Conventional antigen and superantigen may be coupled to distinct and cooperative T-cell activation pathways.

CD4+ T cells are equipped to detect two major classes of ligands. Infectious microbial agents, including bacteria and retroviruses, carry a class of proteins termed superantigens that are recognized by the T-cell receptor in association with class II products of the major histocompatibility complex. Proteins expressed by other cells and organisms are processed by macrophages into peptides that are presented to CD4+ T cells by class II molecules. We have examined CD4+ T-cell clones that proliferate vigorously in response both to conventional peptide antigens and to bacterial or retroviral superantigens. The response to peptide antigen is characterized by a rapid and sustained increase in the levels of intracellular free Ca2+ and a vigorous cytokine response. In contrast, the proliferative response of these clones to bacterial or retroviral superantigen is not accompanied by detectable increases in intracellular Ca2+ or by significant cytokine production. Further analysis of T-cell activation indicates that interaction of a single T-cell receptor with the two types of ligand may be coupled to functionally distinct signaling pathways that interact in a synergistic fashion to achieve T-cell activation.