Critical, but conditional, role of OX40 in memory T cell-mediated rejection

MD Vu, MR Clarkson, H Yagita, LA Turka… - The Journal of …, 2006 - journals.aai.org
MD Vu, MR Clarkson, H Yagita, LA Turka, MH Sayegh, XC Li
The Journal of Immunology, 2006journals.aai.org
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 (ie, 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 …
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 (ie, 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.
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