T cells (Specificity, education, maturation & function) Flashcards
Lymphocytes are vital for
acquired immunity (diversity), memory and
self / non-self recognition
T cells arise from a
common lymphoid progenitor
T cells originate in
the bone marrow from HSC
and mature in the Thymus (hence T cell)
T cells originate in the bone marrow from HSC
and mature in the Thymus (hence T cell)
From here they migrate to
2o lymphoid tissues
(sites of lymphocyte activation)
They circulate between
peripheral blood and
these sites until the encounter antigen (Ag)
Unlike other immune cells T (and B) cells
re-circulate from blood to tissues (patrol)
Each T cell has an
individual type of receptor (like B cells) that is
complementary to a specific epitope
When activated they undergo
clonal proliferation, creating numerous T cell
copies with the same receptor
They have the property of
memory
They have the property of memory, which results in
a quicker immune response of higher magnitude when challenged with the same antigen
primasry lymphoid organs?
–
BM
Thymus
secndary lymphoid organs?
adenoid, tonsil, lymph
nodes, spleen, appendix,
Peyer’s patches
Much like the B cell receptor (ultimately secreted as Ig) the T cell receptor has
constant and variable regions (epitope specific)
The T cell receptor (TCR) is a
heterodimer of αβ subunits
(in most cases) and belongs to
the Ig superfamily
Each chain has 3 domains
- Variable extracellular
domain - Constant extracellular
domain - Constant trans-membrane
domain
The TCR α-chain has a molecular weight of
40-50 kDa and the β-chain
40-45 kDa
The TCR N-terminal (extracellular) domain
contains a
hypervariable region synonymous
with the complementary determining regions
(CDR’s) of the immunoglobulins (Ig)
how many hypervariable region in each tcr chain?
Each TCR chain has 3 hypervariable regions
TCR β-chain has a
fourth hypervariable region, which doesn’t appear to interact with antigen
At the extracellular C domain, each chain
contains a
cysteine residue (consensus sequence) – links αβ via a disulphide
Each chain has a
short cytoplasmic tail (no signalling)
Unlike B cells
which can interact directly with soluble Ag, T cells must
be
shown Ag complexes with MHC
Therefore multiple levels of protein
protein interaction occur at
the MHC / TCR immunological synapse
Each TCR is associated with
ancillary proteins, which come together to form the TCR-complex
CD3 is a
heteromeric membrane complex with extended cytoplasmic regions (phosphorylation sites)
CD4 / CD8 are
co receptors with specificity for MHC-II or MHC-I
CD3 is a heterohexamer complex consisting of
- one εδ heterodimer (epsilon, delta)
- one εγ heterodimer (epsilon, gamma)
- one ζζ homodimer (zeta, zeta)
+ve charged polar residues in the TCR
transmembrane domain attracts…
… -ve charged residues in the CD3 subunit transmembrane domains
MHC-peptide complex associates
with
complementary TCR hypervariable regions
MHC-peptide complex associates
with complementary TCR
hypervariable regions
These intermolecular interactions
(think of what these are) initiate
local (microenvironment)
conformational changes
Conformational ripples are
observed through
the length of the
α and β chains
Conformational ripples are
observed through the length of the
α and β chains
Changes translate to
CD3 complex
resulting in ITAM phosphorylation
MHC-peptide complex is perceived
extracellular
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Like the B cell receptor the TCR has
hypervariable and constant regions
Variation of the TCR is achieved by
somatic recombination
TCR loci contain
numerous gene segments which are inherited through the germ line (accounts for part of the TCR diversity)
From somatic recombination, how many different t cell receptors?
~ 10^18 different T cell receptors!!
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Random V(D)J recom
bination and genetic
splicing occurs for
both α and β chain
genes in immature T
cells
For β chain, the J gene
segments do no
t seem
to be
important for Ag
recognition, however
Dβ1 and Dβ2 do
The joining of α and β
peptide chains in TCR
accounts for
10^18 possible combinations
Like B cell receptor, TCR expression is controlled by
allelic exclusion
what is allelic exclusion?
successful ‘functional’ somatic rearrangement of the TCR genes at one allele results in the switching off of the other allele (paternal or maternal)
During TCR recombination
the α-chain may
sustain many recombination
attempts before functional TCR is
established (bone marrow).
This process occurs during t cell education.
Immature T cells (thymocytes) leave the
bone marrow
& enter the thymus for maturation and development
T cell development ensures that
only self-restricted / self-tolerant
T cells enter the periphery (patrol for Ag)
Two stages of t cell development?
1) CD4- CD8- double negative (DN) develop TCR
2) CD4+ CD8+ double positive (DP) mature to CD4 or CD8 single positive (SP) MHC-II / MHC-I restricted
whats the DN stage?
Early thymocyte maturation
involves cortical interactions
Initially, thymocytes entering
thymus medulla encounter
NOTCH ligands → thymocyte
proliferation
DN1 – function?
plastic thymocytes, up regulate CD25 once in cortex
Lymphocytes are vital for
acquired immunity (diversity), memory and
self / non-self recognition
T cells arise from
a common lymphoid progenitor
dn2 function
commit to T cell lineage
and β chain rearranges
dn3 function
completion of β chain
rearrangement and α/β TCR
development
dn4 function
immature single positive (ISP) before DP stage
By the end of early maturation, CD4+ CD8+ DP thymocytes are
generated and must be selected to ensure MHC self-recognition
DP thymocytes are
small and non
proliferative (~80% cortex thymocytes)
DP thymocytes interact with
cortex epithelial cells which express high
levels of self MHC-I / MHC-II
Moderate to strong binding creates
survival and proliferation
Weak or no binding causes
death by neglect (apoptosis) – positive
selection
DP thymocytes that make it through positive selection progress to
the
negative selection stage
In the medulla, antigen presenting
cells (APC) such as dendritic cells
present MHC coupled self antigen
Cells which bind moderately
survive
Cells which bind with high affinity
undergo
apoptosis
Most DP thymocytes (>98%) do not
make it through thymic selection
Thymic selection ensures that
T cells recognise foreign Ag bound to
self-MHC
The cortex stage; early maturation & proliferation of DN, DP generation and
positive selection takes
13 – 15 days to complete
The medulla stage;
negative selection and
CD4 / CD8 lineage
commitment take
4-5 days to complete
3 weeks for
whole process
The thymic selection process ‘screens’
TCR reactivity
The thymic selection process ‘screens’ TCR reactivity, however
T cells are still CD4 /CD8 double positive
The mechanisms of T helper (CD4+) or T cytotoxic (CD8+) lineage commitment is …
… not fully defined, however three models are proposed
The mechanisms of T helper (CD4+) or T cytotoxic (CD8+) lineage
commitment is not fully defined, however three models are proposed whcih are:
1) Stochastic model
2) Instructive model
3) Kinetic model (duration of signal)
describe the Stochastic model?
- MHC class restriction is
a random process - CD4 or CD8 on immature DP T cell is
‘down-regulated’ - Binding of remaining (CD4 or CD8) to MHC-II
or MHC-I commits T cell class and MHC
restriction.
describe instructive model?
- DP immature T cells bind either MHC-I
or MHC-II - Signal result in the retention of CD8 or
CD4 respectively
describe the kinetic model?
duration of signal
For example, if a DP T cell is persistently engaging with MHC-I; result CD4 down-regulation and CD8 retention
T cell education and maturation occurs
early on in life; we have all of
our T cell repertoire by adolescence (T cells long lived)
Thymus atrophies with
age
Studies show that neonatal thymectomy results in
significant drop in overall T cell number, but no compromise in immune function
If T cell thymic selection fails,
self-reactive T cells may enter the
periphery → autoimmune disease can arise
Broadly there are two major
t cell type
T helper (TH) cells (CD4+T cells) secrete…
… cytokine / help amplify and coordinate the immune response;
what are the different distinct sub classes of t cells?
- TH1 cells produce pro-inflammatory cytokines
- TH2 cells produce cytokines involved with B cell antibody
development
(TH1 and TH2 mutually antagonistic) - TH17 cells important for neutrophil activation and cancer immunity
- Treg cells (regulatory T cells) supress immune response
T cytotoxic (TC) cell (CD8 +T cells) kill
… cells bearing appropriate stimulating Ag – viral Ag or altered-self (tumour antigen)
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Peripheral T cells that make it through thymic selection are termed
naïve
Peripheral T cells that make it through thymic selection are termed
naïve; they reside in
G0 and require proper activation for maturation
- Condensed chromatin, small, re-circulate blood/lymph (12-24 h)
Naïve T cells (CD4 and CD8) require
co-stimulation for full activation and proliferation
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TCR / MHC engagement
without CD28 co-stimulation results in
the generation / proliferation of an anergic
T cell (a T cell which is not immune reactive towards a particular antigen – tolerance)
CD28 stimulation alone has
no effect on T cell
Cytokines also play a central role in
T cell co-stimulation and will drive polarisation
Thus, T cell activation requires (3):
- TCR stimulation
- CD28 co-stimulation
- Cytokine stimulation
antigen presenting cells (APC) also secrete
cytokine -> t cell polarisation
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