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CHaPter 4 Antigen Receptor Genes, Gene Products, and Coreceptors 71

Ag

CD22
IgG
BCR
BCR

Ig-α FcRγIIB Ig-α
Ig-β Ig-β

PTK Lyn
Syk Syk
–
SHIP or – SHP-1
SHP-1
A B
FIG 4.13 Negative Regulation of B Cell Receptor (BCR) Signaling by FcγRIIB and CD22.
(a) Soluble immunoglobulin G (IgG)–antigen immune complexes juxtapose the BCR with FcγRIIB.
The BCR-associated LYN tyrosine kinase subsequently tyrosine phosphorylates the FcγRIIB
immunoreceptor tyrosine-based inhibitory motif (ITIM). In turn, this leads to the recruitment of
the SRC homology 2 (SH2)-containing inositol phosphatase SHIP and tyrosine phosphatase SHP-1
to the phosphorylated FcRγIIB ITIM. Both of these phosphatases have demonstrable inhibitory
activity on BCR-mediated signaling. Although SHIP is believed to be the major effector in the
FcRγIIB-mediated inhibition of BCR signaling, the exact mechanism of its action in this context
has not yet been elucidated. (B) CD22 associated with the BCR is tyrosine-phosphorylated upon
antigen–BCR engagement. SH2-containing signaling molecules dock on tyrosine phosphorylated
residues, including the SHP-1 tyrosine phosphatase that can subsequently dephosphorylate signaling
molecules previously activated by a mIgM-mediated signal.

Tyrosine-phosphorylated CD22 associates with several SH2- KeY ConCePtS
containing signaling molecules, including the LYN and SYK
tyrosine kinases, PI3-kinase, phospholipase C-γ, and SHP-1. T-Cell Receptor (TCR)–CD3 Complex
The 140-amino acid cytoplasmic domain of CD22 includes • Cell-surface expression of the TCR heterodimers requires association
six conserved tyrosine residues. Three of these tyrosines are with a complex of invariant proteins designated CD3.
located within conserved consensus ITIM sequences and possess • Each TCR–CD3 complex contains three CD3 dimers.
a demonstrable capacity to bind the SH2 domain of the SHP-1 • Assembly of the TCR–CD3 complex involves interactions between
phosphatase. The presence of the multiple ITIMs and association TCR transmembrane basic residues and transmembrane acidic residues
with SHP-1 indicated that CD22 might impinge on BCR signaling in each of the CD3 subunits.
in a negative manner. Physiological evidence that CD22 could • Signal transduction by the TCR involves the phosphorylation of
immunoreceptor tyrosine-based activation motifs (ITAMs) in the
act as a coreceptor to negatively regulate mIgM signaling was cytoplasmic domains of CD3 proteins.
provided by the generation of CD22-deficient mice by targeted • Phosphorylated CD3 ITAMs recruit and activate the zeta chain-associated
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mutagenesis. CD22-deficient B cells exhibit hyperactive B-cell protein kinase 70 (ZAP-70) protein tyrosine kinase.
responses upon BCR triggering and an increased incidence of • Deficiency of CD3 proteins impairs T-cell development and can produce
serum autoantibodies. This suggests that B-cell tolerance is altered severe combined immunodeficiency (SCID).
and that B cells are more readily activated in the absence of this
negative regulator of BCR signaling.

THE TCR–CD3 COMPLEX couple to the intracellular signaling events that lead to the
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activation of T-cell effector function. There are four CD3
The αβ and γδ TCR heterodimers, which are responsible for the proteins: γ, δ, ε, and ζ (Fig. 4.14).
recognition of specific antigen by T lymphocytes, associate with
a complex of invariant proteins designated CD3. This association CD3 Proteins
is necessary for TCR cell-surface expression and enables the TCR CD3γ, CD3δ, and CD3ε are structurally similar, and the genes
heterodimers, which have only short cytoplasmic domains, to encoding them map to a locus in chromosome 11q23. The