Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule

Abstract

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...

Crystal structure of human junctional adhesion molecule 1: Implications for reovirus binding

“…However, it is noteworthy that several Ig superfamily receptors engage viral ligands via the GFCCЈ ␤-sheet. The HIV glycoprotein gp120 binds to residues on the GFCCЈ face of its receptor CD4 (47), and the same region of CD4 also interacts with its natural ligand MHC class II (48). Complexes of rhinoviruses and coxsackievirus A21 with their receptor intercellular adhesion molecule-1 (ICAM-1) also show that the interactions involve residues at the top of ICAM-1 D1, a region that includes part of the GFCCЈ face (49,50).…”

CD4 Dimers Constitute the Functional Component Required for T Cell Activation

“…CD4 dimerization could not be observed in the cocrystal of CD4 with MHC class II, since the CD4 component included only the two N-terminal domains of CD4. Arguing against CD4 dimerization, this recent study has reported that alanine substitutions of residues K318 and Q344 are without effect on CD4-MHC II binding, measured by rosette formation between CD4-transfected COS-7 cells and MHC II-expressing Raji cells (42). There are several possible explanations for these findings: 1) overexpression of CD4 molecules in COS-7 cells might facilitate cell-cell adhesion and thus bypass the need for CD4 dimerization in rosette formation; and 2) CD4 dimerization might be required only for T cell activation, when the TCR recognizes its nominal Ag on the MHC.…”

A role for “self” in T-cell activation

“…The role of CD4 in stimulation by heterodimers was also tested in these studies. The original pseudodimer model was partly based on structural data from Reinherz and colleagues 18 , showing that CD4 binds to MHC class II at an angle that would not allow a CD4 molecule to bind the same MHC molecule that the TCR is engaging (Fig.4). Supporting this model are also earlier studies showing that a large fraction of TCRs are constitutively associated with CD4 molecules on antigen experienced T cells.…”