While the T cell receptor (TcR) recognizes cell bound, peptide antigens embedded within major histocompatibility complex (MHC) proteins, this interaction is not sufficient for T cell activation and function. A number of other cell surface molecules, termed co-receptors or accessory molecules, cooperate with the TcR by participating in T cell adhesion to antigen presenting cells (APC) and/or by contributing to T cell signaling. In addition, recent evidence suggests that T cell activation can, in turn, increase the avidity of several of these co-receptors for their ligands. One such co-receptor molecule is CD2, a T cell glycoprotein that not only participates in T cell activation but also provides the T cell with a major adhesion pathway whose avidity is regulated by TcR triggering. Using both cellular and molecular biological approaches, we have mapped the portions of CD2 involved in CD2-dependent signaling and in the regulation of avidity for its ligand CD58 (lymphocyte function associated antigen-3, LFA-3) to structurally distinct portions of the cytoplasmic domain. This delineation of function has allowed us to analyze the contribution of co-receptor basal adhesion, signaling, and avidity regulation in antigen-dependent T cell interactions. The signal transduction pathways recruited for the regulation of CD2 avidity for its ligand differ from those used by other co-receptors such as LFA-1 and CD8 for their respective ligands. Taken together, the multiplicity of co-receptors, their interplay, and their differential regulation contribute to the control and the sensitivity of antigen-dependent immune responses.