CD4 and CD8 Coreceptors Bind to Conserved Regions of MHC Class II or I Molecules

T cells can be subdivided into two populations according to their expression of CD4 or CD8 membrane molecules. As described in preceding chapters, CD4+ T cells recognize antigen that is combined with class II MHC molecules and function largely as helper cells, whereas CD8+ T cells recognize antigen that is combined with class I MHC molecules and function largely as cytotoxic cells. CD4 is a 55-kDa monomeric membrane glycoprotein that contains four extracellular immunoglobulin-like domains (D1-D4), a hy-drophobic transmembrane region, and a long cytoplasmic tail (Figure 9-10) containing three serine residues that can be phosphorylated. CD8 generally takes the form of a disulfide-linked ap heterodimer or of an aa homodimer. Both the a and p chains of CD8 are small glycoproteins of approximately 30-38 kDa. Each chain consists of a single extracellular immunoglobulin-like domain, a hydrophobic transmembrane region, and a cytoplasmic tail (Figure 9-10) containing 25-27 residues, several of which can be phos-phorylated.

CD4 and CD8 are classified as coreceptors based on their abilities to recognize the peptide-MHC complex and their roles in signal transduction. The extracellular domains of CD4 and CD8 bind to the conserved regions of MHC molecules on antigen-presenting cells (APCs) or target cells. Crys-tallographic studies of a complex composed of the class I MHC molecule HLA-A2, an antigenic peptide, and a CD8 aa homodimer indicate that CD8 binds to class I molecules

TABLE 9-4l Selected T-cell accessory molecules

FUNCTION

TABLE 9-4l Selected T-cell accessory molecules

FUNCTION

Name

Ligand

Adhesion

Signal transduction

Member of Ig superfamily

CD4

Class II MHC

+

+

+

CD8

Class I MHC

+

+

+

CD2 (LFA-2)

CD58 (LFA-3)

+

+

+

LFA-1 (CD11a/CD18)

ICAM-1 (CD54)

+

?

CD28

B7

?

+

+

CTLA-4

B7

?

+

-

CD45R

CD22

+

+

+

CD5

CD72

?

+

-

CD8 a p

J

•S

V—/

-s-s-

p

o

o

8

8

8

8

8

8

o

General structure of the CD4 and CD8 coreceptors. CD8 may take the form of an a^ heterodimer, or an aa homodimer. The monomeric CD4 molecule contains four Ig-fold domains; each chain in the CD8 molecule contains one.

by contacting the MHC class I a2 and a3 domains as well as having some contact with ^-microglobulin (Figure 9-11a). The orientation of the class I a 3 domain changes slightly upon binding to CD8. This structure is consistent with a single MHC molecule binding to CD8; no evidence for the possibility of multimeric class I-CD8 complexes was observed. Similar structural data document the mode by which CD4 binds to the class II molecule. The contact between CD4 and MHC II involves contact of the membrane-distal domain of CD4 with a hydrophobic pocket formed by residues from the a2 and (32 domains of MHC II. CD4 facilitates signal transduction and T-cell activation of cells recognizing class II-peptide complexes (Figure 9-11b).

Whether there are differences between the roles played by the CD4 and CD8 coreceptors remains open to speculation. Despite the similarities in structure, recall that the nature of the binding of peptide to class I and class II molecules differs in that class I has a closed groove that binds a short peptide with a higher degree of specificity. Recent data shown below indicate that the angle at which the TCR approaches the pep-tide MHC complex differs between class I and II. The differences in roles played by the CD4 and CD8 coreceptors may be due to these differences in binding requirements. As will be explained in Chapter 10, binding of the CD4 and CD8 molecules serves to transmit stimulatory signals to the T cells; the signal-transduction properties of both CD4 and

Cd4 Cd8 Mhc

Interactions of coreceptors with TCR and MHC molecules. (a) Ribbon diagram showing three-dimensional structure of an HLA-A2 MHC class I molecule bound to a CD8 aa homodimer. The HLA-A2 heavy chain is shown in green, ^-microglobulin in gold, the CD8 a1 in red, the CD8 a2 in blue, and the bound peptide in white. A flexible loop of the a3 domain (residues 223-229) is in con tact with the two CD8 subunits. In this model, the right side of CD8 would be anchored in the T-cell membrane, and the lower left end of the class I MHC molecule (the a3 domain) is attached to the surface of the target cell. (b) Interaction of CD4 with the class II MHC peptide complex (pMHCII). [Part (a) from Gao et al., 1997, Nature, 387:630; part (b) from Wang et al., 2001, PNAS, 98(19): 10799]

Cd8 Molecule
FIGURE 9-11

Interactions of coreceptors with TCR and MHC molecules. (a) Ribbon diagram showing three-dimensional structure of an HLA-A2 MHC class I molecule bound to a CD8 aa homodimer. The HLA-A2 heavy chain is shown in green, ^-microglobulin in gold, the CD8 a1 in red, the CD8 a2 in blue, and the bound peptide in white. A flexible loop of the a3 domain (residues 223-229) is in con tact with the two CD8 subunits. In this model, the right side of CD8 would be anchored in the T-cell membrane, and the lower left end of the class I MHC molecule (the a3 domain) is attached to the surface of the target cell. (b) Interaction of CD4 with the class II MHC peptide complex (pMHCII). [Part (a) from Gao et al., 1997, Nature, 387:630; part (b) from Wang et al., 2001, PNAS, 98(19): 10799]

CD8 are mediated through their cytoplasmic domains. Recent data on the interaction between CD4 and the peptide-class II complex indicates that there is very weak affinity between them, suggesting that recruitment of molecules involved in signal transduction may be the major role for CD4.

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