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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.
Highlights
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As most of our immunosuppressive drugs are designed to target the activation of naive T cells, and memory T cells are clearly different from naive T cells in their activation requirements, understanding the precise molecular pathways that control the memory T cell response is of central importance to the induction of transplant tolerance
In the present study we examined the prerequisite of skin allograft rejection mediated by two types of memory T cells, i.e., memory T cells developed after homeostatic proliferation and memory T cells generated by donor Ag priming, and identified OX40 as a unique alternative costimulatory molecule in memory T cell-mediated rejection
Summary
C57BL/6 (H-2b), DBA/2 (H-2d), and Rag-1-deficient mice in the C57BL/6 background were purchased from The Jackson Laboratory. To generate alloantigen-specific memory T cells, C57BL/6 mice were primed with DBA/2 skin allografts. Four to 6 wk after skin allograft rejection, T cells were isolated from the peripheral lymph nodes of primed C57BL/6 hosts using the T cell enrichment columns (R&D Systems) and used as a source of alloantigen-specific memory T cells. Spleen cells were prepared from Rag-1-deficient host mice at different time points after T cell transfer and homeostatic cell proliferation. The cells were resuspended in PBS/0.5% BSA for surface staining with specific mAbs [22]. For intracellular staining of Bcl-2 and Bcl-xL expression, cells recovered from Rag-1-deficient hosts were stained with CyChrome-anti-mouse CD4 and FITC-anti-mouse CD44 first, fixed and membrane permeabilized in Cytofix/Cytoperm solution (BD Pharmingen) at 4°C for 30 min. The plates were washed and blocked in PBS/1% BSA for 2 h
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