Biomedical Engineering Reference
In-Depth Information
7.6 LYMPHOCYTE MAINTENANCE
Lymphocyte homeostasis is dependent on the survival of mature lymphocytes in
addition to replenishment of the peripheral lymphocyte pool through lymphopoiesis.
Consequently, there is increasing interest in the possible role of NF-
B in the survival
of mature lymphocytes. It is widely accepted that lymphocyte survival is mediated
through tonic stimulation downstream of the AgR, as well as certain cytokine
receptors. As discussed above, genetic targeting experiments support an important
role for NF-
κ
B family members in lymphocyte survival. Naïve T cells require
continued contact with MHC: self-peptides, most likely expressed on lymphoid DCs,
to generate the tonic TCR signal that is essential for continued survival. Survival of
memory cells, on the other hand, is independent of continued contact with self-
peptide:MHC complexes.
B cells are formed at a far higher rate than T cells, but they also undergo a
significantly higher rate of turnover in the periphery. Nonetheless, they too require
maintenance signals to achieve peripheral homeostasis. The antigen receptor on B
cells most likely provides a basal level of signaling, albeit independent of the
presence of antigen, which is required for maintenance of mature B cells. Not
surprisingly, B cells from
p
65
-/-
,
p
100
-/-
,
p
105
-/-
, and
c-Rel
-
/-
mice display increased
sensitivity to apoptosis and/or decreased survival
ex vivo
[54,99,102].
In large part, these defects appear to be due to a loss of BCR signaling, as
demonstrated in an elegant study that demonstrated that deletion of the BCR from
mature B cells led to a complete loss of the peripheral B cell pool [103]. Most likely
this was due to the loss of signaling to NF-
κ
,
NEMO, or components of the CBM complex in mature B cells also results in a
complete loss of peripheral B cells [50,101,104].
The alternative pathway is also relevant to B cell survival, as the loss of IKK
κ
B in these cells because loss of IKK
β
α
results in striking defects in B cell survival [51,52]. However, rather than acting
downstream of tonic BCR signaling, recent studies have implicated signaling from
BAFF-R in this aspect of the B lymphocyte survival (reviewed in [56]). Together
these data suggest that a subset of Bcl-2 family members, e.g., the antiapoptotic
factor A1, are regulated by RelB/p52 containing complexes and are necessary for
the maintenance of mature B cells.
7.7 CONCLUSIONS
NF-
B was originally described as a regulator in the adaptive immune response and
in many respects this continues to be an area of extremely productive research.
Investigations of mice with targeted deletions have shed considerable light on the
process of lymphoid organogenesis and, for example, through characterization of
the
aly/aly
mouse, studies of lymphoid organogenesis have driven the discovery of
the alternative NF-
κ
B. Progress
continues to be made in understanding antigen receptor signaling to NF-
κ
B pathway and various receptors that signal to NF-
κ
B, and
this work has led to the appreciation of regulatory ubiquitination events in IKK
activation (see
Chapter 4
). The specificity of the requirement for the CBM complex
and PKC
κ
θ
/
β
in signaling by T cell and B cell receptors opens the door to the
