section 35.7
B-Cell Clonal Selection and Proliferation
823
CD4 or CCR5. However, three residues in gpl20 appear
to be conserved in primate lentiviruses (of which HIV
is one), a Glu (370), a Trp (427), and an Asp (368).
The residues of gpl20 that interact with the CCR5 also
are highly conserved. The high mutation rate of HIV
is one of the problems for host cell recognition and in
vaccine development. It also affects immunoassays that
are used for detecting the HIV virus and/or antibodies
to it.
It is evident from the examples describing immunoglob-
ulin and TcR structures that only a few residues of each
protein molecule are crucial for the recognition process.
The remainder of the structure of the molecule, the re-
ceptor, or the antigen-presenting protein is involved in
other functions, including localization by other cell surface
proteins.
F I G U R E 3 5 - 1 6
(Also see color figure.) CD4 (cluster differentiation 4) protein. CD4 on T
cells is a component of the MHC class II, TcR complex. Shown are the
extracellular domains that consist of two immunoglobulin-like folds. The
/l-sheet secondary structure is illustrated in one fold; only the a-carbon
backbone is shown in the other. The figure is derived from the coordinates
published in the Protein Data Bank file 1WIO.
receptor molecule and to another coreceptor (not shown),
the chemokine receptor, CCR5. Only a few residues of
gpl20 and CD4 are in contact; two residues of CD4, Phe
(43) and Arg (59), are particularly important for the in-
teraction. The amino acid sequence of gpl20 can vary
extensively without affecting its binding to CD4, an ob-
servation that is explained by the limited contact that is
required for the binding. Many HIV mutations occur on
the gp
! 2 0
surface that do not make contact with either
35.7 B-Cell Clonal Selection and Proliferation
The binding of an antigen, or more precisely the binding of
a specific epitope on an antigen to an IgM or IgD antibody
receptor on a B cell, is a prerequisite to proliferation of
the B cell and the formation of plasma and memory cells.
This restricted recognition of single epitopes on nonself
antigens is one of the important self/nonself discrimina-
tion mechanisms. The interaction between the antigen and
the IgM receptor, the internalization of the antigen by the
B cell, and the proteolytic digestion of the antigen and
presentation of the antigen-derived peptides is shown in
Figure 35-1. After presentation of the peptides on the
MHC II protein of the B cell, a T-helper cell recognizes
the peptides through a specific recognition mechanism that
is a property of the TcR molecule (Figure 35-15). After
stimulation by the Th cells through secreted interleukins
(Table 35-4), proliferation of memory and plasma cells oc-
curs. The clonal proliferation response of B cells to antigen
binding is shown schematically in Figure 35-18.
Stimulation of B cells to proliferate, differentiate, and
synthesize antibodies occurs through signals provided by
molecules synthesized and secreted by T cells. These sig-
naling molecules, the cytokines and particularly the inter-
leukins, are described in Table 35-4.
The critical importance the CD4+ T cells and their mes-
senger molecules for B-cell proliferation is manifest in
AIDS where HIV proteins promote death of CD4+ T cells
resulting in inadequate stimulation of B-cell prolifera-
tion. One of the early clues to this action of HIV was the
change in the ratio of CD4 to CD
8
cells in AIDS patients.
The CD4+ cell count and the CD4/CD8 ratio quickly be-
came markers for the progression of the disease. The im-
munodeficiency that results from destruction of Th cells
