Development of Lymphocytes

Lect. 10
 Origin of Immune Cells
• The capability of responding to immunologic stimuli rests
mainly with lymphoid cells.
• During embryonic development, blood cell precursors
originate mainly in the fetal liver and yolk sac.
• In postnatal life, the stem cells reside in the bone marrow.
• Stem cells differentiate into cells of the erythroid,
myeloid, or lymphoid series. The latter evolve into two
main lymphocyte populations: T cells and B cells (Figure
58–1 and Table 58–1).
• The formation of T cells and B cells from stem cells is
enhanced by interleukin-7 (IL-7) produced by the stromal
cells of the thymus and bone marrow, respectively.
 Origin of B Cells
• B-cell precursors differentiate into immunocompetent B cells in the
bone marrow; they do not pass through the thymus.

• Analogous to T cells, B cells also undergo clonal deletion (apoptosis) of

those cells bearing antigen receptors for self proteins,a process that
induces tolerance and reduces the occurrence of autoimmune diseases.

• B cells bearing an antigen receptor for a self protein can escape clonal
deletion by a process called receptor editing. In this process, a
new,different light chain is produced that changes the specificity of the
receptor so that it no longer recognizes a self protein.

• It is estimated that as many as 50% of self reactive B cells undergo

receptor editing. T cells do not undergo receptor editing.
 Origin of B Cells
• Pre–B cells lack surface immunoglobulins and
light chains but do have μ heavy chains in the
cytoplasm.
• The maturation of B cells has two phases: the
antigen-independent phase consists of stem
cells, pre–B cells, and B cells, whereas the
antigen-dependent phase consists of the cells
that arise subsequent to the interaction of
antigen with the B cells (e.g., activated B cells
and plasma cells) (Figure 58–8).
• B cells display surface IgM, which serves as a receptor for
antigens.

• Surface IgD on some B cells may also be an antigen receptor.

Pre–B cells are found in the bone marrow, whereas B cells
circulate in the bloodstream.

• B cells constitute about 30% of the recirculating pool of small

lymphocytes, and their life span is short (i.e., days or weeks).

• Within lymph nodes, they are located in germinal centers;

within the spleen, they are found in the white pulp. They are
also found in the gut-associated lymphoid tissue (GALT) such
as Peyer’s patches.
 Activation of B Cells
• In the following example, the B cell is the APC.
Multivalent antigen binds to surface IgM (or IgD)
• The activation of B cells to produce the full range of
antibodies requires two other interactions in addition to
recognition of the epitope by the T-cell antigen receptor.
• This complex is recognized by a helper T cell with a
receptor for the antigen on its surface. The T cell now
produces various interleukins (IL-2, IL-4,
and IL-5) that stimulate the growth and differentiation
of the B cell.
• The activation of B cells to produce the full
range of antibodies requires two other
interactions
(1) CD28 on the T cell must interact with B7 on
the B cell (for activation of the T cell to
produce interleukins)
(2) CD40L on the T cell must interact with CD40
on the B cell for class switching from IgM to
other immunoglobulin classes, such as IgG and
IgA, to occur.
• Hyper-IgM syndrome
 Effector Functions of B Cells/Plasma Cells
• The end result of the activation process is the production of
many plasma cells that produce large amounts of
immunoglobulins specific for the epitope.
• Plasma cells secrete thousands of antibody molecules per
second for a few days and then die.
• Some activated B cells form memory cells, which can remain
quiescent for long periods but are capable of being activated
rapidly upon reexposure to antigen.
• Most memory B cells have surface IgG that serves as the
antigen receptor, but some have IgM.
• Memory T cells secrete interleukins that enhance antibody
production by the memory B cells.
• The presence of these cells explains the rapid appearance of
antibody in the secondary response
 Clonal Selection
• How do antibodies arise? Does the antigen “instruct” the B cell to make
an antibody,or does the antigen “select” a B cell endowed with the
preexisting capacity to make the antibody?

• It appears that the latter alternative (i.e., clonal selection) accounts for
antibody formation.

• Each individual has a large pool of B lymphocytes (about 10 7). Each

immunologically responsive B cell bears a surface receptor (either IgM or
IgD) that can react with one antigen (or closely related group of antigens).

• It is estimated that there are at least 10 million different specificities. An

antigen interacts with the B lymphocyte that shows the best “fit” with its
immunoglobulin surface receptor. After the antigen binds, the B cell is
stimulated to proliferate and form a clone of cells.
• These selected B cells soon become plasma
cells and secrete antibody specific for the
antigen.
• Plasma cells synthesize the immunoglobulins
with the same antigenic specificity (i.e., they
have the same heavy chain and the same light
chain) as those carried by the selected B cell.
Biology of T Lymphocytes
 Origin of T Cells
• T-cell precursors differentiate into immunocompetent T
cells within the thymus.
• Prior to entering the thymus, stem cells lack antigen
receptors and lack CD3, CD4, and CD8 proteins on their
surface.
• During passage through the thymus, they differentiate into
T cells that can express both antigen receptors and the
various CD proteins.
• The stem cells, which initially express neither CD4 nor CD8
(double negatives), first differentiate to express both CD4
and CD8 (double-positives) and then proceed to express
either CD4 or CD8.
• A double-positive cell will differentiate into a
CD4-positive cell if it contacts a cell bearing
class II major histocompatibility complex
(MHC) proteins but will differentiate into a
CD8-positive cell if it contacts a cell bearing
class I MHC proteins.
• (Mutant mice that do not make class II MHC
proteins will not make CD4-positive cells,
indicating that this interaction is required for
differentiation into single-positive cells to
occur.)
• The double-negative cells and the double-positive cells are
located in the cortex of the thymus, whereas the single-
positive cells are located in the medulla, from which
they migrate out of the thymus into the blood and
extrathymic tissue.

• Within the thymus, two very important processes called

thymic education occur:
(1) CD4-positive, CD8-positive cells bearing antigen receptors
for “self”proteins are killed (clonal deletion) by a process of
programmed cell death called apoptosis (Figure 58–2).
(2) The removal of these self-reactive cells, a process called
negative selection, results in tolerance to our own
proteins (i.e., self-tolerance) and prevents autoimmune
reactions.
• For negative selection to be efficient, the thymic epithelial
cells must display a vast repertoire of self proteins. A
transcriptional regulator called the autoimmune regulator
(AIRE) enhances the synthesis of this array of self
proteins. Mutations in the gene encoding the AIRE protein
results in the development of an autoimmune disease
called autoimmune polyendocrinopathy.
(2) CD4-positive, CD8-positive cells bearing antigen receptors
that do not react with self MHC proteins (Figure 58–2) are
also killed. This results in a positive selection for T cells
that react well with self MHC proteins.
• These two processes produce T cells that are selected for
their ability to react both with foreign antigens via their
antigen receptors and with self MHC proteins.
• Both of these features are required for an effective
immune response by T cells.
• MHC proteins perform two essential functions in the
immune response:
- one is the positive selection of T cells in the thymus, as just
mentioned, and the other, which is described later, is the
presentation of antigens to T cells, the initial step required
to activate those cells.
- MHC proteins are also the most important antigens
recognized in the graft rejection process.
• During their passage through the thymus, each double-
positive T cell synthesizes a different, highly specific antigen
receptor called the T-cell receptor (TCR).
• The rearrangement of the variable, diversity, and joining
genes that encode the receptor occurs early in T-cell
differentiation and accounts for the remarkable ability of T
cells to recognize millions of different antigens.