title: In vivo helper functions of alloreactive memory CD4+ T cells remain intact despite donor-specific transfusion and anti-CD40 ligand therapy.
abstract: Memory T cells have specific properties that are beneficial for rapid and efficient protection from pathogens previously encountered by a host. These same features of memory T cells may be deleterious in the context of a transplanted organ. Consistent with this contention is the accumulating evidence in experimental transplantation that previously sensitized animals are resistant to the effects of costimulatory blockade. Using a model of murine cardiac transplantation, we now demonstrate that alloreactive memory CD4(+) T cells prevent long-term allograft survival induced through donor-specific cell transfusion in combination with anti-CD40 ligand Ab (DST/anti-CD40L). We show that memory donor-reactive CD4(+) T cells responding through the direct or indirect pathways of allorecognition provide help for the induction of antidonor CD8(+) T effector cells and for Ab isotype switching, despite DST/anti-CD40L. The induced pathogenic antidonor immunity functions in multiple ways to subsequently mediate graft destruction. Our findings show that the varied functions of alloreactive memory CD4(+) T cells remain intact despite DST/anti-CD40L-based costimulatory blockade, a finding that will likely have important implications for designing approaches to induce tolerance in human transplant recipients.
authors.affiliation: Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Yifa
authors.initials: Y
authors.lastname: Chen
authors.forename: Peter S
authors.initials: PS
authors.lastname: Heeger
authors.forename: Anna
authors.initials: A
authors.lastname: Valujskikh
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*; D023201:CD40 Ligand / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016038:Skin Transplantation / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D023201:CD40 Ligand