390 Interactions of TCRs with MHC-peptide complexes: a quantitative basis for mechanistic models David H Margulies The activation of T lymphocytes is initiated by the binding of MHC-peptide complexes on antigen-presenting cells to MHC-restricted, peptide specific TCRs. Significant progress has recently been made in understanding the structure of the TCR and in the direct quantitative examination of the primary binding interactions between MHC-peptide complexes and the TCR. Attempts to develop quantitative models for the differential activation of T cells by MHC-peptide ligands that differ subtly in their structure have largely been based on either the affinity of the MHC-peptide complexe s for the TCR in question or on the dissociation kinetics of the MHC-peptide complex from the T cell. Addresses Molecular Biology Section, Laboratoryof Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 90892-1892, USA; e-mail: dhm@helix.nih.gov Current Opinion in Immunology 1997, 9:390-395 http:llbiomednet.com/elecref10952791500900390 © Current Biology Ltd ISSN 0952-7915 Abbreviations APC C CDR ITAM MHC MHC-I MHC-II sc SPR TCR V antigen-presenting cell constant domain complementarity determining region immunoreceptor tyrosine based activation motif major histocompatibilitycomplex MHC-encoded class I protein MHC-encoded class II protein single chain surface plasmon resonance T cell receptor variable domain Introduction T lymphocytes exert managerial control over the immune response. Like good administrators, they recognize the need for action, recruit aid from others, and perform some of the work themselves. They must sense when to begin their efforts, when to freeze production, and when to divert activity from one line to another. To initiate the immune response, ~13 receptors on the surface of the T cell must bind molecular complexes containing MHC-encoded class I (MHC-I) or class II (MHC-II) glycoproteins. These MHC molecules are tightly complexed with antigenic or self peptide fragments derived from the degradation of proteins either synthesized in the same cell (for MHC-I) or ingested through the endocytic path- way (for MHC-II). The TCR-MHC-peptide recognition event forms the basis of the phenomenon known as antigen-specific MHC-restricted T cell recognition. This process controls the rejection of genetically disparate graft tissues (histoincompatibility), the identification of tissues infected by viruses or intracellular parasitic organisms (infected-self recognition), the immune responses to tumors produced in the host animal (tumor rejection), and it falls under the general heading of self versus nonself discrimination, a function for which the entire immune system clearly evolved. Another result of the engagement of MHC-peptide complexes by the TCR is that which occurs in the thymus where the developmental fate of new clones bearing TCRs is determined as a result of both positive and negative selective events (for reviews see [1,2]). In the past few years, our understanding of the molecular events involved in initiating the immune response has benefited from the determination, at high resolution, of the structures of MHC molecules complexed with peptides [3], TCR fragments [4,5°°,6°], and most re- cently of TCR-MHC-peptide complexes [7°',8"°,9]. In addition, studies of the binding of the TCR to purified MHC-peptide complexes have provided indications of some of the parameters that govern the initial binding events [10-13,14°,15°,16°°]. An added complexity in the nature of the TCR signals delivered by MHC-peptide complexes arises from the identification of variant peptides that signal differently as compared with antigenic peptides [17-19]. The antigenic peptide is commonly referred to as an 'agonisr peptide in that it contributes to a stimulatory form of the MHC-peptide complex. Using terminology borrowed from pharmacologists, peptides that exert negative signals capable of countering the agonist are known as 'antagonists'. Similarly, those peptides that contribute to an intermediate signal are 'weak agonists'. These must be distinguished from 'partial agonists' that elicit some, but not all, downstream signals or functions [20]. Binding measurements have been undertaken to understand the behavior of the antagonist peptide-MHC complexes and their effects on mature peripheral T cells [21°°], and to understand other variant MHC-peptide complexes that have differential effects on positive and negative selection in the thymic development of T cells [22"]. Interactions of MHC-peptide complexes with the TCR in the presence of co-receptors have also been evaluated [23°,24°°]. In parallel with the efforts to develop model systems for measuring the initial TCR binding events, several groups have examined the immunological and biochemical conse- quences of signaling T cells via different MHC-peptide stimuli [17-19]. The intriguing phenomenon by which MHC-peptide complexes containing synthetic variant peptides can cause functional antagonism, partial agonism,