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Microbiology > T cells (Specificity, education, maturation & function) > Flashcards

T cells (Specificity, education, maturation & function) Flashcards

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1
Q

Lymphocytes are vital for

A

acquired immunity (diversity), memory and
self / non-self recognition

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2
Q

T cells arise from a

A

common lymphoid progenitor

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3
Q

T cells originate in

A

the bone marrow from HSC
and mature in the Thymus (hence T cell)

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4
Q

T cells originate in the bone marrow from HSC
and mature in the Thymus (hence T cell)

From here they migrate to

A

2o lymphoid tissues
(sites of lymphocyte activation)

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5
Q

They circulate between

A

peripheral blood and
these sites until the encounter antigen (Ag)

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6
Q

Unlike other immune cells T (and B) cells

A

re-circulate from blood to tissues (patrol)

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7
Q

Each T cell has an

A

individual type of receptor (like B cells) that is
complementary to a specific epitope

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8
Q

When activated they undergo

A

clonal proliferation, creating numerous T cell
copies with the same receptor

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9
Q

They have the property of

A

memory

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10
Q

They have the property of memory, which results in

A

a quicker immune response of higher magnitude when challenged with the same antigen

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11
Q

primasry lymphoid organs?

A

–
BM
Thymus

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12
Q

secndary lymphoid organs?

A

adenoid, tonsil, lymph
nodes, spleen, appendix,
Peyer’s patches

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13
Q

Much like the B cell receptor (ultimately secreted as Ig) the T cell receptor has

A

constant and variable regions (epitope specific)

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14
Q

The T cell receptor (TCR) is a

A

heterodimer of αβ subunits
(in most cases) and belongs to
the Ig superfamily

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15
Q

Each chain has 3 domains

A
  • Variable extracellular
    domain
  • Constant extracellular
    domain
  • Constant trans-membrane
    domain
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16
Q

The TCR α-chain has a molecular weight of

A

40-50 kDa and the β-chain
40-45 kDa

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17
Q

The TCR N-terminal (extracellular) domain
contains a

A

hypervariable region synonymous
with the complementary determining regions
(CDR’s) of the immunoglobulins (Ig)

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18
Q

how many hypervariable region in each tcr chain?

A

Each TCR chain has 3 hypervariable regions

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19
Q

TCR β-chain has a

A

fourth hypervariable region, which doesn’t appear to interact with antigen

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20
Q

At the extracellular C domain, each chain
contains a

A

cysteine residue (consensus sequence) – links αβ via a disulphide

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21
Q

Each chain has a

A

short cytoplasmic tail (no signalling)

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22
Q

Unlike B cells
which can interact directly with soluble Ag, T cells must
be

A

shown Ag complexes with MHC

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23
Q

Therefore multiple levels of protein
protein interaction occur at

A

the MHC / TCR immunological synapse

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24
Q

Each TCR is associated with

A

ancillary proteins, which come together to form the TCR-complex

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25
CD3 is a
heteromeric membrane complex with extended cytoplasmic regions (phosphorylation sites)
26
CD4 / CD8 are
co receptors with specificity for MHC-II or MHC-I
27
CD3 is a heterohexamer complex consisting of
- one εδ heterodimer (epsilon, delta) - one εγ heterodimer (epsilon, gamma) - one ζζ homodimer (zeta, zeta)
28
+ve charged polar residues in the TCR transmembrane domain attracts...
... -ve charged residues in the CD3 subunit transmembrane domains
29
MHC-peptide complex associates with
complementary TCR hypervariable regions
30
MHC-peptide complex associates with complementary TCR hypervariable regions These intermolecular interactions (think of what these are) initiate
local (microenvironment) conformational changes
31
Conformational ripples are observed through
the length of the α and β chains
32
Conformational ripples are observed through the length of the α and β chains Changes translate to
CD3 complex resulting in ITAM phosphorylation
33
MHC-peptide complex is perceived
extracellular
34
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11
36
Like the B cell receptor the TCR has
hypervariable and constant regions
37
Variation of the TCR is achieved by
somatic recombination
38
TCR loci contain
numerous gene segments which are inherited through the germ line (accounts for part of the TCR diversity)
39
From somatic recombination, how many different t cell receptors?
~ 10^18 different T cell receptors!!
40
13
41
Random V(D)J recom bination and genetic splicing occurs for
both α and β chain genes in immature T cells
42
For β chain, the J gene segments do no t seem to be
important for Ag recognition, however Dβ1 and Dβ2 do
43
The joining of α and β peptide chains in TCR accounts for
10^18 possible combinations
44
Like B cell receptor, TCR expression is controlled by
allelic exclusion
45
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)
46
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.
47
48
Immature T cells (thymocytes) leave the
bone marrow & enter the thymus for maturation and development
49
T cell development ensures that
only self-restricted / self-tolerant T cells enter the periphery (patrol for Ag)
50
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
51
whats the DN stage?
Early thymocyte maturation involves cortical interactions
52
Initially, thymocytes entering thymus medulla encounter
NOTCH ligands → thymocyte proliferation
53
DN1 – function?
plastic thymocytes, up regulate CD25 once in cortex
54
Lymphocytes are vital for
acquired immunity (diversity), memory and self / non-self recognition
55
T cells arise from
a common lymphoid progenitor
56
dn2 function
commit to T cell lineage and β chain rearranges
57
dn3 function
completion of β chain rearrangement and α/β TCR development
58
dn4 function
immature single positive (ISP) before DP stage
59
By the end of early maturation, CD4+ CD8+ DP thymocytes are
generated and must be selected to ensure MHC self-recognition
60
DP thymocytes are
small and non proliferative (~80% cortex thymocytes)
61
DP thymocytes interact with
cortex epithelial cells which express high levels of self MHC-I / MHC-II
62
Moderate to strong binding creates
survival and proliferation
63
Weak or no binding causes
death by neglect (apoptosis) – positive selection
64
DP thymocytes that make it through positive selection progress to
the negative selection stage
65
In the medulla, antigen presenting cells (APC) such as dendritic cells
present MHC coupled self antigen
66
Cells which bind moderately
survive
67
Cells which bind with high affinity undergo
apoptosis
68
Most DP thymocytes (>98%) do not
make it through thymic selection
69
Thymic selection ensures that
T cells recognise foreign Ag bound to self-MHC
70
The cortex stage; early maturation & proliferation of DN, DP generation and positive selection takes
13 – 15 days to complete
71
The medulla stage; negative selection and CD4 / CD8 lineage commitment take
4-5 days to complete
72
3 weeks for
whole process
73
The thymic selection process ‘screens’
TCR reactivity
74
The thymic selection process ‘screens’ TCR reactivity, however
T cells are still CD4 /CD8 double positive
75
The mechanisms of T helper (CD4+) or T cytotoxic (CD8+) lineage commitment is ...
... not fully defined, however three models are proposed
76
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)
77
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.
78
describe instructive model?
- DP immature T cells bind either MHC-I or MHC-II - Signal result in the retention of CD8 or CD4 respectively
79
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
80
T cell education and maturation occurs
early on in life; we have all of our T cell repertoire by adolescence (T cells long lived)
81
Thymus atrophies with
age
82
Studies show that neonatal thymectomy results in
significant drop in overall T cell number, but no compromise in immune function
83
If T cell thymic selection fails,
self-reactive T cells may enter the periphery → autoimmune disease can arise
84
Broadly there are two major
t cell type
85
T helper (TH) cells (CD4+T cells) secrete...
... cytokine / help amplify and coordinate the immune response;
86
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
87
T cytotoxic (TC) cell (CD8 +T cells) kill
... cells bearing appropriate stimulating Ag – viral Ag or altered-self (tumour antigen)
88
28
89
Peripheral T cells that make it through thymic selection are termed
naïve
90
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)
91
Naïve T cells (CD4 and CD8) require
co-stimulation for full activation and proliferation
92
29
93
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)
94
CD28 stimulation alone has
no effect on T cell
95
Cytokines also play a central role in
T cell co-stimulation and will drive polarisation
96
Thus, T cell activation requires (3):
- TCR stimulation - CD28 co-stimulation - Cytokine stimulation
97
antigen presenting cells (APC) also secrete
cytokine -> t cell polarisation
98
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