NF-kB in the Adaptive Immune System: Lymphocyte Survival and Function - Transcription Factors NF-kappaB - page 144

while B cells from p52 -/- mice mount inadequate humoral responses to various
T-dependent antigens, they exhibit a normal response following adoptive transfer
into rag-1 -/- mice, indicating that this deficit is not intrinsic to B cells [29]. Further-
more, B cells from RelB -/- mice, although crippled in their proliferative response,
undergo normal IgM secretion and class switching in response to various stimuli
[90]. Therefore, it is likely that alternative pathway activation downstream of CD40
is not required for class switching during T-dependent antigen responses.
Analysis of the classical pathway is complicated by more generalized defects
in lymphocyte responses due to the requirement for this pathway in AgR signaling.
Nevertheless, whether downstream of CD40 or other stimuli, evidence supports
classical pathway activation in the process of class switch recombination. Following
adoptive transfer, B cells from p65 -/- mice exhibit markedly diminished class switch-
ing, despite a less severe loss of lymphocyte proliferation following various stimuli
[91]. Likewise, c-Rel deficient mice, or mutants lacking the c-Rel TAD, fail to
generate a productive humoral immune response suggesting a requirement for c-Rel
in class switch recombination [78,92,93]. B cells from p50 -/- mice exhibit decreased
proliferation in response to mitogenic stimulation, and p65/p50 dKO B cells exhibit
greater defects in proliferation and class switching [90,94]. Therefore, analyses of
knockout animals suggest that the classical NF- B pathway likely has a role in

maturation of the B cell response in addition to directly mediating proliferative
responses following BCR ligation.
As discussed in Chapter 6 , signaling through TLRs has an important role in
the initiation of the adaptive immune response via antigen presenting cells of the
innate immune system. In recent years, however, there has also been increasing
interest in the ability of TLR signaling to directly modulate the adaptive response.
For example, it has been observed that homeostatic polyclonal activation of B
cells, which results in so called serological memory, i.e., detectable antibody to
antigens that are no longer present in the host, can be induced/maintained by TLR
ligation [95]. Analogously, TLR2 is upregulated in CD4 + T cells following TCR
stimulation, and TLR2 ligands may thus provide an activation/maintenance signal
in these cells [96]. More recently, it has been suggested that TLR signaling in B
cells may also be required for optimal response to TD antigens [97]. That signaling
through TLRs in these aspects of B cell responses requires NF-

κ

κ B seems likely,

but has yet to be demonstrated.
Thymus independent antigens have an intrinsic ability to activate B cell
responses in the absence of T cell help by acting as B cell mitogens, TLR ligands,
for example, or by having high avidity binding to the BCR through repetitive
structural features. In such cases it is expected that B cell responses are more
dependent on members of the classical pathway that have well-documented roles in
TLR signaling (Chapter 6) or BCR signaling (as discussed above). For example, c-
Rel-deficient B cells are highly sensitive to apoptosis following BCR cross-linking
[98,99,100]. As mentioned above, p50 and p50/p65 dKO B cells are deficient in
responses to TI stimulation. Likewise, IKK

β -deficient B cells fail to mount TI or

TD responses [101]. These IKK β -deficient B cells also exhibit increased spontaneous

apoptosis, suggesting that NF- κ B is important in survival of B cells.