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In unimmunized mice:
1 in 26,300 spleen B cells could make anti-SRC IgM
no detectable (<1 in a million) B cells that could make antiSRC IgG
(Martínez-Maza, et al. Scandinavian J. Immunol 17:251, 1983)
In immunized mice:
1 in 219 B cells could make anti-SRC IgM
(5d post-immunization)
1 in 112 B cells could make anti-SRC IgG (12d)
1 in 3,030 B cells could make anti-SRC IgG (180d)
(Martínez-Maza, et al. Scandinavian J. Immunol 17:345, 1983)
Calame, K. 2001.
Plasma cells: finding new
light at the end of B cell
development . Nature
Immunology 2:1103.
T CELL DEVELOPMENT AND ACTIVATION
• There are a lot of similarities between T and B cells, in their
development:
– arise from hematopoietic precursors that are generated
in the bone marrow
– undergo similar DNA rearrangements to generate the
genes for their antigen receptor molecules
– have the capacity to respond to nearly any antigen
– the initial stages of development are antigenindependent, with final differentiation occurring after
exposure to antigen
– cells that express antigen-receptors that react with self
are eliminated
• However, there are some significant differences:
– since the T cell receptor can interact with antigen
only when it is presented in association with selfMHC molecules, T cells need to be able to bind
to a complex of self MHC + Ag peptide
– in addition to this (perhaps because of this) T cells
do not develop in the bone marrow, they undergo
development in a specialized organ, the thymus.
• T lymphocytes or T cells got their name from original
observations that indicated that they were thymusderived lymphocytes.
• T cell precursors travel from the bone marrow to the
thymus:
• Following development into mature, antigen-responsive
T cells, these T cells emerge from the thymus and
migrate to secondary lymphoid tissues, where they
interact with antigen, antigen-presenting cells, and other
lymphocytes:
• The importance of the thymus in T cell development is
demonstrated by inherited immune deficiencies: people that
do not have a thymus (DiGeorge’s syndrome, aka Thymic
Aplasia) do not develop functional T cells.
• DiGeorge’s syndrome results from a developmental defect –
the failure of the third and fourth pharyngeal pouches to
develop, which results not just in thymic defects, but also in
absent parathyroids and in aortic arch defects.
• Thymectomy early in life reduces the ability to produce T cells.
• Thymectomy later in life does not markedly impair T cell
number.
• In fact, the thymus decreases in size with age.
• However, the thymus can still produce new T cells up to
middle-age, especially in situations where there is loss of T
cells (HIV/AIDS).
• While in the thymus, immature T cells, or thymocytes,
undergo several changes that allow them to develop into
mature T cells, ready for contact with antigen.
• Thymocytes interact with thymic
epithelial cells and various
other cells while in the thymus.
• The thymus is composed of several lobes, each of which
has cortical and medullary regions:
• The cortex contains immature thymocytes in close
contact with thymic epithelial cells.
• Medullary areas contain more mature thymocytes,
epithelial cells, and dendritic cells and macrophages
• During thymic
differentiation,
the great majority of
thymocytes
die by apoptosis, and
are ingested by
macrophages.
• Only a small minority of
these T cell progenitors
make it out as mature T
cells
•
Thymic development occurs in two phases:
1) production of T cell receptors for antigen, by
rearrangement of the TCR genes
2) selection of T cells that can interact effectively with
self-MHC
•
Changes in the expression of cell-surface molecules
accompany the thymic differentiation of T cells:
– entering thymocytes are TCR, CD3, CD4, and CD8negative
– as thymocytes mature, and undergo rearrangement of
their TCR genes to generate a functional TCR, they
begin to express CD3, CD4, and CD8
– mature T cells ready to go to the periphery are
TCR/CD3+, and either CD4 or CD8 positive
First phase of thymic development:
rearrangement of TCR genes to
produce a functional TCR
• Progenitor T cells enter the thymus
(sub-capsular region of the outer cortex).
• These cells do not have rearranged TCR genes and
lack expression of characteristic T cell surface
molecules.
• Interaction with thymic stromal cells induces these
progenitor T cells to proliferate.
• These immature thymocytes do not yet express CD4
or CD8, molecules that are expressed by mature T cells:
double-negative thymocytes.
• There are two types of T cell
receptors: gd and ab
 ab TCR T cells are the most
abundant, by far:
(or g & d chain)
Unlike B cells, in
which the genes
that encode the
BCR rearrange in
a set order, the
TCR b, g, and d
genes start to
rearrange at about
the same time.
If a productive g or
d rearrangement
occurs first, the T
cell is committed
to that lineage,
and stops further
rearrangement of
the b TCR gene.
However, if b is
rearranged first,
then the T cell
continues to
proliferate, and
undergoes further
rearrangements.
This results either
in rearranged a
TCR gene,
yielding an ab
TCR lineage cell,
or rearranging g
and d genes,
resulting in a gd
TCR cell.
Rearrangements
that lead to an ab
T cell begin the
rearrangement of
the b TCR gene.
The first step is
D-J joining,
followed by VDJ
rearrangement.
Expression of b
chain stops
further b chain
rearrangements.
 b chain is then expressed on the surface of the
thymocyte in association with a surrogate a chain
(pTa).
• Following this, there is rearrangement of the a TCR
gene, resulting in a functional a chain, and in the
expression of surface TCR, in association with other T
cell-associated cell surface molecules.
• During this process, a cell that makes an unproductive
a chain rearrangement can try again until gets a good
a chain, or it exhausts its possibilities:
• Thymocytes that have a functional b rearrangement,
and express ab or b + the surrogate a chain (pTa)
are induced to express both CD4 and CD8
simultaneously – these are called double-positive
cells.
• Immature T cells that do not undergo a productive
rearrangement die by apoptosis.
Second phase of thymic development:
selection of T cells that can interact with
self MHC and antigen
• This applies only to ab TCR-bearing cells (>95% of T
cells).
 gd T cells are not restricted to interactions with MHC
class I or class II molecules
• This phase of T cell development consists of two steps:
– positive selection (TCR that can interact with
self-MHC)
– negative selection (eliminate self-reactive cells
that are stimulated by MHC + self)
Positive Selection
• Positive selection refers to the selection of
thymocytes that are able to bind to, and interact
with, self-MHC molecules
• In positive selection developing thymocytes
continue to live if they bind MHC well enough to
receive a signal through their TCR.
• This signal is mediated by the interactions of these
cells with MHC-expressing thymic cortical
epithelial cells.
• The ~95% of thymocytes that do not receive this
signal undergo apoptosis.
Positive selection takes place in the cortex of the thymus lobules:
• These CD4+ CD8+ TCR+ thymocytes interact with
thymic epithelial cells that express both MHC
class I and MHC class II molecules, complexed
with self-peptides.
• Thymocytes that bind MHC survive; those that
don’t bind to self-MHC die.
• TCR a chain rearrangements can continue during
positive selection, allowing cells to explore
alternative a chains for MHC binding.
• Once a T cell is positively selected, TCR
rearrangement stops.
• The expression of either CD4 or CD8 by a given T
cell is determined during positive selection, leading
to single-positive cells (CD4 or CD8-positive).
• Those cells that have a TCR that binds to MHC
class II end up as CD4 single-positive cells
• Those that bind MHC class I as CD8 positive
cells:
Negative Selection
• Negative selection refers to the elimination of those
thymocytes that bind to self-MHC molecules + self with
high affinity.
• In negative selection developing thymocytes die if they
bind MHC + self peptides too well (strongly enough so
that they would be activated by this interaction, via
signaling through their TCR).
• Thymocytes undergo negative selection in the
medullary region:
• There, they interact with antigen-presenting cells
(dendritic cells, macrophages) that express selfantigens + MHC class I or MHC class II molecules.
• Thymocytes that bind to self + MHC too strongly are
eliminated as possibly self-reactive cells, and
undergo apoptosis.
• If self-reactive T cells were allowed to exit the thymus,
such cells would mediate autoimmune disease.
• Some T cells are
reactive with self
molecules that are not
expressed in the
thymus:
– such cells can be
eliminated in
peripheral lymphoid
tissues by the
induction of anergy
– signal 1 only incomplete
stimulation via their
TCR)
thymocyte
anergy or apoptosis
X
• T cells that exit the thymus have undergone a
series of changes that allow them to:
– develop a functional TCR
– interact with self-MHC
– while eliminating self-reactive T cells
The specificity or
affinity of positive
selection must differ
from that of negative
selection:
Antigen-driven T cell Differentiation
in Secondary Lymphoid Organs
• Mature T cells leave the thymus and migrate to
secondary lymphoid tissues (lymph nodes, spleen,
mucosa-associated lymphoid tissue), recirculating via
the blood and lymph, just like mature B cells do.
• Mature T cells are longer lived than mature B cells, and
can survive for years without antigenic stimulation.
• Unlike B cells, which have just one type of
terminally-differentiated cell (plasma cell), there are
various types of effector T cells:
– CD8 T cells, which can differentiate into
cytotoxic T cells
– CD4 T cells, which can become either TH1 or
TH2 helper cells.
T cells interact with antigen in the T cell-rich areas of
peripheral lymphoid tissues:
T cells (and B cells) are targeted to, and enter, secondary
lymphoid organs by their expression of various adhesion
molecules.
These molecules interact with ligands expressed on
endothelial cells, allowing these lymphocytes to bind and
enter these lymphoid organs:
There, they can interact with antigen-presenting cells
(dendritic cells, macrophages, B cells) and be
stimulated on encounter with an appropriate
antigen, and function as helper T cells,
interacting with B cells and other lymphocytes.
• Ligation of the T cell’s receptor for antigen results in
an initial activation signal (first signal), as is true for B
cells.
• Again, as with B cells, this
first signal is not sufficient
to activate the cell:
– second signals
(co-stimulatory signals)
are necessary for
activation
– The principal
co-stimulatory signal for
T cells is delivered via
ligation of CD28 by B7
on the APC
• Ligation of the TCR without co-stimulation results in T
cells becoming non-responsive or apoptotic:
Activation,
proliferation,
survival
modified from Laâbi, Y. and A. Strasser. Science 289:883, 2000
• T cell signaling occurs via the cytoplasmic tails of the
molecules that make up the CD3 complex, which is
associated with the TCR.
• These associate with protein tyrosine kinases and initiate
intracellular signaling that results in altered gene expression:
• Encounter with antigen can result in
the formation of memory T cells.
• Some immunologists have claimed
that continuing re-contact with antigen
may be important for the survival of
these memory T cells.
• One significant differences between
memory T cells and memory B cells is
that the TCR does not undergo
isotype switching or affinity
maturation by somatic mutation,
unlike the BCR.
• However, it is clear that there are
long-lived CD4 and CD8 cells that are
rapidly activated on contact with
antigen.
• Memory T cells can be defined by a change in the
expression of certain surface molecules: