In Vivo T Cell Signaling Leading to Apoptosis vs. Cytokine Production.

摘要

Two signals are hypothesized as necessary for the activation of T cells leading to cytokine production. The first signal is delivered by the T cell receptor (TCR) and the second by a costimulatory signal, the best defined being CD28 and its homologue CTLA-4 (cytotoxic T lymphocyte associated protein- four). Treatment of T cells with antibodies against the invariant CD3-E chain of the TCR-CD3 complex is a widely used model for T cell activation and is being considered as an immune suppressant for clinical trials, since mitogenic anti-CD3 antibodies administered in vivo induce T cell tolerance and depletion. Although extensive studies have been performed with anti-CD3 antibodies, little is known concerning the mechanisms involved in either anti-CD3 antibody-induced cytokine production or subsequent T cell depletion in vivo. Previous studies have suggested three possible fates for T cells stimulated by anti-CD3 antibodies: TCR blockade or modulation. functional nonresponsiveness or anergy, and apoptosis. In this investigation three assays were adapted to detect apoptosis of peripheral T cells. My findings suggest that anti-CD3 antibody- induced peripheral T cell depletion results from apoptosis following high but not low dose administration of anti-CD3 antibodies. This high density TCR ligation is sufficient to rapidly promote T cell differentiation to cytokine secretion in the absence of CD2S/CTLA- 4 costimulatory signals. At lower anti- CD3 antibody doses T ceil cytokine production is dependent on CTLAA ligands, suggesting that quantitative differences in TCR signaling influence the requirement for these costimulatory signals. The rapid expression of cytokines was detected in both CD4, NK1.1 and CD4. NK1.1 T cells. In addition anti-CD3 antibody-induced deletion of CD8 but not CD4 T cells was determined to be IL-2- dependent.