrophages infected with L. major in vitro up-regulate their surface expression of Fas in response to IFN-gamma and as a result become susceptible to CD4+ T cell-induced apoptotic death. These results suggest that the CD4+ T cell-induced apoptotic death of MHC class II-expressing antigen-presenting cells, observed in vitro and operating through the Fas (Apo-1/CD95) pathway, is relevant in vivo.
Conceição-Silva
F
F
WHO Immunology Research & Training Center, University of Lausanne, Epalinges, Switzerland.
Hahne
M
M
Schröter
M
M
Louis
J
J
Tschopp
J
J
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004198:Disease Susceptibility; D053222:Fas Ligand Protein; D007371:Interferon-gamma / Q000494:pharmacology; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D011994:Recombinant Proteins / Q000276:immunology; D014945:Wound Healing; D019014:fas Receptor / Q000235:genetics / Q000276:immunology*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D019014:fas Receptor; D007371:Interferon-gamma