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1178 Part IX: Lymphocytes and Plasma Cells Chapter 76: Functions of T Lymphocytes: T-cell Receptors for Antigen 1179

accessory proteins at the site of contact between the T cell and the specific recognition of “processed” antigen that is cradled within the
antigen-presenting cell (APC). MHC glycoproteins. However, CD4 and CD8 differ in their expres-
sion patterns (see section “Helper and Cytotoxic T Cells and CD4+ T
CD4 AND CD8 Cell Subsets” below) and MHC-binding specificities: CD8 binds to the
nonpolymorphic α domain of the HLA class I molecule (HLA-A, -B,
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STRUCTURE OF CD4 AND CD8 or -C), whereas CD4 binds to the nonpolymorphic β domain of
2
HLA class II molecules (HLA-DP, -DQ, and -DR). Therefore, T cells
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CD4 and CD8 are glycoproteins that share structural features of other expressing CD4 or CD8 generally recognize antigens presented by class
immunoglobulin superfamily receptor molecules. CD8 has two iso- II or class I MHC glycoproteins, respectively. This selectivity is under-
forms with different expression patterns and presumably different func- scored by studies on knockout mice that lack expression of either of
tions, and is expressed as a CD8α/CD8β heterodimer or as a CD8α/ these accessory molecules. Mice lacking CD4 or CD8 fail to develop
CD8α homodimer. These chains are encoded by genes that are linked class II-restricted or class I-restricted T cells, respectively, indicating
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closely to the immunoglobulin κ light-chain locus at band p12 on the that these coreceptors play essential roles in the maturation of T cells in
short arm of chromosome 2. The protein sequence of the aminotermi- the thymus. A similar defect is observed in patients with the bare lym-
nal domains of each CD8 chain shares greater than 28 percent homol- phocyte syndrome who have a congenital immune deficiency caused
ogy with κ light-chain variable regions. Therefore, these domains are by genetic defects in their capacity to make MHC class II molecules.
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called the variable-region-like (V-like) domains. Following this V-like Although patients have normal numbers of B cells and T cells, they have
domain, the CD8 molecule has a short region rich in prolines, threon- markedly reduced numbers of CD4+ T cells, thus accounting in part for
ines, and serines that resembles the immunoglobulin hinge region. This their profound immune deficiency.
region also contains sites for O-linked glycosylation. A hydrophobic In addition to serving as coreceptors, CD4 or CD8 molecules
transmembrane region anchors the hinge-like region. The CD8 mole- enhance antigen responsiveness by transducing a signal either directly
cule has a 25-amino-acid cytoplasmic tail consisting of highly basic res- or in concert with the CD3/TCR complex. This is mediated through
idues. Two cysteines within the V-like domain form a disulfide bridge their interaction with the SRC family tyrosine kinase Lck. Lck is non-
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that stabilizes the immunoglobulin-like fold. An additional cysteine covalently associated with the cytoplasmic tails of CD4 and/or CD8.
residue is located each within the V-like domain, the hinge region, the When a T cell recognizes a peptide presented by an appropriate MHC
transmembrane segment, and the cytoplasmic domain. These cysteines antigen, the interaction of CD4 or CD8 with the MHC molecule brings
form intermolecular disulfide bridges between two CD8 molecules, Lck close to the TCR complex. Lck then phosphorylates the tyrosine
thereby stabilizing the CD8α/CD8β heterodimers or CD8α/CD8α residues in the ITAMs of CD3 polypeptides and the ζ chain, thereby
homodimers on the T-cell surface. The cell surface CD8 heterodimer initiating the receptor signaling required for T-cell activation.
shares structural geometry with the heterodimers formed by the pairing Finally, CD4 also is a cellular coreceptor for HIV. Binding of CD4
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of immunoglobulin light and heavy chains. along with chemokine receptors such as CCR5 or CXCR4 facilitates
CD4, on the other hand, is expressed as a monomer on the sur- entry of the virus into host T cells and stimulates them in an antigen-
face of a subset of peripheral T cells, mononuclear phagocytes and some driven immune response. Targeting HIV entry/fusion by specific
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blood-derived dendritic cells. It is a 55-kDa monomeric glycoprotein monoclonal antibodies and/or inhibitors is, therefore, an important
that is encoded by a gene that maps to the short arm of chromosome 12. therapeutic approach in HIV. Additionally, CD4 is also of prognos-
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It consists of 5 external domains, a stretch of hydrophobic transmem- tic relevance, as disease progression correlates with depletion of blood
brane residues, and a highly basic cytoplasmic tail of 38 residues. T cells that express CD4 (Chap. 81).
Similar to CD8, the aminoterminal domain of CD4 also has extensive
homology to immunoglobulin light-chain variable regions. However, T-CELL SUBSETS
following this immunoglobulin-like domain is a domain of 270 amino
acids that bears little resemblance to other proteins of the immunoglob- PRECURSOR THYMOCYTES
ulin superfamily.
The cytoplasmic regions of CD4 and CD8 are conserved among T lymphocytes develop in the marrow from a common lymphoid
vertebrates, suggesting that they are essential for the function of these progenitor that also gives rise to B lymphocytes. While B-lymphocyte
molecules. The cytoplasmic region of CD4 contains five serines and precursors remain in the marrow, T-cell precursors migrate to the thy-
threonines, one or more of which is phosphorylated by PKC upon acti- mus, where they undergo distinct maturation steps and immunologic
vation of T cells by phorbol esters or exposure to antigen. Subsequent education. This is accompanied by characteristic TCR gene and sur-
to phosphorylation, the CD4 glycoprotein is internalized concomitant face expression changes of the CD3 complex, CD4, and CD8. At the
with T-cell activation. Similarly, the CD8 protein also possesses a highly early stage, thymocytes are double-negative and express neither CD4
charged and conserved cytoplasmic domain that may be involved in nor CD8. This is a highly heterogeneous population, which includes γδ
transmembrane signal transduction. T cells, αβ T cells that also express the NK1.1 receptor commonly found
on natural killer (NK) cells, and immature thymocytes that do not yet
FUNCTION OF CD4 AND CD8 express a complete TCR molecule, but are thought to be precursors to

In addition to MHC antigen presentation, TCRs generally require the αβ lineage. The latter start to express CD8 and CD4 and enter the
double-positive stage, where they undergo positive/negative selection
activation via CD4 and CD8 as coreceptors. Imaging studies and affin- events and CD4/CD8 cell fate choice. This results in the generation of
ity measurements have demonstrated that CD4 and CD8 molecules mature thymocytes and peripheral T cells that express either CD4 or
associate on the plasma membrane with components of the TCR and CD8, but not both (Chap. 74). 33
contribute to antigen recognition and stabilization of TCR–MHC
interactions. The adhesion between the CD3/TCR complex and the
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MHC glycoproteins expressed by an APC or target cell is more than HELPER AND CYTOTOXIC T CELLS
100-fold enhanced by CD8 or CD4, probably by focusing MHC mol- The mutually exclusive expression of CD4 or CD8 on mature T cells
ecules of the APC or target cell onto the T-cell surface, allowing for defines two major blood T-cell subsets: blood T cells that express CD8

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