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

The parent-into-F-1 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 how 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 Fast 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 F-1 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.