Biomedical Engineering Reference
In-Depth Information
CD34
+
Prosurvival role, potentially in
response to or by regulating
expression of TNFα
Pro-B
Regulation of survival
downstream and induction
of light chain rearrangement
downstream of pre-BCR
Pre-B
Constitutive NF-κB activity
provides a prosurvival signal
Immature
B cell
++
Induction of apoptosis in
self-reactive immature B
cells, perhaps through
downregulation of NF-κB
activity
Transitional
B cell
Survival and splenic
maturation require alterna-
tive (BAFF-induced) and
classical NF-κB
Mature B cells
FIGURE 7.4
Role of NF-
κ
B in B cell development. See text for detailed discussion.
medullary negative selection of TCR transgenic thymocytes may be Fas-dependent
at high antigen doses [44], suggesting NF-
B could mediate negative selection by
sensitizing thymocytes to FasL expressed in the thymus [45]. Although negative
selection appears normal in Fas-deficient mice, suggesting this is not the target of
NF-
κ
κ
B in negative selection; this example provides a model for conceptualizing how
NF-
B might promote negative selection. Arguably, this example may be more akin
to clonal deletion of peripheral T cells than to negative selection of thymocytes;
however, the underlying theme of robust TCR activation inducing NF-
κ
κ
B-dependent,
pro-apoptotic genes is germane.
While the role of NF-
B in positive selection of thymocytes is more in keeping
with widely held views of NF-
κ
B, e.g., as an inducer of antiapoptosis genes, the details
remain to be fully understood. Studies of transgenic mice expressing constitutively
active I
κ
B may be preferentially required for the positive
selection of those cells destined to become CD8
+
SP cells. It is thought that NF-
κ
B
α
mutants suggest that NF-
κ
B
acts in this capacity by regulating the expression of prosurvival Bcl-2 family members.
The molecular mechanisms by which strength of signaling through the TCR determines
whether NF-
κ
κ
B mediates positive or negative selection, however, remain unclear.
7.3.1.3 Negative Selection of B Cells
As in thymocytes, negative selection of immature B cells is mediated by strength
of signaling through the antigen receptor; that is, high affinity BCR binding to self-
