Page 88 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 4 Antigen Receptor Genes, Gene Products, and Coreceptors 73

targeted to a lysosomal degradation pathway rather than to the (Fig. 4.15). During antigen recognition, CD4 and CD8 are thought
cell surface. 18,60-62 to bind the same pMHC complex as the TCR and thus are true
68
Because the structures of most of the individual components coreceptors for the TCR. The cytoplasmic domains of CD4
of the TCR–CD3 complex are known, a model of the overall and CD8 associate with LCK and serve to bring LCK into contact
structure of the receptor has been proposed. This model envisions with the CD3 chains of the pMHC-engaged TCR/CD3 complexes,
a compact TCR–CD3 complex, with trimeric contacts occurring leading to the phosphorylation of CD3 ITAMs and initiation of
within the transmembrane regions of all components (i.e., TCR signaling (Chapter 12).
TCRα–CD3ε–CD3δ, TCRβ–CD3ε−CD3γ, and TCRα–CD3ζ– The expression of the CD4 and CD8 coreceptors is highly
CD3ζ) and with the TCRαβ projecting further from the regulated during T-cell development in the thymus (Chapter 8).
membrane (80 Å) than the CD3 chains (40 Å). 18,62 Thymocytes initially express neither coreceptor (“double nega-
−
−
Mutations in the CD3D, CD3E, CD3G, and CD3Z genes have tive”). CD4 CD8 thymocytes destined to become TCRαβ T
+
+
been described in humans. 63-65 The clinical consequences of these cells progress through a CD4 CD8 (“double-positive”) stage to
mutations underscore the importance of the CD3 proteins for become mature CD4 or CD8 T cells. Positive and negative selec-
the normal development and function of T cells. tion of thymocytes on the basis of their TCR specificities, and
Homozygous mutations leading to complete deficiencies of commitment to the CD4 or CD8 lineages occur during the
either CD3δ, CD3ε, or CD3ζ protein produce a form of SCID double-positive stage.
(Chapter 35) characterized by severe T-cell lymphopenia, but
in the presence of phenotypically normal B cells and NK cells CD4: Structure and Binding to MHC Class II Molecules
− +
+
(T B NK SCID). 63,64 A member of the IgSF, CD4 is a 55 kDa glycoprotein whose
Mutations in CD3G leading to deficiency of CD3γ produce relatively rigid extracellular region contains four IgSF domains
considerable clinical heterogeneity ranging from severe immu- (designated D1–4). Its cytoplasmic domain contains two cysteine
nodeficiency in infants to mild forms of autoimmunity in residues that mediate a noncovalent interaction with LCK through
adulthood. Homozygous deficiency in CD3γ impairs, but does a “zinc clasp”–like structure formed with a dicysteine motif in
not abrogate, T-cell development, leading to mild T lymphopenia, the N-terminal region of LCK. 66,69-71
reduction in cell-surface expression of the TCR–CD3 complex The N-terminal domain (D1) of CD4 binds between the
on peripheral T cells by 75–80%, and impaired in vitro prolifera- membrane-proximal α 2 and β 2 domains of MHC class II. Thus
tive T-cell responses to lectins and to anti-CD3 mAbs. In CD4 interacts with pMHC class II at a distance from the α
peripheral blood, there are differential effects on phenotypically helices and peptide contacted by the TCR, enabling the TCR and
defined T-cell subsets, with very few CD8 T cells, a 10-fold CD4 to bind the same MHC class II molecule simultaneously.
+
reduction in CD45RA CD4 T cells (“naïve helper” subset), and Although MHC molecules are highly polymorphic, the CD4
+
normal numbers of CD45RO CD4 T cells (“memory” cells). 65 contact sites are highly conserved. In humans, CD4 targets
nonpolymorphic residues shared by all three MHC class II
Early Events in TCR–CD3 Signaling molecules (HLA-DR, -DP, and -DQ). The crystal structure of
Stimulation of the TCR–CD3 complex by pMHC leads to the the TCRαβ–pMHC–CD4 ternary complex assumes a V-shape
phosphorylation of tyrosine residues in the CD3 ITAMs by the with pMHC at the apex and with TCRαβ and CD4 forming the
66
SRC-like protein tyrosine kinase, LCK. The phosphorylated arms of the V. There is no direct interaction between the corecep-
CD3 ITAMs, in turn, create high-affinity binding sites for the tor and the TCR heterodimer, indicating that pMHC brings the
SH2 domains of the zeta chain-associated protein kinase 70 TCR and CD4 together. The approximately 70 Å of separation
(ZAP-70) protein tyrosine kinase, leading to its recruitment to between the membrane-proximal domains of TCRαβ and CD4
the TCR–CD3 complex and to its activation (Chapter 12). 66,67 would allow the CD3 chains to lie within the open angle between
The consequences of ZAP-70 deficiency (selective T-cell immu- TCRαβ and CD4, promoting interactions between CD3 chains
nodeficiency in humans) underscore the centrality of its role in and CD4-associated LCK. 66,69,71
T-cell activation (Chapter 35). Experiments using soluble forms of CD4 and pMHC have
The TCR appears to act as a mechanosensor to trigger the revealed that monomeric CD4 binds pMHC with very low affinity
cascade of complex biochemical events leading to the activa- (Kd approximately 200 µM). The binding of CD4 to pMHC is of
tion of T-cell effector function. As the T cell migrates over the lower affinity than that of TCRαβ to pMHC (Kd 1–10 µM) and
cell surface of an APC or target cell, the binding of the pMHC displays a far more rapid off time. Because of the low affinity and
complex to the TCR causes the TCR to act as a lever, convert- the rapid off time, it is unlikely that interactions of CD4 with
ing horizontal force into a vertical force that acts on the CD3 MHC class II molecules initiate the interaction between a T cell
chains, exposing their ITAMs for phosphorylation. Following and an APC (Chapter 6). Rather, these binding characteristics
the initiation of signaling, sustained signaling appears to involve are more compatible with a model in which the initial event is
multimerization of TCR–CD3 complexes and engagement of the interaction between the TCR and pMHC, followed by the
coreceptors. 18,62 recruitment of CD4, which acts primarily to promote signaling
events through the delivery of LCK. 66,69,71
T-CELL CORECEPTORS: CD4 AND CD8 CD8: Structure and Binding to MHC Class I Molecules
Expression of CD4 and CD8 divides mature T cells into two There are two CD8 polypeptides, α and β, and these are expressed
distinct subsets: CD4 T cells (Chapter 16), which recognize on the cell surface either as a disulfide-linked CD8αα homodimer
peptides in the context of class II MHC molecules, and CD8 T or as a disulfide-linked CD8αβ heterodimer. On most αβ T cells,
cells (Chapter 17), which recognize antigens presented by class CD8αβ is the predominant form of CD8 while natural killer
I MHC molecules. Indeed, CD4 binds directly to class II MHC (NK) cells (Chapter 17), intestinal intraepithelial T cells, and γδ
molecules, and CD8 interacts directly with class I MHC molecules T cells exclusively express CD8αα. 66,69-71