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DIFFERENTIATION AND MATURATION OF T CELLS IN
THE THYMUS
REGULATED T-CELL DIFFERENTIATION
preT-
CD4+CD8+
TCR
APC
Epithelial cell
immature T cell
pre T cell
pro T cell
SIGNALING RECEPTOR
NO ANTIGEN RECOGNIZING
RECEPTOR
ANTIGEN RECOGNIZING
RECEPTOR
Lymphoid precursor
T- CELL
DEVELOPMENT
NK cell
No
rearrangement
c-kit/CD44
RAG-1/RAG-2
Pro-T
-rearrangement
Pre-T
H rearrangement
Pre-T
-rearrangement

Surrogate L
Pre-B
L rearrangement
T
B
Selection
clonal deletion
Selection
clonal deletion
B
T
B
T
Mature-T
Pro-B
T
B
Mature-B
EVENTS OF T CELL DIFFERENTIATION IN THE THYMUS
1. Generation of NK cells
– no TCR
2. Differentiation of γδ and αβ
TCR carrying T cells
3. Selection of αβ TCR
– positive selection
– negative selection
4. Differentiation of CD4+ and
CD8+ T cell lineages
γδ T-cell
No selection
Pro-T
Early pre-T
Pre-Tαchain
Lck signal
IL-7-dependent
proliferation
β rearrangement
unsuccesful βchain
Late pre-T
CD4+CD8+
α rearrangement
αβ NKT-cell
CD4+CD8+
αβCD4+ αβCD8+
unsuccesful α-chain
no positive selection
negative selection
SELECTION OF T LYMPHOCYTES IN THE THYMUS
UNDER THE
CAPSULE
IL-7-dependent proliferation
CORTEX
CD4-CD8DN
β+preTα
TCRαβ
CD4+CD8+
TCR(-) sMHC+sP sMHC+fP fMHC+fP DP
selection
CORTEX/
MEDULLA
+
+


NO 
MEDULLA
–
AICD
αβTCR
CD4+
– selection
1. The primary T cell pool is biased
to MHC-specificity (V genes) 1-2%
for one allotype
2. Focusing the T cell pool to self
MHC recognition (+)
3. Elimination of useless and self
agressive clones (-)
4. CENTRAL TOLERANCE
5. Focusing the T cell repertoire for
recognition of non self
6. CD4+ and CD8+ T cell use the
same TCR repertoire
7. Individualized T cell repertoire
available in the periphery
8. CD4 and CD8 co-stimulatory
molecules are involved in positive
selection
AICD – Activation
Induced Apoptosis
αβTCR
CD8+
PERIPHERAL TOLERANCE
POSITIVE SELECTION OF DOUBLE POSITIVE (DP) T CELLS ALSO
DIRECTS CD4 AND CD8 SINGLE POSITIVE (SP)
T CELL COMMITMENT
CD4+CD8+
CD4+CD8+
Thymic
epithelial cell
MHC-I + peptide
complexes recruit CD8
MHC-II + peptide
complexes recruit CD4
POSITIVE SELECTION FOR 3 – 4 DAYS, SUCCESSIVE α-GENE
REARRANGEMENTS
BARE LYMPHOCYTE SYNDROME (BLS)
Lack of MHC class I – no CD8+ cells
Lack of MHC class II – no CD4+ cells
SELECTION OF THE T CELL REPERTOIRE – CENTRAL TOLERANCE
POSITIVE SELECTION – Thymic education (no instruction for specificity)
Low avidity interaction of MHC - self peptide - TCR
Thymic epithelial cells
Self peptide composition and concentration (foreign peptides are not present)
Low peptide dose induces positive selection – special ligands
80-90% of DN (CD4-CD8-) T cells is NOT positively selected
PASSIVE CELL DEATH BY NEGLECTION
NEGATIVE SELECTION – Central self tolerance
High avidity of MHC - self peptide - TCR interaction
Ubiquitous and abundant self antigens are present in the thymus
High peptide dose induces negative selection
Any thymic antigen presenting cell: epithelial cells, bone marrow-derived
macrophages, dendritic cells
THE GENERATION OF SELF MHC + FOREIGN PEPTIDE SPECIFIC T
CELLS REQUIRES WEAK INTERACTION WITH SELF MHC + SELF PEPTIDE
SELF RESTRICTED AND TOLERANT PERIPHERAL T CELL REPERTOIRE
PHYSIOLOGICAL TRESHOLD
NOT COMPLETE
HOMEOSTASIS OF POSITIVE AND NEGATIVE SELECTION IN
THE DEVELOPMENT OF THE AVAILABLE T LYMPHOCYTE
REPERTOIRE
Homozygote
Heterozygote
Ratio of negative selection increases with the
number of MHC genes
Ratio of positive selection
Number of MHC molecules
T-CELL DIFFERENTIATION IN THE PERIPHERY
CD8 TCR
CD8 TCR
CD8 TCR
CD4 TCR
CD4 TCR
APC
APC
CD4 TCR
APC
Ag
Ag
Ag
APC
APC
Memory T-cell
Activated T-cell
Mature naive T-cell
APC
PERIPHERAL TOLERANCE
IMMUNE RESPONSES ARE NOT INITIATED IN THE PERIPHERY
Normal tissue cells do not express MHC class II
NO SIGNAL 1. for CD4+ Th activation
Normal tissue cells do not express co-stimulatory molecules
and do not produce T cell differentiating cytokines
NO SIGNAL 2. for CD4+ Th activation
Migration of naive T lymphocytes to normal tissues is limited
Antigen presenting cells are not activated in normal tissues
NO SIGNAL 3. for CD4+ Th activation
PERIPHERAL TISSUES TOLERIZE THEMSELVES
MECHANISMS OF PERIPHERAL TOLERANCE
ANERGY – Functional unresponsiveness, no IL-2 secretion
SIGNAL 1
SIGNAL 2
SIGNAL 3
Recognition of auto-antigen on tissue cell
No B7 and CD40 expression, no co-stimulation
Tissue resident professional APC are not activated
Innate immunity is not activated
No inflammation
CLONAL DELETION – Activation induced cell death
Requires persistant high antigen dose
Fas – FasL interaction
SUPPRESSION – Activity of other cells
Cytokine-mediated balance
Effector functions are inhibited by regulatory T cells
CLONAL IGNORANCE
No contact with the immune system
Immunologically privileged sites
Central nervous system, eye
No recognition in the periphery
Arming of effector T cells
Clonal selection and differentiation
APC
T
Activation of NAÏVE T cells by signal 1
and 2 is not sufficient to trigger effector
function, but…..
the T cell will be activated to proliferate
and differentiate under the control of
autocrine IL-2 to an effector T cell.
These T cells are ARMED
IL-2
Effector
T cell
How can this cell give help
to or kill cells that express
low levels of B7 family
costimulators?
Effector function or Anergy?
Clonally selected,
proliferating and
differentiated
T cell sees antigen on
a B7 negative epithelial cell
The effector programme
of the T cell is activated
without costimulation
Armed
Effector
T cell
Armed
Effector
T cell
IL-2
This contrasts the
situation with naïve T
cells, which are
anergised without
costimulation
Naïve
T cell
CD28
TcR
Co-receptor
Kill
Epithelial
cell
Epithelial
cell
Epithelial
cell