Chimeric T-cell receptors: highly specific tools to target cytotoxic T-lymphocytes to tumour cells

Abstract

Cellular immune defence involves cells that both recognize antigens in a nonspecific way, such as natural killer (NK) cells, monocytes, macrophages and granulocytes, and those that do so in a highly specialized fashion, such as Tcells. Upon specific interaction, T-cells direct their effector function to their target cells or mediate their immunoregulatory function to cells of the immune system. The specificity of this interaction is mediated by the T-cell receptor (TCR) complex. The TCR exists in two types of heterodimers composed of two disulphide-linked polypeptide chains; U-P and y-6. This heterodimer is part of a receptor complex consisting of different polypeptide chains associated in the cell membrane (Figure 1). Each of the a-P and y-6 TCR chains is composed of a variable region 0.4, participating in antigen binding, and a constant region (C), involved in the signalling for cellular activation. For functional expression on the T-cell surface, the c+B and the y-6 heterodimeric TCR must be complexed with a group of proteins known as the CD3 complex. The CD3 chains participate in the transduction of the specific signal that is initiated by the interaction of the TCR V region with the particular ligand. The TCR complex, however, recognizes antigens in association with the major histocompatibility complex (MHC) class I or class II molecules expressed on antigen presenting cells (APO. T-cells, therefore, respond to processed antigenic determinants only in the membrane-bound form. Stimulation of the TCR by antigen results in at least two signal transduction events; activation of the phosphatidylinositol-specific