Shapes of MHC Restriction

The purpose of TCR ligand binding is to initiate signal transduction that results in the activation of functional programs within the cell. How does binding of ligand on the extracellular V domains of the TCR translate into a functional message inside the cell? One model to explain these events is that ligand binding by the TCR V domains induces a conformational change in the C domains that, in turn, changes the dynamics of the interactions with CD3 chains and/or ζ chains associated with the receptor and thus transduces a signal through these associated components. However, a comparison of the liganded and unliganded forms of 2C showed that the conformational changes that occurred in the TCR as a result of antigen binding did not appear to involve the constant domains of the molecule (Garcia et al. 1998xStructural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Garcia, K.C, Degano, M, Pease, L.R, Huang, M, Peterson, P.A, Teyton, L, and Wilson, I.A. Science. 1998; 279: 1166–1172CrossRef | PubMed | Scopus (517)See all ReferencesGarcia et al. 1998). In addition, comparison of the Cα-Cβ interfaces of the liganded B7 TCR with unliganded 2C and N15 showed that they were nearly identical (Ding et al. 1998xTwo human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids. Ding, Y.-H, Smith, K.J, Garboczi, D.N, Utz, U, Biddison, W.E, and Wiley, D.C. Immunity. 1998; 8: 403–411Abstract | Full Text | Full Text PDF | PubMed | Scopus (359)See all ReferencesDing et al. 1998). Thus, the current structural evidence does not support the conformational change model.An alternate model for signal transduction by the TCR postulates that ligand binding induces receptor aggregation and/or oligomerization that segregates the bound receptors into cell–cell attachment patches (Davis et al. 1998xLigand recognition by αβ T cell receptors. Davis, M.M, Boniface, J.J, Reich, Z, Lyons, D, Hampl, J, Arden, B, and Chien, Y.-H. Annu. Rev. Immunol. 1998; 16: 523–544CrossRef | PubMed | Scopus (632)See all ReferencesDavis et al. 1998). Such receptor aggregation would facilitate clustering of intracellular components required for the recruitment and phosphorylation of signal transduction components. The adoption of a uniform orientation in TCR binding to peptide/MHC complexes may provide a mechanism that facilitates TCR aggregation and interactions with the coreceptors (CD3s, CD4/CD8) that can generate a T cell signal (Davis et al. 1998xLigand recognition by αβ T cell receptors. Davis, M.M, Boniface, J.J, Reich, Z, Lyons, D, Hampl, J, Arden, B, and Chien, Y.-H. Annu. Rev. Immunol. 1998; 16: 523–544CrossRef | PubMed | Scopus (632)See all ReferencesDavis et al. 1998). At this juncture, no evidence for dimerization or oligomerization of liganded TCRs is provided from the crystallographic data. However, the conditions used to produce these complexes may not favor multimerization, whereas the conditions of cell surface TCRs associated with CD3s/ζ chains could be much more favorable. Future structural studies of unliganded and liganded TCRs in association with the CD3 chains and ζ chains could provide new insights into the mechanisms of the initiation of signal transduction by the TCR.‡E-mail: web@helix.nih.gov and dgarboczi@atlas.niaid.nih.gov.