title: Critical, but conditional, role of OX40 in memory T cell-mediated rejection.
abstract: Memory T cells can be a significant barrier to the induction of transplant tolerance. However, the molecular pathways that can regulate memory T cell-mediated rejection are poorly defined. In the present study we tested the hypothesis that the novel alternative costimulatory molecules (i.e., ICOS, 4-1BB, OX40, or CD30) may play a critical role in memory T cell activation and memory T cell-mediated rejection. We found that memory T cells, generated by either homeostatic proliferation or donor Ag priming, induced prompt skin allograft rejection regardless of CD28/CD154 blockade. Phenotypic analysis showed that, in contrast to naive T cells, such memory T cells expressed high levels of OX40, 4-1BB, and ICOS on the cell surface. In a skin transplant model in which rejection was mediated by memory T cells, blocking the OX40/OX40 ligand pathway alone did not prolong the skin allograft survival, but blocking OX40 costimulation in combination with CD28/CD154 blockade induced long-term skin allograft survival, and 40% of the recipients accepted their skin allograft for >100 days. In contrast, blocking the ICOS/ICOS ligand and the 4-1BB/4-1BBL pathways alone or combined with CD28/CD154 blockade had no effect in preventing skin allograft rejection. OX40 blockade did not affect the homeostatic proliferation of T cells in vivo, but markedly inhibited the effector functions of memory T cells. Our data demonstrate that memory T cells resisting to CD28/CD154 blockade in transplant rejection are sensitive to OX40 blockade and suggest that OX40 is a key therapeutic target in memory T cell-mediated rejection.
authors.affiliation: Transplant Research Center, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Minh Diem
authors.initials: MD
authors.lastname: Vu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Clarkson
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Xian Chang
authors.initials: XC
authors.lastname: Li
mesh_terms: D053330:4-1BB Ligand; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D000939:Epitopes / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics; D007156:Immunologic Memory; D060889:Inducible T-Cell Co-Stimulator Protein; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000502:physiology*; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D053330:4-1BB Ligand; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D000939:Epitopes; D018398:Homeodomain Proteins; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D007519:Isoantigens; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse; C505975:Tnfsf9 protein, mouse; D048069:Tumor Necrosis Factors; C064658:RAG-1 protein; D023201:CD40 Ligand