Signal requirements for the generation of CD4+ and CD8+ T-cell responses to human allogeneic microvascular endothelium

R. Pardi, J. R. Bender

Research output: Contribution to journalArticlepeer-review

Abstract

Microvascular endothelium has been implicated as a major target in the rejection of vascularized allografts. In an attempt to dissect the stepwise generation of the T-cell-mediated immune response to microvascular endothelial cells (ECs), we analyzed the requirements for the two major T-cell subsets, CD4+ and CD8+, in the triggering of proliferative and cytotoxic responses to allogeneic ECs in vitro. Results demonstrate that resting ECs are unable to stimulate a functional response by purified T, CD4+, and CD8+ cells in the absence of costimulatory signals. T cells and CD8+ cells develop both proliferative and cytotoxic anti-EC responses by the addition of as little as 2 units/ml interleukin-2, 10 units/ml interleukin-1, or irradiated monocytes autologous to the responder lymphocytes, whereas only autologous monocytes are capable of triggering CD4+ T-cell precursors to proliferate and become anti-EC-specific effector cytotoxic T lymphocytes. CD8+ cell-mediated anti-EC cytotoxicity is directed toward allogeneic major histocompatibility complex (MHC) class I determinants on ECs and involves recognition by the CD3/T-cell receptor complex and the CD8 molecule on the effector T cells. CD4+ cells can be driven to proliferate, produce interleukin-2, and become anti-EC-specific cytotoxic T lymphocytes despite the lack of detectable membrane MHC class II determinants on the target cells. Chloroquine inhibition experiments demonstrate that autologous monocytes/macrophages are required by CD4+ T-cell precursors for the processing of EC-derived alloantigens and their subsequent presentation in the context of self-MHC molecules. These results are in agreement with the adoptive transfer experiments in experimental allograft models and suggest that the coordinate engagement of cells of the CD4, CD8, and monocyte/macrophage series is more effective than the individual cell subsets in the generation of a functional response to allogeneic nonlymphoid tissues.

Original languageEnglish
Pages (from-to)1269-1279
Number of pages11
JournalCirculation Research
Volume69
Issue number5
Publication statusPublished - 1991

Keywords

  • Allograft rejection
  • Alloreactivity
  • Cytotoxic T lymphocytes
  • Microvascular endothelium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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