title: Activation of alloreactive CD8+ T cells operates via CD4-dependent and CD4-independent mechanisms and is CD154 blockade sensitive.
abstract: CD154, one of the most extensively studied T cell costimulation molecules, represents a promising therapeutic target in organ transplantation. However, the immunological mechanisms of CD154 blockade that result in allograft protection, particularly in the context of alloreactive CD4/CD8 T cell activation, remain to be elucidated. We now report on the profound inhibition of alloreactive CD8(+) T cells by CD154 blockade via both CD4-dependent and CD4-independent activation pathways. Using CD154 KO recipients that are defective in alloreactive CD8(+) T cell activation and unable to reject cardiac allografts, we were able to restore CD8 activation and graft rejection by adoptively transferring CD4(+) or CD8(+) T cells from wild-type syngeneic donor mice. CD4-independent activation of alloreactive CD8(+) T cells was confirmed following treatment of wild-type recipients with CD4-depleting mAb, and by using CD4 KO mice. Comparable levels of alloreactive CD8(+) T cell activation was induced by allogenic skin engraftment in both animal groups. CD154 blockade inhibited CD4-independent alloreactive CD8(+) T cell activation. Furthermore, we analyzed whether disruption of CD154 signaling affects cardiac allograft survival in skin-sensitized CD4 KO and CD8 KO recipients. A better survival rate was observed consistently in CD4 KO, as compared with CD8 KO recipients. Our results document CD4-dependent and CD4-independent activation pathways for alloreactive CD8(+) T cells that are both sensitive to CD154 blockade. Indeed, CD154 blockade was effective in preventing CD8(+) T cell-mediated cardiac allograft rejection.
authors.affiliation: Dumont-University of California, Los Angeles, Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, School of Medicine, 90095, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhai
authors.forename: Lingzhong
authors.initials: L
authors.lastname: Meng
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D016827:CD8 Antigens / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology; D007275:Injections, Intravenous; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D008211:Lymphocyte Cooperation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D016038:Skin Transplantation / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016827:CD8 Antigens; D007519:Isoantigens; D023201:CD40 Ligand