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DEVELOPMENT OF T LYMPHOCYTES
ARPAD LANYI PhD
[email protected]
Further reading: Peter Parham, The Immune System 4th Ed. Chapter 5 (5.1-5.5), Chapter 7
THE CELLULAR ORGANIZATION OF THE THYMUS
THE PROPORTION OF THE THYMUS THAT
PRODUCES T-CELLS DECREASES WITH AGE
Thymic involution occurs at a rate of
3%/year. Over 40 years of age bone
marrow transplantation is unlikely to
generate
a
full
naive
T-cell
repertoire.
EARLY PHASE
Generation of antigen recognition receptors
SELECTION
Deletion
Anergy
BONE MARROW
CD19
CD127
CD
34
CLP
pro
B
pre
B
IgM
pre pre pre
preB
B
B
Heavy chain
Light chain
B
rearrangement pre pre pre rearrangement Imm
B
B B B
Commitment
CD2
CD127
THYMUS
pro
T
CENTRAL
TOLERANCE
Allelic exclusion
Receptor
editing
1st checkpoint
2nd checkpoint
β-chain
rearrangement
γ-, δ-chain
rearrangement
γδ
T
Negative
selection
α-chain
rearrangement
pre pre
T pre
T
γ-, δ-chain
pre pre T rearrangement
pre
T
T
pre pre T
γδ
T
T
T
DP
T
Negative
selection
Positive
selection
SECONDARY LYMPHOID
TISSUES
IgM;IgD
Tr.
B
IgM;IgD
Positive
selection
Treg
CD4
CD8
MHC
restriction
Death by neglect
Deletion
Mat
B
COMMITMENT TO THE T-CELL LINEAGE IS
DRIVEN BY THE NOTCH 1 RECEPTOR
COMMITMENT TO THE T-CELL LINEAGE CHANGES RECEPTOR
EXPRESSION
Lack of IL7 signaling (IL7 or IL7R) stalls early
T-cell development.
SCIDs.
Cells are beginning to rearrange
the TCR loci
TCR β-, α-, δ- and γ-chain loci
The basic rules of TCR rearrangement are identical to that of the BCR
Each germline TCR locus includes variable (V), joining (J) and
constant (C) gene segments
TCR β and TCR δ loci have D segments,
like the Ig heavy chain locus
δ gene segments are embedded within the a-chain locus
α-chain gene rearrangement results in the deletion of the δchain locus
REARRANGEMENT OF β, γ AND δ LOCI STARTS
AT THE SAME TIME
If δ- and γ-chain genes rearrange before βchain, γ:δ receptor assembles
variable region (V)
constant region (C)
transmembrane region
cytoplasmic tail
γδ T-cells
•MHC-independent, CD1c and CD1d dependent.
•Double megative.
•Comprise about 1-5% of the T-cells found in the
circulation, but can be the dominant (up to 50%)
T-cell population in epithelial tissue.
•A population that is expanded in intra(Mycobacterium
tuberculosis
and
Listeria
monocytogenes)
and
extracellular
pathogens
(Borrelia burgdorferi) and certain disease states
such as celiac disease.
REARRANGEMENT OF β, γ AND δ LOCI STARTS
AT THE SAME TIME
If β-chain gene rearranges before δ- and γ-chain
genes, pre T-cell receptor assembles
(the more frequent outcome of the competition)
1ST CHECKPOINT
β-chain is tested for its capacity
to bind to an invariant polypeptide
called pTα, which acts as a
surrogate α-chain
A nonproductively rearranged
β-chain gene can be rescued by
a second rearrangement at the
same locus
This possibility is not available to the immunoglobulin heavychain genes, because the V-DJ recombination excises all the
non-rearranged D segments.
If a rearrangement at one β-chain locus is
nonproductive, a thymocyte can attempt a
rearrangement at the β-chain locus on the
homologous chromosome
Thymocytes can make FOUR
attempts to rearrange the βchain gene
80% of thymocytes make a productive rearrangement of the
β-chain gene, compared with a 55% success rate for heavychain gene rearrangement by developing B cells.
SUCCESSIVE GENE REARRANGEMENTS
ON TCRα LOCI
Multiplicity of V (~70) and J gene ( 61)
segments allows many attempts
2ND CHECKPOINT
α-chain is tested for its
capacity to bind the β-chain
and assembles a T-cell receptor
SUMMARY FOR EARLY STAGES OF T-CELL DEVELOPMENT
Cells are now ready for positive and negative selection
Only a small fraction of T cells mature into functional T cells
POSITIVE SELECTION
-Occurs in the cortex, requires thymic epithelial cells
-αβ double-positive thymocytes must recognize selfMHC/auto-antigen complex
-Continuing α-chain gene rearrangement increases the
chance for positive selection
-Ca. 10-12% of thymocytes survive!
Positive selection --- results in clones that are
reactive to SELF MHC.
BASIS OF MHC RESTRICTION!!!
Positive selection of double
positive (dp) T-cells also directs
CD4 and CD8 single positive (sp)
T-cell commitment
THYMIC EPITHELIAL CELLS
ARE MHCI/MHCII POSITIVE!
BARE LYMPHOCYTE SYNDROME (BLS)
Lack of MHC class I – no CD8+ T-cells
Lack of MHC class II – no CD4+ T-cells
The response of the immune system
to the stimuli of the outer and inner environment
Environment
Immune system
Tolerance
Self
Non-self
Dangerous
Pathogenic
Immune
response
Immunological tolerance
Definition:
Lack of adaptive immune response against a given antigen.
The interaction of the antigen with the lymphocytes induces unresponsiveness.
ANTIGEN SPECIFIC!!!
Unlike immunosuppression.
Why is this important?
-All individuals are tolerant to their own antigens (self tolerance).
-Failure of self tolerance results in autoimmunity.
-Terapeutic potential:
Treat autoimmune diseases, allergic reaction or even tissue rejection.
T-cells with high affinity TCR towards the self MHC/self peptide
complex are eliminated, but clones with intermediate affinity survive.
NEGATIVE SELECTION
Elimination of potentially
CENTRAL
TOLERANCE
KEYWORD: AFFINITY
of T-cells in THE
the thymus
autoreactive clones
A percentage of self-reactive T-cells – that have high affinity
TCRs, bordering negative selection – will survive the negative
selection process and differentiate into regulatory T-cells.
CENTRAL T-CELL TOLERANCE MEDIATED BY
NEGATIVE SELECTION IS SURPRISINGLY EFFECTIVE.
HOW CAN TISSUE-RESTRICTED ANTIGENS BE
EXPRESSED IN MEDULLARY THYMIC EPITHELIAL CELLS?
AUTOIMMUN REGULATOR (AIRE)
A transcription factor expressed by thymic medullary epithelial cells
and induces expression of many tissue-specific genes
Deficiency in establishing central T-cell tolerance
allows too many
self reactive T-cell clones to leave the thymus
AUTOIMMUNE POLYENDOCRINOPATHYCANDIDIASIS-ECTODERMAL DYSTROPHY
(APECED)
Rare disease, but more frequently seen in inbred
populations
Finnish, Iranian Jews and in the island of Sardine
SYMPTOMS OF APECED
• Anti-Th17 specific
antibodies!!!!!
• Role of Th17 discovered by
studying a rare
immunodeficiency
• https:///jimneydandme.wordp
ress.com/james-story
SUMMARY
EARLY PHASE
Generation of antigen recognition receptors
SELECTION
Deletion
Anergy
BONE MARROW
CD19
CD127
CD
34
CLP
pro
B
pre
B
IgM
pre pre pre
preB
B
B
Heavy chain
Light chain
B
rearrangement pre pre pre rearrangement Imm
B
B B B
Commitment
CD2
CD127
THYMUS
pro
T
CENTRAL
TOLERANCE
Allelic exclusion
Receptor
editing
1st checkpoint
2nd checkpoint
β-chain
rearrangement
γ-, δ-chain
rearrangement
γδ
T
Negative
selection
α-chain
rearrangement
pre pre
T pre
T
γ-, δ-chain
pre pre T rearrangement
pre
T
T
pre pre T
γδ
T
T
T
DP
T
Negative
selection
Positive
selection
SECONDARY LYMPHOID
TISSUES
IgM;IgD
Tr.
B
IgM;IgD
Positive
selection
Treg
CD4
CD8
MHC
restriction
Death by neglect
Deletion
Mat
B

THANK YOU
NEGATIVE SELECTION
of T-cells in the thymus
CENTRAL TOLERANCE
Elimination of potentially
autoreactive clones
T-cells with high affinity TCR towards the self MHC/self peptide
complex are eliminated, but clones with intermediate affinity survive.
A percentage of self-reactive T-cells – that have high affinity
TCRs, bordering at negative selection – will survive the negative
selection process and differentiate into regulatory T-cells.
THE KEYWORD: AFFINITY