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

all T cells that express αβ or γδ heterodimers. The CD3 polypeptides are organization and the mechanisms by which this is regulated are, however,
designated CD3γ, CD3δ, and CD3ε. The CD3ε chain couples with either still poorly understood. Upon binding to a specific ligand, the TCR αβ
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the CD3γ or the CD3δ chain to generate heterodimers that each form a (or γδ) heterodimer undergoes steric changes that result in the phos-
tight association with the αβ (or γδ) receptor heterodimer on the T-cell phorylation of the ITAMs of the ζ chain and each of the CD3 polypep-
surface (see Fig. 76–1). Each CD3 polypeptide has a negatively charged tides (see Fig. 76–1). When tyrosine residues in the ITAMs become
amino acid in the central portion of the hydrophobic transmembrane phosphorylated, they can act as docking sites for adapter proteins or
region that stabilizes the CD3 complex with the two chains of the TCR. tyrosine kinases, such as the zeta-associated protein of 70 kDa (ZAP-
The ζ chain (CD247), on the other hand, forms a disulfide-like homodi- 70), which possesses a Src homology 2 (SH2) domain and a Src homol-
mer that primarily associates with the two TCR chains and only weakly ogy 3 (SH3) domain. Following ligation of the TCR, Src family protein
associates with the CD3 complex. As such, it cannot be coimmunopre- tyrosine kinases (e.g., Lck) are recruited and become activated. This
cipitated easily with antibodies to the CD3 polypeptides. In addition, differentially phosphorylates the ITAMs of the accessory molecules in
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the ζ chain lacks a significant extracellular domain (see Fig. 76–1). the TCR complex. ZAP-70 is recruited to the phosphorylated ITAMs
of the ζ chain via its SH2 and SH3 domains, and subsequently becomes
MOLECULAR FEATURES OF THE T-CELL activated. Activated ZAP-70 phosphorylates tyrosine residues in the
RECEPTOR COMPLEX intracytoplasmic segments of surface CD6 and membrane-anchored
adapter protein called linker of activation of T cells (LAT), both of
The genes encoding CD3γ, CD3δ, or CD3ε chains are clustered on the which constitute a device for the amplification and diversification of
long arm of chromosome 11 in band q23. CD3γ has a 16-kDa polypep- signals that are responsible for most of the responses that result from
tide backbone that is heavily glycosylated to assume a final molecular engagement of the TCR. 23
mass of 25 to 28 kDa. CD3δ and CD3ε are each 20 kDa in molecular The network of proteins that interact with the LAT signalosome
mass. The CD3δ is a glycoprotein consisting of 30 percent carbohy- includes SLP-76, phospholipase Cγ (PLC-γ ) and GRAP2. Activated
1
1
drate. In contrast, CD3ε is not glycosylated. CD3δ and CD3γ are highly PLC-γ mediates hydrolysis of phosphatidylinositol-(4,5)-bisphosphate
1
homologous at both the protein and nucleic acid sequence level. The at the cell membrane, which generates the second messengers inosi-
nucleic acid sequence of each predicts CD3δ and CD3γ to have typical tol-(1,4,5)-trisphosphate and polyunsaturated diacyglycerols, leading to
signal peptides, respective hydrophilic extracellular domains of 79 to a rapid increase in cytosolic free calcium and activation of the θ isoform
89 amino acids, hydrophobic transmembrane regions of 27 amino acids, of protein kinase C (PKC). Cytosolic free calcium binds to calmodulin,
and hydrophilic intracellular domains of 44 to 55 amino acids. CD3ε an ubiquitous calcium-dependent regulatory protein. The calcium–
is similar, with a 22-residue signal peptide, an extracellular domain of calmodulin complex activates the cytoplasmic phosphatase calcineurin,
104 amino acids, a transmembrane domain, and a comparatively long which, in turn, catalyzes the removal of an inhibitory phosphate group
intracellular domain of 81 amino acids. Each CD3 polypeptide has one on the nuclear factor of activated T cells (NFATs) that retains NFAT
immunoglobulin-like domain in its extracellular domain that is defined proteins in the cytoplasm. Removal of the phosphates from NFAT1 and
by an intrachain disulfide bond (see Fig. 76–1), indicating that these NFAT2 by activated calcineurin allows these transcription factors to
polypeptides are members of the immunoglobulin superfamily. How- translocate into the nucleus, where they enhance transcription of sev-
ever, unlike the αβ or γδ chains of the TCR, there is no variability in the eral activation-induced genes, including those encoding interleukin
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extracellular domains of the CD3 proteins, indicating that these mole- (IL)-2, IL-4, and tumor necrosis factor. The importance of this path-
cules do not contribute to the specificity of antigen recognition. way in T-cell activation is underscored by the strong immunosuppres-
The ζ chain has no sequence or structural homology to the other sive activity of calcineurin inhibitors such as cyclosporine and FK506,
three CD3 chains. It is a nonglycosylated protein of 16-kDa molecular which are commonly administered in the clinic to treat autoimmune
mass that is encoded by a gene found on chromosome 1. The ζ chain has diseases and to prevent graft rejection.
only a very short extracellular domain of 6 to 9 amino acids, a trans- In parallel, diacylglycerol in the plasma membrane recruits Ras-
membrane domain of 21 amino acids, and a long intracellular domain GRP1, a guanine nucleotide-exchange factor (GEF), which acts on Ras
of 113 amino acids. to activate extracellular receptor-activated kinase 1 and 2 (ERK1/2).
The cytoplasmic domains of all the CD3 polypeptides and the ζ Activated ERK phosphorylates Elk, which, in turn, stimulates transcrip-
chain each contain sequences termed immunoreceptor tyrosine-based tion of Fos, a component of the activation protein-1 (AP-1) factor that
activation motifs (ITAMs). Each ITAM contains two copies of the is a necessary component of the transcription-factor complex required
sequence tyrosine-X-X-leucine separated by six to eight amino acid res- for expression of IL-2 and other critical T-cell proteins. LAT-bound
idues, in which X represents an unspecified amino acid. The cytoplas- SLP-76 also interacts with Nck and with Vav1 to promote reorgani-
mic domains of each CD3 polypeptide contain one ITAM, whereas each zation of the actin cytoskeleton, and with FYB to increase the bind-
ζ chain contains three ITAMs (see Fig. 76–1). These sequences allow ing of the integrin CD58 (LFA-1) to its ligand intercellular adhesion
the CD3 proteins to associate with cytosolic protein tyrosine kinases molecule (ICAM)-1. DYN2, a member of the dynamin superfamily of
following TCR ligation, thus transducing a signal to the interior of the large guanosine triphosphatases (GTPases), is also recruited by phos-
T cell. The cytoplasmic domains of CD3ε and CD3ζ are particularly phorylated LAT molecules and participates in the generation of fila-
important in this regard. mentous actin. Dedicator of cytokinesis 2 (DOCK2), another GEF, also
activates GTPases of the Rac family, which, in turn, activate another
SIGNAL TRANSDUCTION VIA THE T-CELL mitogen-activated protein (MAP) kinase called p38, and initiate a par-
RECEPTOR COMPLEX allel enzymatic cascade resulting in the activation of yet another MAP
kinase called c-Jun N-terminal kinase (JNK), otherwise known as
Although the major components of the TCR signaling machinery have stress-activated protein kinase (SAPK). Activated JNK phosphorylates
been identified and mapped, key components continue to be discov- c-Jun, the second component of the AP-1 transcription factor required
ered, adding to the complex network of TCR signal transduction. Sig- for IL-2 transcription. The guanosine triphosphate (GTP)-bound form
nal transduction from the TCR heterodimer to intracellular proteins of Rac also induces cytoskeletal reorganization, thereby facilitating
is mediated by the CD3 polypeptides and the ζ chain. Their spatial the clustering of the TCR complex, accessory molecules, and other

Kaushansky_chapter 76_p1175-1188.indd 1178 9/17/15 4:00 PM