The crystal structure of a complex involving the D10 T cell receptor (TCR), 16-residue foreign peptide antigen, and the I-Ak self major histocompatibility complex (MHC) class II molecule is reported at 3.2 angstrom resolution. The D10 TCR is oriented in an orthogonal mode relative to its peptide-MHC (pMHC) ligand, necessitated by the amino-terminal extension of peptide residues projecting from the MHC class II antigen-binding groove as part of a mini beta sheet. Consequently, the disposition of D10 complementarity-determining region loops is altered relative to that of most pMHCI-specific TCRs; the latter TCRs assume a diagonal orientation, although with substantial variability. Peptide recognition, which involves P-1 to P8 residues, is dominated by the Valpha domain, which also binds to the class II MHC beta1 helix. That docking is limited to one segment of MHC-bound peptide offers an explanation for epitope recognition and altered peptide ligand effects, suggests a structural basis for alloreactivity, and illustrates how bacterial superantigens can span the TCR-pMHCII surface.

The thymus leukemia antigen (TL) is a nonclassical class I molecule, expressed abundantly on intestinal epithelial cells. We show that, in contrast to other major histocompatibility complex (MHC) class I molecules that bind CD8alphabeta, TL preferentially binds the homotypic form of CD8alpha (CD8alphaalpha). Thus, TL tetramers react specifically to CD8alphaalpha-expressing cells, including most intestinal intraepithelial lymphocytes. Compared with CD8alphabeta, which recognizes the same MHC as the T cell receptor (TCR) and thus acts as a TCR coreceptor, high-affinity binding of CD8alphaalpha to TL modifies responses mediated by TCR recognition of antigen presented by distinct MHC molecules. These findings define a novel mechanism of lymphocyte regulation through CD8alphaalpha and MHC class I.

The structural basis of the interaction between the CD4 coreceptor and a class II major histocompatibility complex (MHC) is described. The crystal structure of a complex containing the human CD4 N-terminal two-domain fragment and the murine I-A k class II MHC molecule with associated peptide (pMHCII) shows that only the ''top corner'' of the CD4 molecule directly contacts pMHCII. The CD4 Phe-43 side chain extends into a hydrophobic concavity formed by MHC residues from both ␣2 and ␤2 domains. A ternary model of the CD4-pMHCII-T-cell receptor (TCR) reveals that the complex appears V-shaped with the membrane-proximal pMHCII at the apex. This configuration excludes a direct TCR-CD4 interaction and suggests how TCR and CD4 signaling is coordinated around the antigenic pMHCII complex. Human CD4 binds to HIV gp120 in a manner strikingly similar to the way in which CD4 interacts with pMHCII. Additional contacts between gp120 and CD4 give the CD4 -gp120 complex a greater affinity. Thus, ligation of the viral envelope glycoprotein to CD4 occludes the pMHCII-binding site on CD4, contributing to immunodeficiency. T he adaptive immune response depends on the specific recognition by a T-cell receptor (TCR) of an antigenic peptide bound to a major histocompatibility complex (MHC) molecule (pMHC), as well as interaction of this same pMHC with a CD8 or CD4 coreceptor (1-4). The structural basis of the TCRpMHCI, TCR-pMHCII, and CD8␣␣-pMHCI interactions has been crystallographically defined (1, 5-8), whereas the structural nature of CD4-pMHCII is not yet known. The extracellular rod-like CD4 segment consists of four concatamerized Ig-like domains (D1-D4) (9-11). Mutagenesis studies have suggested that residues in the membrane distal D1-D2 module bind to predominantly nonpolymorphic residues of MHC class II molecules (12-14). During pMHCII recognition, CD4 and TCR colocalize to interact with the same pMHCII (2). Hence, CD4 brings the p56 lck that associates with the short CD4 cytoplasmic tail to the site of immune recognition (15). In fact, such tyrosine kinase recruitment, rather than any major contribution to binding energy, appears to be the major function of CD4 (16).Structural information about the CD4 receptor-ligand interaction would be of particular importance, given the expression of CD4 on the surface of all helper T cells and the essential role of this protein in their activation. Once triggered, helper T cells stimulate B-cell antibody production and cytolytic T-cell generation, thereby regulating the induction of the immune response. Development of methods to block CD4-pMHCII interaction might lead to an important new class of immunosuppressive compounds, depending on structural data. With this goal in mind, we have determined the crystal structure of a CD4-pMHCII complex. As reported below, it is now possible to compare the nature of coreceptor binding to pMHC for both CD4 and CD8 T-cell subsets as well as to examine how CD4 is ligated by its physiologic pMHCII ligand versus the pathologic HIV1 gp120 ligand. Material...