384
Antigen Presenting Cells (APCs)
activation of bystander B cells: (1) the
Frst activation signal is dependent on
an antigen-speciFc BCR; (2) binding of
an antigen, endocytosis, processing and
loading onto MHC class II molecules
occurs at 10
4
to 10
6
-fold lower antigen dose
in B cells expressing an antigen-speciFc
BCR than in other cells; (3) only B cells
that remain in prolonged and tight contact
with a T cell have access to cytokines
secreted by T cells in a polarized fashion
upon activation. This is accomplished by
formation of the immunological synapse
(cf. Sect. 7.3.).
9.2.2
CD40–CD40L Engagement
CD40 is a member of the TN± receptor
family and constitutively expressed on the
surface of B cells. Its ligand, CD40L, is
only found on the surface of T cells upon
seeing cognate antigenic peptide in the
context of MHC class II molecules and cos-
timulatory molecules CD80 and/or CD86.
When these activated helper T cells bind
antigen-presenting B cells, CD40–CD40L
interactions lead to CD40 oligomerization.
This oligomerization initiates enzyme cas-
cades Fnally leading to the activation and
nuclear translocation of transcription fac-
tors, including N±-
κ
Ba
n
dA
P
-
1
.T
h
i
s
pathway has already been discussed in the
context of T cell–mediated macrophage ac-
tivation; hence, it is a general mechanism
for the stimulation of target cells by helper
T cells.
The importance of the CD40–CD40L
interaction in humoral immunity is un-
derscored by the observations that CD40 or
CD40L gene knockout mice and humans
with mutations in the CD40L gene exhibit
profound defects in afFnity maturation
of immunoglobulin and memory B-cell
generation. Interestingly, a transforming
protein
of
Epstein–Barr
Virus
(EBV),
which infects human B cells, utilizes the
same signaling pathway as CD40, with
the consequence that EBV-transformed
B cells proliferate rather rapidly, leading
to lymphomas.
Three helper T-cell derived cytokines, IL-
2, IL-4, and IL-5, contribute to proliferation
of activated B cells (±ig. 9). Besides CD40-
mediated signals, it is again cytokines,
mainly IL-2, IL-4, and IL-6, that stimulate
antibody
synthesis,
the
production
of
secreted Ig and switching from IgM to
the IgG, IgA, or IgE isotype. There is
a clear preference of some cytokines to
induce secretion of particular Ig isotypes,
for example, I±N-
γ
promotes secretion of
IgG2a, IL-4 favors IgG1, and IgE ad IL-
5/TG±-
β
favor IgA production.
Ig-secreting B cells are found in the red
pulp of the spleen, the medulla of the
lymph nodes, and the bone marrow. Many
of the antibody-secreting B cells change
into plasma cells, which are specialized in
producing and secreting soluble antibody.
9.3
Antigen Presentation in the Germinal
Center
Within 4 to 7 days after antigen exposure,
some of the activated B cells migrate
back toward the center of the follicle
and begin to proliferate rapidly, thereby
forming the germinal center. The B cells in
the germinal center are named
centroblasts
and
centrocytes
. They have a doubling time
o
f6to12h
,soth
a
t1Bc
e
l
lg
i
v
e
sr
i
s
e
to a clone of about 5000 centroblasts
in
5 days.
It
was
estimated
that
on
average, three B-cell clones colonize each
follicle after a single immunization. In
particular, CD40–CD40L interactions and
presentation of cognate peptide antigens
on MHC class II molecules are required to
maintain proliferation of centroblasts and
to allow further differentiation.
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