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CD8 is expressed on the surface of a subset of T lymphocytes which have two broadly defined functions: (1) class I major histocompatiblity complex (MHC)-restricted cytotoxicity against virally-infected, allogeneic, and other cellular targets; and (2) immunoregulation of other lymphocytes. In order to define the role of CD8 in mediating these two distinct T cell functions, an experimental approach utilizing gene transfection analysis to modulate CD8 surface expression in natural and foreign cellular settings was conceived. The development of an Epstein-Barr virus-based episomal expression system and a methodology for stably transfecting nontransformed human T cell clones and other human cell types provided the means for generating antisense and sense cellular pairs which were used to define the molecular functions of the CD8 molecule. By antisense-mediated inhibition of CD8 expression in nontransformed human CD8+ T cell clones and expression of CD8 in non-T cell lines, several sets of CD8+/CD8- paired cells lines were produced. These cellular reagents were used to demonstrate that the CD8 molecule plays an important, but distinct, role in each of the two classes of CD8+ T cell function. First, the CD8 molecule plays an essential accessory role as a co-receptor to the T cell receptor in class I MHC-restricted recognition of antigen which is subsequently required to trigger a number of T cell functional responses such as cytotoxicity, lymphokine secretion, lymphokine receptor expression and proliferation. Second, CD8 can serve as a novel inhibitory ligand permitting cells which express CD8 to modulate immune responses. Analysis of a genetically engineered, glycoinositophospholipid-modified variant of human CD8α revealed that the inhibitory ligand function was found to reside in the extracellular domain of the CD8α polypeptide. These data support a multifunctional perspective for the cell surface-associated CD8 glycoprotein, ascribing to it an inhibitory ligand function in addition to its conventionaly recognized receptor function. |
