Reduction of antiviral CD8 lymphocytes in vivo with dendritic cells expressing Fas ligand-increased survival of viral (lymphocytic choriomeningitis virus) central nervous system infection.
In vivo administration of APC expressing Fas ligand (Fas-L(+) dendritic cells (DCs)) has shown promise in dampening allergic reactions and transplant rejection. Since the effect in these studies was mainly on CD4 lymphocytes, our goal was to evaluate the ability of such killer DCs to eliminate antiviral CD8 lymphocytes and in this way ameliorate viral immunopathology or, conversely, impede viral clearance. Intravenous administration of Fas-L(+) DCs resulted in a 50% reduction of lytic CD8 precursors following intracerebral infection with lymphocytic choriomeningitis virus (LCMV), and accordingly, immunopathology and survival of LCMV meningitis were improved, whereas viral clearance remained unaffected. In transfer studies the effect of the Fas-L(+) DCs was only quantifiable on experienced, not naive, CD8 lymphocytes. Importantly, loading of Fas-L(+) DCs with viral Ag before therapy was not necessary to achieve this effect, indicating that non-LCMV-infected Fas-L(+) DCs acquired viral Ag during acute LCMV infection in vivo. Our studies delineate important aspects for the clinical use of Fas-L(+) DCs in vivo. One should expect that they acquire viral Ags and suppress antiviral CD8 responses to some degree when given while an acute infection is ongoing. In terms of safety it is encouraging that resolution of the infection, at least in the case of LCMV, is not inhibited.
Wolfe
Tom
T
Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
Asseman
Chrystelle
C
Hughes
Anna
A
Matsue
Hiroyuki
H
Takashima
Akira
A
von Herrath
Matthias G
MG
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation / Q000821:virology; D053222:Fas Ligand Protein; D007275:Injections, Intravenous; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000401:mortality* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D016019:Survival Analysis; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor