CD2 AND T-CELL ADHESION AND ACTIVATION

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The relative roles of basal adhesion, T cell receptor (TcR)-regulation of avidity, and signaling in T cell coreceptor function and antigen responsiveness have been difficult to assess. The T cell surface glycoprotein CD2, by binding its ligands CD58 (LFA-3) and CD59, plays a dual role in T cell activation, serving to initiate signal transduction events and to promote cellular adhesion. Furthermore, the avidity of CD2 for CD58 is regulated by TcR signaling. To gain further insight into the molecular mechanisms involved in these key regulatory processes, wild-type human CD2 and a series of mutated CD2 molecules have been expressed in a murine antigen-specific T cell hybridoma. Structure-function studies using these stably transfected cell lines have led to the identification of three distinct regions of the cytoplasmic domain of CD2 that are required for signaling (IL-2 production and generation of cAMP), TcR-regulation of avidity of CD2 for CD58, and cytoskeletal (tubulin) associations. The intracellular mechanisms important for each of these functions will now be investigated, and a number of approaches to identify cytoplasmic effector molecules that interact with CD2 during signaling events and avidity regulation will be employed. The respective portions of the CD2 cytoplasmic domain required for interaction with other proteins will be mapped. An investigation of the complex interplay between adhesive and signaling events at the molecular level is essential to understanding the regulation of T cell activation. The potential relevance of the CD2/tubulin association to T cell activation will be analyzed as a model of the role of the cytoskeletal interactions with membrane receptors in signaling. Lastly, the physiological role of the interaction of CD2 with CD59 will be investigated and compared to that of the interaction of CD2 with CD58. The study of CD2 interactions serves as a model system for the definition of the structural requirements and the biological effectors of cytoplasmic signaling. CD2 is an attractive target for immunomodulatory therapies as it is involved both in adhesion and T cell signaling. The structure- function analysis may allow identification of specific motifs or domains important for basal adhesion, upregulation of avidity, cytoskeletal interactions, and signaling. These motifs will represent sequence-specific targets for immune modulation and interventions, and may, for example, ultimately be used for screening peptide libraries for small molecule inhibitors of signaling and avidity regulation. The definition of the minimum requirements for the CD2/CD58 and CD2/CD59 receptor-ligand interactions and for signaling will contribute to our understanding of the regulation and modulation of the immune response. This understanding may ultimately lead to novel immunotherapeutic approaches to enhance the T cell response to weak viral or tumor specific antigens, or to modulate the T cell response in autoimmune disease.