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CHaPter 4 Antigen Receptor Genes, Gene Products, and Coreceptors 69

of BCR–antigen interaction include the nature of the foreign consequences in terms of infection, B-cell immortalization, and
antigen, the mode of activation, the developmental stage of the the potential for oncogenesis, the in vivo relevance of any
B cell, and the microenvironment in which antigen encounter CD21–CD23 interaction remains unclear.
occurs. Exactly how these variables ultimately result in the dif-
ferential activation of diverse intracellular signaling pathways CD19
with fundamentally divergent outcomes is still under study. CD19 is an IgSF surface glycoprotein of 95 kDa that is expressed
Emerging from these studies is an appreciation of the role of from the earliest stages of B cell development until plasma cell
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BCR coreceptors, which have been shown to be capable of terminal differentiation, when its expression is lost. FDCs also
modulating antigen receptor signaling in response to antigen. express CD19. CD19 maps to chromosome 16p11.2, where it
encodes a 540 amino acid protein with two extracellular C-type
BCR Coreceptors IgSF domains as well as a large, approximately 240 residue,
The initiation of a humoral immune response results from antigen cytoplasmic tail that exhibits extensive conservation between
interaction with the antigen receptors on mature peripheral mice and humans. This relatively large cytoplasmic domain
lymphocytes. However, the manner in which mature B and T includes nine conserved tyrosine residues which, upon phos-
lymphocytes recognize antigen is fundamentally different (Chapter phorylation, serve as docking sites for other SH2-containing
6). Surface Ig, as a component of the BCR on B lymphocytes, effector molecules. The signaling capacity of CD19 has been
typically recognizes an antigenic epitope in its native three- shown to result from tyrosine phosphorylation, which occurs
dimensional configuration which, upon engagement with mIg, upon engagement of the BCR, CD19 or, optimally, by collication
is capable of transmitting a signal to the cell interior. In contrast, of CD19 and IgM. Known signaling effector molecules that have
the antigen receptor expressed by T lymphocytes typically rec- been identified in association with tyrosine-phosphorylated CD19
ognizes an antigen-derived peptide associated with an appropriate include the LYN and FYN protein tyrosine kinases, the Rho-family
MHC structure (Chapter 5). Further, for this T-cell recognition guanine nucleotide exchange factor, VAV, and phosphatidylinositol
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event to be productive, a CD4 or CD8 coreceptor must also bind 3-kinase. Although specific ligands for CD19 have been proposed,
to the MHC structure presenting the foreign antigen. the physiological relevance of CD19 engagement by putative
Antigen recognition by the BCR on B lymphocytes is also ligands has not been demonstrated.
influenced by coreceptors present on mature B cells (see Table In vitro studies using mAbs directed against CD21 or CD19
4.3). In this case, the coreceptors may also recognize antigen, provided initial evidence that these B-cell surface antigens could
but only in a form that has been modified by other components influence mIg-mediated signaling. 51-53 Genetic deficiencies of
of the immune system, as described below. In general, these CD21 (CVID7) or CD19 (CVID3) promote the development
coreceptors and coreceptor complexes can be divided into those of common variable immune deficiency (CVID), which is
that regulate BCR signaling in a positive manner and those that characterized by hypogammaglobulinemia (Chapter 34). In mice,
regulate in a negative manner. Thus the ultimate outcome of CD21 and CD19 deficiencies demonstrate impaired antibody
+
signaling via the BCR depends not only on the signals transduced response to T-dependent antigens. The paucity of CD5 B cells
via the Igα/β heterodimer but also how these signals are perceived in CD19-deficient mice suggests a role for this molecule in
by the cell in association with the signals propagated by the the generation and maintenance of the B1 lineage of B cells
various coreceptors that are concomitantly engaged. (Chapter 7). CD19 is expressed from the earliest stages of B cell
ontogeny and, accordingly, a signaling function for CD19 in B
Coreceptors That Positively Regulate BCR Signaling lymphopoiesis has been demonstrated. 54
CD21
Mature B lymphocytes express two receptors for complement CD21–CD19 Coreceptor Complex
C3 components, CD35 (CR1) and CD21 (CR2) (Chapter 21). A mechanism by which these molecules could augment BCR-
Of these, CD21 fulfills the requirements of a BCR coreceptor mediated signaling was provided by the identification of a
(vide infra). The expression of CD21 is restricted to mature B CD21–CD19 coreceptor complex on mature B cells that also
cells and follicular dendritic cells (FDCs), whereas CD35 is also includes CD81 (Fig. 4.12). CD81, also known as TAPA-1, is a
found on erythrocytes, monocytes, and granulocytes. CD21 is 26-kDa tetraspan molecule widely expressed on a number of
a 140 kDa surface glycoprotein encoded by the CR2 locus on cell types, including lymphocytes. The CD21–CD19 coreceptor
chromosome 1q32 (see Table 4.3). Expression of CD21 begins model predicted that as a result of complement activation, C3d
at approximately the same time as IgD during B lymphopoiesis would be deposited on an antigen, thereby providing a bridge
(Chapter 7). CD21 is subsequently expressed on all mature B by which a CD21–CD19 receptor complex could associate with
cells until terminal differentiation, albeit at different levels mIgM and the BCR complex. 51-53 Clustering of CD19 close to
depending on B cell population. The extracellular domain of the BCR by the C3d–antigen complex would effectively recruit
CD21 is composed of 15–16 short consensus regions (SCRs), the signal transduction effector molecules associated with CD19
each composed of 60–70 amino acids, and a relatively short to the Igα/β heterodimer. As a consequence, the CD19-associated
34-amino acid cytoplasmic tail. The two-amino terminal SCRs LYN and FYN tyrosine kinases, VAV, and PI3-kinase signaling
constitute the region that interacts with one of the third comple- effector molecules would be in a position to exert their activities
ment component (C3) cleavage products, iC3b, C3d, g, and C3d on the Igα/β heterodimer–mediated signaling events initiated
(Chapter 21). 51 by antigen engagement of mIgM.
CD21 is a receptor for Epstein-Barr virus (EBV), which Strong support for CD21–CD19 coreceptor physiological
similarly binds the two N-terminal SCRs via its major envelope function in BCR signaling was subsequently provided by experi-
glycoprotein gp350/220. CD21, through its oligosaccharide chains, ments using a murine model of immune response. Immunization
also binds CD23, the low-affinity IgE receptor (FcεRII). Whereas with an antigen covalently attached to C3d dramatically reduced
EBV utilization of CD21 for cell entry has clear physiological the signaling threshold necessary for antigen to elicit an immune