Role of 4-1BB in allograft rejection mediated by CD8+ T cells

Jun Wang, Zhong Guo, Ying Dong, Oliver Kim, John Hart, Andrew Adams, Christian P. Larsen, Robert S. Mittler, Kenneth A. Newell

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

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 TNFα 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.

Original languageEnglish (US)
Pages (from-to)543-551
Number of pages9
JournalAmerican Journal of Transplantation
Volume3
Issue number5
DOIs
StatePublished - May 2003
Externally publishedYes

Keywords

  • Chemokines
  • Intestine
  • T lymphocytes
  • TNF receptor superfamily
  • Transplantation

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