The Development of Lymphocytes

1

• Lecture 8
• The Development of Lymphocytes

2
Core content
3
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 donor-derived T cells to be
  functional in recipient?

4
Generation of naïve T cells in thymus
T cell progenitors
TCR gene rearrangement
TCRab
100
TCRgd
not selected
Selections for T cells that are MHC-restricted
and not self reactive
2
Blood
CD4 or CD8 TCRab T cells
5
Generation of T cell clones clonality
A
G TCR in germ line configuration A, B, C
rearranged TCRs with different specificities
A
A
A
Ag For TCR A
A
G
G
B
B
C
C
C
Ag For TCR B
C
Secondary Lymphoid tissues Ag-dependent expansion
of clones
Thymus Selection of T cells with Good TCR
Thymus TCR recombination
C
Stem cells
6
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

7
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.
8
Figure 5-3 part 1 of 2
Differentiation
9
Figure 5-3 part 2 of 2
10
Lineage commitment to ab or gd T cells

• Successful gene rearrangement in g and d before b
  ? gd T
• Successful gene rearrangement in b before g or d
  ? pTab 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
  ab or gd T-cell receptor is made first.
• More ab T cells are made than gd T cells

11
Figure 5-5
12
TCR gene rearrangement generates the TCR
repertoire
13
Gene rearrangement at b
14
Gene rearrangement at a
Pre-TCR complex stops further gene rearrangement
at b locus, and induces thymocyte
proliferation Finally DP cells are made
15
Two chances for productive (correct reading
frame) rearrangement b chain
16
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.
17
gd T cells with different TCRs are generated at
different time points during life time
Intestinal epithelium or lymphoid tissues
Reproductive tract homing
Epidermis homing
18
CD8 binds MHC class ICD4 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
19
CD4CD8 DP cells To be CD4 or CD8?
Interaction of DP cells with AgMHC I ? CD8 T
cells Interaction of DP cells with AgMHC II ?
CD4 T cells
20
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 dont survive to
become SP cells.
21
Positive selection selects T cells that recognize
peptides on self MHCThis 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 dont
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).
22
Step 1 Selected people for the show by
CBS(selected useful T cells by epithelial
cells)
Is this a positive or negative selection?
23
Step 2 Selected persons are eliminated (eliminat
ed harmful T cells by thymic APC)
Is this a positive or negative selection?
24
Figure 5-15 part 1 of 2
The effects of pos. and neg. selections on TCR
repertoire size
In this example, the child has twice more
positively selected TCR repertoire but 4 times
more negatively deleted TCR repertoire
25
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.
26
Figure 5-10
Bone marrow transplantation therapy
What happens if there is a complete mismatch in
MHC I/II TYPE? See the next slide.
27
Figure 5-11
28
Figure 5-18
29
Figure 5-19
30
Figure 5-14
Mixed Lymphocyte Reaction (MLR) is used to test
for HLA compatibility between individuals
Person B
Person A
White blood cells
The higher the response The higher the mismatch
31
What happens if you do not have the thymus? It
depends on age. DiGeorges syndrome No or few T
cells Symptoms similar to SCID patients