title: Differential expression of Fas and Fas ligand in acute and chronic graft-versus-host disease: up-regulation of Fas and Fas ligand requires CD8+ T cell activation and IFN-gamma production.
abstract: The parent-into-F1 model of acute and chronic graft-vs-host disease (GVHD) was used as an example of in vivo cell-mediated or Ab-mediated responses, respectively, and the roles of Fas and Fas ligand (FasL) were investigated. Using both flow cytometry and PCR methodologies, we found that acute GVHD mice exhibited significant up-regulation of Fas and FasL, whereas Fas/FasL up-regulation in chronic GVHD mice was equal to or marginally greater than that in uninjected mice. Functional studies confirmed that Fas/FasL contributed to the anti-host CTL activity of splenocytes from acute GVHD mice, although a perforin-dependent pathway was also identified. Despite the presence of FasL on both donor CD4+ and CD8+ T cells in acute GVHD mice, depletion studies demonstrated that all the in vitro anti-host CTL activity resided in the CD8+ population. Furthermore, injection of CD8-depleted B6 spleen cells into F1 mice blocked Fas/FasL up-regulation and IFN-gamma production, resulting in chronic GVHD. Lastly, up-regulation of Fas/FasL in acute GVHD mice could be blocked by anti-IFN-gamma mAb in vivo. Thus, in this in vivo model of alloantigen immune responsiveness, Fas/FasL up-regulation is critically dependent on Ag-specific (donor) CD8+ T cell activation and IFN-gamma production. Donor CD4+ T cell activation in the absence of CD8+ T cell activation results in an autoantibody-mediated response, no significant Fas/FasL up-regulation, impaired elimination of autoreactive B cells, and persistent humoral autoimmunity.
authors.affiliation: Department of Veteran Affairs Medical Center, Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore 21201, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shustov
authors.forename: P
authors.initials: P
authors.lastname: Nguyen
authors.forename: F
authors.initials: F
authors.lastname: Finkelman
authors.forename: K B
authors.initials: KB
authors.lastname: Elkon
authors.forename: C S
authors.initials: CS
authors.lastname: Via
mesh_terms: D000208:Acute Disease; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002908:Chronic Disease; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis*; D008024:Ligands; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000637:transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014019:Tissue Donors; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma