Critical, but Conditional, Role of OX40 in Memory T Cell-Mediated Rejection

• Published in: Journal of Immunology 2006-02, Vol.176 (3), p.1394-1401
• Main Authors: Vu, Minh Diem, Clarkson, Michael R, Yagita, Hideo, Turka, Laurence A, Sayegh, Mohamed H, Li, Xian Chang
• Format: Article
• Language: English
• Subjects: 4-1BB Ligand; Animals; Antigens, Differentiation, T-Lymphocyte - metabolism; CD28 Antigens - immunology; CD40 Ligand - immunology; Cell Proliferation; Cell Survival - immunology; Cells, Cultured; Epitopes - immunology; Graft Rejection - immunology; Homeodomain Proteins - genetics; Immunologic Memory; Inducible T-Cell Co-Stimulator Protein; Isoantigens - immunology; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Receptors, OX40; Receptors, Tumor Necrosis Factor - metabolism; Receptors, Tumor Necrosis Factor - physiology; Skin Transplantation - immunology; T-Lymphocytes - immunology; Tumor Necrosis Factors - metabolism
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.176.3.1394

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.