Signal Requirements for the Generation of CD4+ and CD8+ T-Cell Responses to Human Allogeneic Microvascular Endothelium

• Published in: Circulation research 1991-11, Vol.69 (5), p.1269-1279
• Main Authors: Pardi, Ruggero, Bender, Jeffrey R
• Format: Article
• Language: English
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Antibody Formation; Antibody-Dependent Cell Cytotoxicity; Antigen-Presenting Cells - immunology; Antigens, Surface - immunology; Biological and medical sciences; CD4 Antigens - immunology; CD8 Antigens - immunology; Clone Cells; Endothelium, Vascular - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunobiology; Microcirculation; Organs and cells involved in the immune response; Signal Transduction; T-Lymphocytes - immunology
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.69.5.1269

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. (Circulation Research 1991;69:1269–1279)