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4.1 Transfusion and Transplant Immunology > Lymphocyte Activation > Flashcards

Lymphocyte Activation Flashcards

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1
Q

Why is an understanding of lymphocyte activation important in transfusion and transplantation?

A

Rejection reactions of both solid organ transplants and Human Stem Cell Transfusions are reliant on T cell and subsequently B cell activation

Many immunosuppressive therapies used in preventing rejection are based on interfering with different points in the lymphocyte activation process e.g. stopping proliferation etc

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2
Q

On what cells is MHC II found?

A

On antigen presenting cells such as macrophages, dendritic cells, monocytes and B cells

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3
Q

What does T cell activation ultimately end in?

A

Clonal expansion of T cells
Subsequent activation of B cells and thus a humoral response

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4
Q

What reaction is required for T cell Activation?

A

The interaction of the TCR-CD3 complex with a processed exogenous antigen bound to an MHC class II molecule preseented by an APC

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5
Q

What must the T-cell receptor complex with for lymphocyte activation and why must it do so?

A

The TCR must complex with CD3

The TCR’s tails are not long enough to induce signal transduction throughout the cell on its own -> requires the longer cytoplasmis tails of CD3

Long tails of CD3 go much deeper into the cell cytoplasm for signal transduction to occur

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6
Q

What is the principal function of the TCR?

A

The specific recognition of an antigen
-> TCR different on all T cells

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7
Q

What molecules are found on the surface of the T cell which play a role in signal transduction?

A

CD3
CD4/CD8 depending on the type of T cell
CD28

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8
Q

What is the role of integrin?

A

Adhesion

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9
Q

What is the role of the TCR coreceptor?

A

The TCR coreceptor strengthens the reaction between MHC II and CD4 molecule

Does so through the D1 domain of the CD4 molecule and the alpha and beta chains of the MHCII molecule

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10
Q

What is the role of the TCR coreceptor?

A

The TCR coreceptor strengthens the reaction between MHC II and CD4 molecule

Does so through the D1 domain of the CD4 molecule and the alpha and beta chains of the MHCII molecule

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11
Q

What is found on the tail of CD4 molecules?

A

A tyrosine kinase (enzyme) known as p56 Lck

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12
Q

What is p56 Lck and what does it do?

A

It is a tyrosine kinase which phosphorylates tyrosine residues found in ITAMS in the tails of CD3

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13
Q

Briefly describe the structure of CD3

A

Composed of 6 chains which penetrate the T cell surface

6 chains, 3 pairs of 2

ITAMS are present in the cytoplasmic tail of each CD3 chain

The phosphorylation of these ITAMS forms signal 1 in lymphocyte activation

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14
Q

What does ITAM stand for?

A

Immunoreceptor
Tyrosine-based
Activation
Motifs

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15
Q

Describe in you own words what an ITAM is

A

An imunoreceptor -> a receptor on an immune cell
Tyrosine-based -> a protein consisting of the amino acid tyrosine
Activation -> involved in cell activation
Motif -> a specific sequence of amino acids

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16
Q

What is CD28?

A

A co-stimulatory molecule i.e. it works along side another system to bring about a response

CD28 must bind with either protein B7-1 (CD80) or B7-2 (CD86) to produce signal 2 in lymphocyte activation

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17
Q

What is CD28?

A

A co-stimulatory molecule i.e. it works along side another system to bring about a response

CD28 must bind with either protein B7-1 (CD80) or B7-2 (CD86) to produce signal 2 in lymphocyte activation

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18
Q

In your own words, what are the two signals needed for lymphocte activation?

A

Signal 1 -> CD4 binds to MHC II, p56 lcK of CD4 acts on the ITAMs of CD3 to phosphorylate the tyrosine residues

Signal 2 -> CD28 binds to protein B7-1 (CD80) or B7-2 (CD86) of the APC

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19
Q

On what cells are proteins B7-1 and B7-2 (CD80 and CD86) expressed on?

A

These proteins are expressed on the antigen presenting cells

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20
Q

What is the area of space between the T cell and the APC known as?

A

Used to be called the immunological synapse

Now known as The Supramolecular Activation Complex (SMAC) which is further divided into the central-SMAC (C-SMAC) and peripheral-SMAC (p-SMAC)

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21
Q

What does SMAC stand for?

A

The Supramolecular Activation Complex

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22
Q

What six T cell proteins are foun in the c-SMAC

A

TCR -> T Cell receptor
CD2 -> promotes intercellular adhesion
CD4/CD8 -> depending on if Helper or Cytotoxic
CD28 -> costimulatory receptor -> signal 2
PKC-theta -> protein kinase C-theta -> downstream signalling

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23
Q

What 3 proteins are found in the p-SMAC?

A

LFA-1
ICAM-1
Talin

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24
Q

What is LFA-1?

A

Lymphocyte Function Associated antigen 1

An integrin that transmits information in two directions across the plasma membrane of leukocytes

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25
What is an integrin?
A type of protein found on the surface of cells that helps them attach to and communicate with nearby cells
26
What is ICAM 1?
An intracellular adhesion molecule (ICAM)
27
What is talin?
A cytoskeletal protein Its found concentrated at regions of cell-cell contact
28
What is meant by Naive T cells?
These are T cells which are fully competent i.e. have developed their TCR but have not met their antigen yet
29
How many signals do naive T cells need for activation and what are these signals?
Naive T cells require 2 signals for activation and subsequent proliferation Signal 1 -> initial signal Signal 2 -> a co-stimulatory signal
30
What is Signal 1 in lymphocyte activation?
The initial signal generated by interaction of an MHC antigenic peptide complex with the TCR-CD3 complex
31
What is signal 2?
A co stimulatory signal Signal provided primarily by interactions between CD28 on the T cell and proteins B7-1 or B7-2 on the APC
32
On what cells is CD28 expressed on? (Hinted to come up on exam)
Expressed on 95% of human peripheral blood T helper cells Expressed on 50% of human CD8+ T cells NB:
33
On what cells is CD28 expressed on? (Hinted to come up on exam)
Expressed on 95% of human peripheral blood T helper cells Expressed on 50% of human CD8+ T cells NB:
34
What does the lack of CD28 on a CD8+ cell mean? (Hinted to come up on exam)
These cells are a type of regulatory T cell involved in immunosenescence (diminished immune activity) The presence of these cells may promote graft tolerance -> think organ transplant Can use flow cytometry to detect this i.e. CD8+, CD8- cells
35
CD28 is expressed on what % of murine naive T cells?
Expressed on 100% of murine naive T cells
36
What are the different types of T cell receptors?
There are two main types of T cell receptors: - alpha beta receptors - gamma delta receptors
37
What type of T cell receptor is most common in human blood?
Alpha-beta TCRs
38
Briefly describe the structure of T cell receptors
TCRs are composed of heterodimers of either alpha beta or gamma delta Associated with invariant CD3 complexes on the lymphocyte surface
39
Briefly describe the structure of T cell receptors
TCRs are composed of heterodimers of either alpha beta or gamma delta Associated with invariant CD3 complexes on the lymphocyte surface
40
What is protein B7-1 and B7-2 also known as?
CD80 and CD86
41
What is protein B7-1 and B7-2 also known as?
CD80 and CD86
42
If cells want to proliferate what do they require after signal 2 etc?
Interleukin 2 -> this is the growth factor for lymphocytes
43
What is CD45R? (Hinted to come up on exam)
A tyrosine phosphatase expressed on both T cells and B cells Essential in TCR and BCR cell receptor signalling
44
What is the role of CD45R? (from what info you found online)
CD45 (receptor???) A protein tyrosine kinase phosphatase Helps to regulate TCR costimulation by controlling the activation state of Lck which increases T cell activity -> CD45 activates Lck which is responsible for signal 1
45
What is your understanding of the role of PKC-theta (Protein kinase C-theta)? (from what you looked up online)
TCR/CD28 engagement i.e. signal 2 triggers the translocation of the cytosolic PKC-theta to the plasma membrane At the plasma membrane PKC-theta localises at the centre of the immunological synapse/c-SMAC Here a proline rich motif of PKC-theta becomes anchored in the cytoplasmic tail of CD28 Anchoring to CD28 is done indirectly through p56 lck PKC-thta anchoring and localisation is needed for further downstream signalling
46
What is CD45? Where is it found and why is this significant? (lecture notes)
A tyrosine phosphatase It removed a phosphate group It is found in the membrane of the T cell It is found close enough to p56lck to have an affect on it
47
What are the three confirmations of p56Lck?
Closed/inactive Primed/inactive Open/inactive
48
What reaction is responsible for the closed/inactive confirmation of p56Lck?
Phosphorylation of an inhibitory tyrosine @ position 505 (Y505) by Csk is responsible for the closed position
49
What phosphorylates Y505 (tyrosine505) in p56Lck to result in a closed/inactive p56Lck?
Csk
50
What is Csk and what is its role
Csk is a c-terminal-SRC kinase Responsible for phosphorylating the y505 in p56Lck to form an inactive/closed p56Lck i.e. it inactives p56Lck
51
What reaction is required to put p56Lck in the primed/inactive confirmation i.e. how does the molecule got from closed to primed?
The dephosphorylation of y505 by CD45 primes the enzyme
52
What reaction is needed to activate p56lck after it has been primed by CD45?
Auto-trans-phosphorylation of y394 across the molecule then occurs to result in an open/active confirmation i.e. the 2nd tyrosine of p56lck is self phosphorylated
53
What reaction is needed to put p56Lck back in the primed confirmation after it has been activated?
Dephosphorylation of Y394 by phosphatases revert the enzyme back to the primed confirmation
54
What is y394 of p56Lck also known as
Activation loop tyrosine
55
What is the role of CD45 in non-stimulated cells?
CD45 will dephosphorylate both the y505 and y394 in p56Lck
56
In excessive detail, what happens when the y505 of p56Lck is phosphorylated
Terminal tyrosine binds the SH2 domain and the linker region binds the SH3 domain to result in a closed confirmation
57
In excessive deetail, what happens when the terminal tyrosine of p56Lck is dephosphorylated?
The SH3 domain of p56Lck releases the linker region
58
What part oof p56Lck does SH2 bind?
It binds phosphorylated tyrosine residues of p56Lck
59
What part oof p56Lck does SH2 bind?
SH2 is one of the molecules responsible for confirmational change in p56Lck SH2 region is of p56Lck is found just after SH3 SH2 binds to terminal phosphorylated tyrosine at the end of the chain It binds phosphorylated tyrosine residues of p56Lck
60
What part of p56Lck does the SH3 bind to?
SH3 is a proline-rich sequence in p56Lck SH3 is one of the molecules responsible for confirmational change in the p56lck molecule SH3 binds to a linker region of p56Lck further down the chain
61
What is the tyrosine at position 505 of p56Lck called?
Inhibitory tyrosine -> since when it is phosphorylated it binds to SH2 to result in closed/inactive p56Lck
62
Define clonal anergy?
A state of non-responsiveness, marked by the inability of cells to proliferate in respose to a peptide-MHC complex The outcome is determined by the presence or absence of a co-stimulatory signal
63
When does clonal anergy occur?
It happens if a co-stimulatory signal is absent e.g. if CD28 and B7 reaction doesnt occur
64
What does clonal anergy result in?
A state of unresponsiveness The T cell cant proliferate
65
give two examples of co-stimuatory signals which would prevent clonal-anergy build up
B7/CD28 signal absent CD40/CD40L signal absent (CD40 on dendritic cells and CD40L on CD4+ cells)
66
What happens if there is a build of of anergy e.g. no co-stimulatory signal?
There is minimal cytokine production e.g. IL-2
67
Talk a little about the production of IL-2 in T cells
T cells produce their own IL-2 when stimulated to do so Dont do this normally so the cell needs transcription factors These transciption factors are needed to change the expression profile of the cell to produce IL2 IL-2 produced will then have a paracrine response on nearby cells (in activated T cells the same thing happens to upregulate cytokine production)
68
In the lack of co-stimulatory signals, i.e. in the build up of anergy, why was it found that IL-2 wasn't being produced by T Cells
mRNA coding for ubiquitin ligases were found by microarray analysis in the absence of a c-stimulatory signal It was found that ubiquitin was being added to some of the important components of the T cell activation cascade
69
What is a ubiquitin ligase, what is its role?
A ligase is something that adds something to its target => ubiquitin ligase adds ubiquitin to targegts Tagging with ubiquitin marks the molecule for degradation in a cell Any proteins destined to be broken down are tagged with ubiquiin and brought to the proteosome where they are broken down into peptides (process that happens in antigen processing)
70
What are the three molecules involved in preventing anergy?
B7 CD28 CTLA-4
71
What are the three molecules involved in preventing anergy?
B7 CD28 CTLA-4
72
What are the two forms of B7?
B7-1 (CD80) -> this exists as a dimer on the cell surface B7-2 (CD86) -> this exists as a monomer on the cell surface Both are integral/inbedded in the cell membrane Both bring about the same response when they bind
73
Where is B7 found?
Inbedded in the cell membrane of Dendritic cells, macrophages and B cells Constitutively expressed on dendritic cells i.e. always expressed Expression has to be induced on activated macrophages and activated B cells
74
What exactly are the B7 proteins?
Integral membrane glycoproteins They are members of the Ig superfamily
75
How does B71 compare to B72?
They have similar extracellular domins but have markedly different cytosolic domains
76
How can the expression of B7 proteins be induced on activated macrophages and activated B cells How can expression og B7 proteins be increased?
Microbial products that bind TLRs such as LPS in the cell walls of gram negatives Cytokines such as interferon gamma CD40L (T cells) binding CD40 (APC)
77
Explain in your own words how the detection of LPS by TLR4 on T cells can be used by APCs to upregulate B7 protein expression
Need to look into this more
78
How does B7 proteins bind to CD28 to bring about the co-stimulatory signals
CD28 binds to B7 protein The tyrosine reside of the YMNM motif of CD28 is phosphorylated by p56Lck
79
How is YMNM read?
Tyrosine, methionine, aspargine, methionine
80
What two motifs of CD28 are we interested in?
YMNM Proline-rich region
81
What is the two jobs of p56Lck?
Phosphorylation of ITAMs in CD3 Phosphorylation of tyrosine residue of YMNM motif of CD28
82
What is considered the STOP and GO co-stimulatory signals?
CD28 binding to B7 = GO CTLA-4 binding to B7 = STOP
83
How does CD28 bind to B7? What is the GO co-stimulatory signal? (6 steps)
Cytoplasmic region of CD28 contains a proline-rich motif that binds the SH3 domains of Lck and Itk p56-Lck phosphorylates tyrosine residues in CD28s (YMNM) cytoplasmic region This results in the activation of PI3 kinase PI3 kinase converts PIP2 in the phospholipid in the outermembrane of the T cell into PIP3 PIP3 then recruits Itk PLC-gamma then becomes activated
84
After binding to B7, what does CD28 bind to?
The SH3 domains of Lck and Itk
85
After binding to CD7, what part of CD28 binds to Lck and Itk?
proline-rich motif
86
After B7 binding, what happens after Cd28 binding to p56-lck?
p56-Lck phosphorylates tyrosine residues in CD28s (YMNM) cytoplasmic region This activates PI3 kinase
87
What does PI3 kinase do?
PI3 kinase converts PIP2 in the phospholipid in the outermembrane of the T cell into PIP3
88
What does PIP3 do?
PIP3 then recruits Itk
89
What is ITK and what does it do?
Inducable T cell kinase It activates PLC-gamma (phospholipid C gamma)
90
What is the CD number for CTLA-4?
CD152
91
What happens if B7 binds CTLA-4?
STOP signal CTLA-4 recruits a phosphatase (SHP-2) to the immunological synapse that blocks normal phosphorylation of the ITAMS
92
What happens if B7 binds CTLA-4?
STOP signal CTLA-4 recruits a phosphatase (SHP-2) to the immunological synapse that blocks normal phosphorylation of the ITAMS
93
What molecule does CTLA-4 recruit to stop T cell signalling cascade?
SHP-2
94
Comment on B7:CD28 effect on effector and memory T cell
Previously activated effector and memory T cells are less dependent on B7:CD28 co-stimulaition than naive T cells
95
What does SH2 domain stand for?
SRC homology 2 domain
96
How does SH2 binding work?
Bind in a sequence-specific fashion They recognise a phosporylated tyrosine (pY) and typically the amino acid 3 position after
97
What is the ITAM motif that the SH2 of Lck binds to?
tyrosine-x-x-leucine/isoleucine-6-9aminoacids-tyosine-x-x-leucine/isoleucine
98
What can the ITAM motif of CD3 bind to toher than p56Lck?
ITAM motif attracts proteins wit h2 tandem SH2 domains = Lck and ZAP-70
99
Explain how SH3 binding occurs?
SH3 domains bind to clusters of proline residues e.g. Lck and Itk
100
What is the PH domain?
Pleckstrin homology domain
101
How does PH domain binding occur?
PIP is generated from PIP through action of PI3 kinase PH domain binds to PIP3 in the plasma membrane PLC gamma and Itk????
102
How could you describe the action of CD28 vs CTLA-4
They act antagonistically
103
What is the end result of CD28 binding to B7? (4)
Signalling through CD28 delivers a positive co-stimulatory signal to the T cell This increases cytokine production especially IL2 Increases anti-apoptotic protein Bcl-x and activation of PI3 kinase
104
What is the end result of B7 binding to CTLA-4?
Signalling through CTLA-4 is inhibitory and down-regulates the activity of the T cell It has a 20-fold higher affinity for B7 than CD28 and may recruit a phosphatase (SHP-2) to the synapse which blocks normal phosphorylation of ITAM chains
105
What cells express CD28?
Both resting and activated T cells
106
What is ICOS?
Inducible co-stimulator
107
What does ICOS do? (4)
Its homologous to CD28 Its induced on T cells after activation Its ligand is LICOS (B7h) is homologous to B7 proteins Its important for IL-10 production and for activation of previously differentiated effectors
108
On what cells is CTLA-4 found?
Its virtually undetectable on resting cells Engagement of TCR causes rapid induction of its expression at the synapse
109
What happened when CTLA-4 was knocked out of mice? What did we learn from this?
T cells proliferative massively causing lymphadenopathy and splenomegaly Caused death in 3 to 4 weeks after birth => CTLA-4 plays an important role in lymphocyte homeostasis

4.1 Transfusion and Transplant Immunology (24 decks)

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