Role of 4-1BB in Allograft Rejection Mediated by CD8+ T Cells |
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Authors: | Jun Wang Zhong Guo Ying Dong Oliver Kim John Hart rew Adams Christian P Larsen Robert S Mittler Kenneth A Newell |
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Institution: | Emory Transplant Center and the Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. |
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Abstract: | Blockade of traditional costimulatory molecules fails to inhibit rejection in many models where CD8+ T cells are sufficient to mediate rejection. This observation demonstrates that in many settings CD8+ T cells are not dependent upon CD28 or CD154 signals to mediate rejection. 4-1BB (CD137) has been shown to be an important regulatory molecule for CD8+ T cells in a variety of nontransplant models. Here we show that blocking the 4-1BB pathway significantly inhibited rejection of intestinal allografts by CD8+ but not CD4+ T cells. This effect was associated with significantly decreased expression of the genes encoding TNFalpha and secondary lymphoid chemokine (SLC) within the spleens of recipient mice. Disruption of the 4-1BB pathway also impaired the priming of alloantigen-specific CD8+ T cells and the accumulation of recipient dendritic cells within the spleen. These data directly demonstrate an important role for 4-1BB in allograft rejection; particularly rejection mediated by CD8+ T cells. Our data suggest that in addition to providing a direct costimulatory signal to T cells, the 4-1BB pathway may regulate other important steps in the immune response such as the migration of T cells and dendritic cells. |
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Keywords: | Chemokines intestine T lymphocytes TNF receptor superfamily transplantation |
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