T Cell Activation and Inactivation

T cells utilize the T cell receptor (TCR) to specifically recognize antigen in association with self MHC and to signal one of several distinct responses. Under different circumstances, a T cell responds to TCR stimulation by proliferating, differentiating along a particular developmental pathway, producing lymphokines, releasing cytotoxic granules, dying or by becoming anergic. It remains unclear how the functional outcome of TCR engagement is determined. Recent data indicate that the molecular reorganization of proteins at the T cell/antigen presenting cell interface is required in order to initiate and sustain TCR engagement and signal transduction. Proteins which hinder TCR/MHC-peptide interaction and downregulate TCR signals must be excluded from the contact cap and T cell proteins facilitating these event must be recruited. How this molecular reorganization is initiated and maintained remains one of the most poorly understood aspects of T cell activation. Our recent work indicates recruitment of pre-formed lipid rafts enriched in proteins which facilitate TCR/peptide-MHC binding, signal transduction and cytoskeletal assembly are essential for early TCR signal transduction, cytoskeletal reorganization, and regulation of T cell functional outcome. Our data further indicate that endogenously expressed immune modulatory proteins can bind T cell surface molecules and: 1) facilitate events required to sustain TCR engagement and complete T cell activation (IL-2 production) or 2) limit the extent of TCR engagement and molecular reorganization and result in immune inactivation (apoptosis or anergy). Further elucidation of modulators of TCR signals and functions may allow for the intelligent design of vaccines or therapies aimed at immune activation or tolerance induction. Our work directly relates to basic mechanisms of immune regulation, signal transduction, tolerence induction, autoimmunity, and oncogenesis