Biomedical Engineering Reference
In-Depth Information
7.3
NF-
κ
B AND LYMPHOPOIESIS
NF-
B also has a vital role in the development and function of the effector cells
of the adaptive immune system. The selection process leading to the production of
functional lymphocytes is characterized by a high rate of apoptosis. Thus, the
antiapoptotic effect of NF-
κ
B is important in many aspects of lymphopoiesis. For
example, during T cell development, most of the requirements for signaling to
NF-
κ
B, i.e., through the T cell receptor, can be overcome by transgenic expression
of the antiapoptotic protein Bcl-2 [35]. In some cases, the embryonic lethality of
NF-
κ
B knockouts precedes the development of the mature hematopoietic system
and, as such, impedes analysis of the hematopoietic pathways of the adult organism.
Furthermore, the defects in both primary and secondary lymphoid tissues make
analyses of mice that do survive to adulthood quite difficult. Nevertheless, efforts
to circumvent these obstacles through adoptive transfer of lymphocyte precursors
and, more recently, use of conditional genetic alterations have supported the crucial
role of NF-
κ
B in lymphopoiesis. Finally, there are examples from human diseases
that further support the importance of NF-
κ
B in lymphopoiesis. The gene encoding
NEMO is located on the X-chromosome and is therefore subject to random inac-
tivation. In female patients who are heterozygous for a mutant version of NEMO
all peripheral lymphocytes possess an intact NEMO gene (see
Chapter 9
). Thus,
in the absence of NF-
κ
κ
B signaling, the key cells of the adaptive immune response
fail to develop.
Lymphopoiesis is, in and of itself, an area of intense research, and a thorough
analysis of this topic is well beyond the scope of this chapter. Instead, the level of
detail given in
Figure 7.2
is sufficient to allow an uninitiated reader a basic under-
standing of B and T cell development with which to ascertain the importance of
NF-
B in these processes. Both B and T cells develop from hematopoietic stem
cells in the bone marrow and from there proceed through partially analogous devel-
opmental paths.
T cell development occurs primarily in the thymus (Figure 7.2). Lymphoid
precursors leave the bone marrow and undergo proliferation following immigration
to the thymus and interaction with cortical epithelial cells therein. Thymocyte mat-
uration occurs along a spatial path from the cortical to medullary space of the thymus.
Thymocytes are typically classified by their expression of CD4 and CD8 — markers
of mature helper (T
H
) and cytotoxic (T
C
) T cells, respectively. Initially cells lack
both CD4 and CD8, and are referred to as double negatives (DNs). Thymocytes
undergo recombination of the TCR locus to produce the
κ
β
-chain of the T cell receptor
(TCR) during the DN stage. Successful
-chain rearrangement results in expression
of the pre-TCR consisting of recombined
β
β
-chain and germline encoded pre-T
α
.
Signaling through the pre-TCR halts
-chain rearrangement and induces prolifera-
tion and expression of CD4 and CD8. Double positive (DP) thymocytes then reex-
press the recombination machinery required for rearrangement of the TCR-
β
α
chain,
resulting in expression of a mature
α
/
β
TCR. DP thymocytes undergo positive selec-
tion through interaction of the
TCR with self-peptide: MHC expressed on thymic
stroma. Thymocytes that lack TCRs capable of initiating signaling will undergo
apoptosis — a failure of positive selection termed death by neglect. Thymocytes
α
/
β
