Signal Transduction in T Helper Cells: CD4 Coreceptors Exert Complex Regulatory Effects on T Cell Activation and Function

The immune system provides a highly sophisticated surveillance mechanism to detect diverse antigens and protect the host organism from invading pathogens and altered cells (e.g., virus-infected and tumor cells). Adaptive immune responses depend on the recognition of antigen by specific antigen receptors that are expressed on the surface of T and B lymphocytes. Helper T cells provide regulatory functions and direct the adaptive immune system to respond appropriately to a particular antigen (i.e., cytotoxic T cell responses against viral infections and tumor cells, humoral responses against extracellular bacteria and parasitic worms). Helper T cells express CD4 co-receptors, which recognize conserved domains on MHC class II proteins, the same proteins that present antigen to the T cell receptor. Recent progress in T cell biology has identified multiple regulatory functions of the CD4 coreceptor during thymocyte development and antigen stimulation of mature T helper cells. These regulatory functions of CD4 depend on T cell receptor-independent signal transduction. In this review, I discuss the regulation of T cell signaling and emphasize the functional consequences of proper and improper CD4 coreceptor signaling.