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Lecture 8
The Development of Lymphocytes
Core content
Students should know:
•
•
•
•
•
T cell receptor gene rearrangement and lineage commitment
preTCR
Positive selection
Negative selection
Changes in surface phenotype during T cell maturation in
thymus.
• The order and location of T cell selection
• Cell types involved in T cell selection
• Why it is important to match MHC molecules between donor
and recipient during bone marrow transplantation for donorderived T cells to be functional in recipient?
Generation of naïve T cells in thymus
T cell progenitors
TCR gene rearrangement
TCRgd
100%
not selected
Blood
TCRab
Selections for T cells that are MHCrestricted and not self reactive
2%
CD4 or CD8 TCRab T cells
Generation of T cell clones:
clonality
G: TCR in germ line configuration
A, B, C: rearranged TCRs with different specificities
G
G
A
A
B
B
C
Stem cells
Thymus
TCR
recombination
C
Thymus
Selection of
T cells with
Good TCR
Ag For
TCR A
A
A
A
C
Ag For
TCR B
Secondary
Lymphoid
tissues
Ag-dependent
expansion of
clones
C
C
Origin, generation and differentiation
of T cells
• T cell progenitors migrate from bone marrow and seed thymus. T cell
progenitors undergo differentiation to CD4, CD8 and NKT cells in
thymus. Mature CD4 and CD8 T cells circulate between blood and
lymphoid tissues until they meet antigens presented on dendritic cells in
lymphoid tissues. T cells further undergo maturation to become
functional memory or effector T cells in LT
Figure 5-2 Thymic involution: Human
thymus is fully developed
before birth and increases in
size until puberty. It then
progressively shrinks during
adult life.
Thymectized adults have no
problem in T cell immunity
because enough T cells are
present in periphery, and these
T cells are long-lived.
Differentiation
Figure 5-3 part 1 of 2
Figure 5-3 part 2 of 2
Lineage commitment to a:b or g:d T cells
•
Successful gene rearrangement in
g and d before b  g:d T
•
Successful gene rearrangement in
b before g or d  pTa:b T (not
committed yet). This signals to
halt rearrangement of the b, g and
d-chain genes and to enter a phase
of proliferation.
•
Further rearrangement in a, g and
d. Lineage commitment now
depends on whether a functional
a:b or g:d T-cell receptor is made
first.
More a:b T cells are made than
g:d T cells
•
Figure 5-5
TCR gene rearrangement generates
the TCR repertoire
Gene rearrangement at b
Gene rearrangement at a
Pre-TCR complex stops
further gene rearrangement at
b locus, and induces
thymocyte proliferation
Finally DP cells are made
Two chances for productive (=correct
reading frame) rearrangement: b chain
Multiple chances for productive (=correct
reading frame) rearrangement: a chain
Successful rearrangement at one a copy does not block at the other.
Therefore, many T cells express two different a chains.
g:d T cells with different TCRs are generated
at different time points during life time
Intestinal epithelium or lymphoid tissues
Reproductive tract homing
Epidermis homing
CD8 binds MHC class I
CD4 binds MHC class II
Most mature T cells are either CD4+ or CD8+.
CD8 T cells kill cells infected with intracellular pathogens or tumor cells
while CD4 T cells regulate other immune cells’ function to respond to pathogens
CD4+CD8+ DP cells: To be CD4 or CD8?
Interaction of DP cells with Ag:MHC I  CD8+ T cells
Interaction of DP cells with Ag:MHC II  CD4+ T cells
To survive, T cells need to bind self MHC but not too strongly
Positive
selection
Negative
selection
Both selections
occur at DP
stages
Self MHCs shape the TCR repertoire. Individuals with different MHCs will
have different TCR repertoire. Most DP thymocytes don’t survive to become
SP cells.
Positive selection selects T cells that recognize peptides
on self MHC
This is to assure that mature T cells can respond to antigen-presented on self
MHC.
-Self MHC I and II harboring self peptides on thymic epithelial cells recognize
and activate TCRs on some DP thymocytes.
-DP thymocytes should receive this signal within 3-4 days to survive.
Otherwise they undergo apoptosis.
After positive selection, rearrangement at remaining a locus stops.
Negative selection eliminates T cells with TCRs that
bind too strongly to self antigen/MHC complex.
This is to assure that T cells don’t react against self antigens. In other words,
autoreactive cells are removed by this process.
Dendritic cells and macrophages in cortico-medullary junction mediate it.
Negative selection cannot eliminate T cells whose receptors are specific for self
peptides that are present outside of thymus (These cells enter circulation, but
soon to be rendered anergic or unresponsive).
Step 1: Selected people for the show by CBS
(=selected “useful” T cells by epithelial cells)
Is this a positive or negative
selection?
Step 2: Selected persons are eliminated
(=eliminated “harmful” T cells by thymic APC)
Is this a positive or negative
selection?
The effects of pos. and neg. selections on TCR repertoire size
Figure 5-15 part 1 of 2
In this example, the child has twice more positively selected TCR
repertoire but 4 times more negatively deleted TCR repertoire
The number of MHC molecules changes
selected T cell repertoire
As the number (N) of MHC molecules
increases, the proportion of T cells that are
positively selected (= # of the cells that
survive) goes up arithmetically (N times),
while that of negatively selected (=# of deleted
cells) goes up geometrically (N2 times).
N= number of MHC isotypes a person
expresses
Therefore the magic N to result in maximum T
cell repertoire is around 12.
Bone marrow transplantation therapy
Figure 5-10
What happens if there is a complete mismatch in MHC I/II TYPE?
See the next slide.
Figure 5-11
Figure 5-18
Figure 5-19
Mixed Lymphocyte Reaction (MLR) is used to test for HLA
compatibility between individuals
Figure 5-14
Person B
Person A
White blood cells
The higher the response
The higher the mismatch
What happens if you do not have the thymus?
It depends on age.
DiGeorge’s syndrome
No or few T cells
Symptoms similar to SCID patients