CD4 and CD8 are T-cell coreceptors that bind to nonpolymorphic regions of MHC molecules, are brought adjacent to the TCR complex upon antigen recognition, and facilitate signaling by the TCR complex during T-cell activation (see Fig. 1). Mature αβ T cells express either CD4 or CD8, but not both. CD8 and CD4 interact with MHC class I and class II molecules, respectively, and are responsible for the MHC class I or class II restriction of these classes of T cells.
Fig1. Ligand-receptor pairs involved in T-cell activation. (A) The major surface molecules of CD4+ T cells involved in the activation of these cells (the receptors) and the molecules on APCs (the ligands) recognized by the receptors are shown. CD8+ T cells use most of the same molecules, except that the T-cell receptor (TCR) recognizes peptide–MHC-I (major histocompatibility complex I) complexes, and the coreceptor is CD8, which recognizes MHC-I. Immunoreceptor tyrosine-based activation motifs (ITAMs) are the regions of signaling proteins that are phosphorylated on tyrosine residues and become docking sites for other signaling molecules. CD3 is composed of three polypeptide chains, named γ, δ, and ε, arranged in two pairs (γε and δε), as shown in Fig. 7.8. Some inhibitory receptors, such as programmed death–1 (PD-1), contain cytoplasmic immunotyrosine-based inhibitory motifs (ITIMs) as well as “switch” motifs (ITSMs). (B) Important molecules of T cells that participate in activating or inhibiting responses to antigens, but are not the receptors for antigen, are summarized. CTLA-4, Cytotoxic T-lymphocyte antigen–4; ICAM-1, intercellular adhesion molecule 1; LFA-1, leukocyte function-associated antigen 1; PDL-1/2, programmed death ligands 1 and 2.
CD4 and CD8 are transmembrane glycoprotein members of the Ig superfamily (Fig.2). CD4 is expressed as a monomer on the surface of peripheral T cells and thymocytes and is also present at lower levels on mononuclear phagocytes and some dendritic cells. CD4 has four extracellular Ig-like domains, a hydrophobic transmembrane region, and a highly basic cytoplasmic tail 38 amino acids long. The two N-terminal Ig-like domains of the CD4 protein bind to the nonpolymorphic α2 and β2 domains of the MHC class II molecule. The human immunodeficiency virus (HIV) uses CD4 as a receptor to gain entry into T lymphocytes and other immune cells that express the molecule.
Fig2. A schematic view of the structure of the CD4 and CD8 coreceptors. (A) The CD4 protein is an integral membrane monomer consisting of four extracellular immunoglobulin (Ig) domains, a transmembrane domain, and a cytoplasmic tail. The CD8 protein is either a disulfide-linked αβ integral membrane heterodimer or a disulfide-linked αα homodimer (not shown). Each chain has a single extracellular Ig domain. (B) CD4 on T cells associates with an invariant portion of the MHC-II heterodimer on an APC that is interacting with the TCR on the same T cell. Note that the cytoplasmic portions of both CD4 and CD8 can associate with LCK and that the ζ chain is depicted schematically. ITAM, Immunoreceptor tyrosine-based activation motif. (B, Adapted from Garcia KC, Adams E. How the T-cell receptor sees antigen—a structural view. Cell. 2005;122:333–336.)
Most CD8 molecules exist as disulfide-linked heterodimers composed of two related chains called CD8α and CD8β (see Fig.2). Both the α and β chains have a single extracellular Ig domain, a hydrophobic transmembrane region, and a highly basic cytoplasmic tail that is about 25 amino acids long. Activated T cells as well as γδ T cells can express CD8αα homodimers. The Ig domains of CD8 bind mainly to the non polymorphic α3 domain of MHC-I molecules, and also interact with portions of the α2 domain and with β2 microglobulin.
The SRC family kinase LCK, which is noncovalently bound to the cytoplasmic tails of both CD4 and CD8, initiates signaling upon antigen recognition. The ability of the extracellular domains of these coreceptors to bind to MHC molecules draws these proteins adjacent to the TCR that contacts the same MHC molecule that is displaying a peptide on the APC. As a result, on the cytosolic face of the plasma membrane, LCK is brought in close proximity to the ITAMs in CD3 and ζ proteins. LCK then phosphorylates the tyrosine residues in these ITAMs, thus facilitating the subsequent recruitment and activation of the ZAP70 tyrosine kinase. Note that LCK is always associated with both CD4 and CD8 coreceptors and is active before antigen exposure; the other proteins in the TCR complex, CD3 and ζ, contain ITAMs that need to be phosphorylated before they can recruit a kinase. Thus, the coreceptor provides the earliest enzymatic activity for initiating signals after T-cell recognition of peptide-MHC complexes.
