Transcript 10_21_tcelld~1

Transcomplementation can result from the combination in trans of
a and b chains encoded by MHC class II genes on different
chromosomes.
Inter-isotypic molecules also can be formed by a and b chains of
two different loci (for example: DR a - DQ b).
HLA-DP, -DQ, and –DR (MHC class II) are expressed on APC
(classical MHC molecules).
HLA-DM and HLA-DN/DO are not, but are involved in the
regulation of class II expression:
From Dr. Robert Busch’s web site: http://www.stanford.edu/~rbusch/research1.htm
“… frequency of naive lymphocytes specific for any given antigen is
estimated to be between 1 in 10,000 and 1 in 1,000,000 …”
In unimmunized mice:
1 in 26,300 B cells could make anti-SRC IgM
no detectable (<1 in a million) B cells that could make anti-SRC 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)
• Ag-activated B cells give rise to germinal centers (GC), zones
of proliferating activated B cells:
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 antigen-independent,
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 self-MHC
molecules, T cells need to learn how 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 thymus-derived
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 middleage, especially in situations where there is loss of T cells
(HIV/AIDS).
• 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
• 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.
• 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 CD8-negative
– 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
Phase 1 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 and
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 DJ 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.
Phase 2 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
• In positive selection, developing thymocytes continue to
live if they 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 selfpeptides.
• Thymocytes that bind MHC survive; those that don’t 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 singlepositive 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
• Thymocytes undergo negative selection in the medullary
region:
• There, they interact with antigen-presenting cells
(dendritic cells, macrophages) that express self-antigens +
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
– (incomplete stimulation via their TCR)
• 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
– (incomplete stimulation
via their TCR)
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
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 terminallydifferentiated 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.