Molecular Basis of HEL 74-96-Specific CD8-CD4 Cell Interactions

Georgetown University, Washington DC

Investigators

Abstract

Prevention of auto-immune reactions and the self-limiting nature of normal immune responses require inactivation of mature lymphocytes. This research focuses on understanding mechanisms by which suppressor T lymphocytes, that class of lymphocyte responsible for a wide range of immune cell regulation, are involved in down-regulation of antigen-specific responses of other, so-called helper T lymphocytes. A notable function of helper T cells is to stimulate yet another class of lymphocytes to secrete antibodies. The helper T cells are formally designated CD4 T cells on the basis of their surface molecules. The suppressor T cells are designated CD8 T cells. The molecular mechanism by which the CD8 T cells interact with CD4 T cells to inactivate them is not well understood and currently is an important area of immunological research. Preliminary evidence in support of this project suggests a novel model for this interaction. In this model, antigen-specific receptors of CD8 T cells recognize two cell surface molecules on either CD4 cells or other cells that function to present these molecules. The first is the antigenic peptide itself and the second is the CD4 antigen-specific receptor. Current thinking suggests that each molecule is bound as a complex to a class of tissue compatibility molecules called class I major histocompatibility complexes (MHC). The novelty of the hypothesis is that a single CD8 T cell receptor would recognize two distinct molecules simultaneously, something that has not been proposed before for this type of regulation. To substantiate these results, the project will pursue two specific aims in which responses to a defined peptide antigen will be monitored. Aim 1 is to isolate and characterize the antigen-specific CD8 T cells that are activated by the CD4 cells and peptide. The molecular structure of the receptors of these CD8 T cells will be determined. Conversely, aim 2 is to characterize the antigen-specific CD4 T cell receptors that activate the CD8 cell counterparts. The experiments as a whole have the potential of defining a new and generalized mechanism for the self-regulation of lymphocytes during the course of an immune response.