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Cellular and Molecular Immunology > 16. Peripheral Tolerance 1 > Flashcards

16. Peripheral Tolerance 1 Flashcards

1
Q

Why are TCRs so diverse?

A
  1. It is essential for survival.
  2. They are diverse to detect a huge number of different things
  3. It protects us from lots of different pathogens.
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2
Q

What is the disadvantage of having diverse TCRs?

A
  1. The same mechanisms that give us diversity could make TCRs dangerous.
  2. The random generation of TCRs by somatic recombination could lead to TCRs that recognise self-antigens.
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3
Q

What do T cells need to be able to do to avoid autoimmunity?

A

They must be able to distinguish between self-antigens and non self antigens.

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4
Q

What do naive T cells that leave the thymus need to be?

A
  1. Self MHC restricted
  2. Non-self reactive
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5
Q

Why do TCRs need to be able to recognise your own MHC?

A

In order to recognise the peptide presented on the MHC, the T cell needs to recognise and bind a self MHC.

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6
Q

What happens to T cells in the thymus that are self-reactive and not self MHC restricted?

A
  1. Death by neglect for thymocytes that have no affinity to recognise self MHC.
  2. Negative selection is the deletion of strongly self-reactive thymocytes.
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7
Q

Are all self reactive thymocytes deleted in the thymus?

A
  1. No
  2. Central tolerance is 60-70% efficient.
  3. This means self-reactive thymocytes escape to the periphery.
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8
Q

What would happen if all weakly self reactive thymocytes were deleted?

A

You would be massively limiting the diversity of TCRs.

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9
Q

What is TCR degeneracy?

A
  1. Every T cell has a unique TCR.
  2. This TCR can recognise a range of antigens that all look a bit similar at different affinities.
  3. This means if you delete all weakly self reactive T cells you lose a lot of T cell repertoire.
  4. This means you cannot respond effectively to pathogens.
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10
Q

Does the potential for autoimmunity exist in everyone?

A
  1. Yes
  2. Due to self reactive T cells existing in the periphery.
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11
Q

What keeps peripheral self reactive T cells in check?

A

peripheral tolerance mechanisms

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12
Q

Why do some self-reactive T cells escape central tolerance?

A
  1. Low avidity self-reactive T cells routinely escape negative selection.
  2. Not all self-antigens are expressed in the thymus.
  3. Limits in thymic antigen processing can hide epitopes from T cells.
  4. Self-antigens are expressed at too low a concentration to induce negative selection
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13
Q

What is autoimmunity?

A

A failure in self-tolerance

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14
Q

Why is the prevalence of autoimmunity low?

A

Due to peripheral tolerance

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15
Q

What is peripheral tolerance?

A
  1. Mechanisms which control mature T cells in the periphery to maintain self-tolerance and prevent autoimmunity.
  2. Most of these mechanisms overlap in function
  3. Mechanisms of tolerance help distinguish between self and non-self antigens
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16
Q

What else does peripheral tolerance help tolerate?

A
  1. Food antigens
  2. Pollen
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17
Q

What is a problem with peripheral tolerance?

A
  1. Short peptides that are generated by antigen processing can look identical
  2. This means pathogen and self derived proteins can look the same.
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18
Q

How do T cells distinguish between self and non-self?

A
  1. They don’t distinguish self and non-self antigens at a molecular level.
  2. There is a complex array of signals that tell T cells how to respond.
  3. These normally come as environmental cues like co stimulation.
  4. The signals provide clues as to whether a peptide is self and if a T cell response is needed.
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19
Q

What are intrinsic tolerance mechanisms?

A

Act directly on the self-reactive T cells

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20
Q

What are extrinsic tolerance mechanisms?

A

They act indirectly via something like an APC

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21
Q

What does tolerance need to do overall?

A

Strike a balance between damping immunity enough and causing autoimmunity

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22
Q

What is ignorance of self-peptides?

A

This is the physical separation of the T cell from the antigen they are specific for.

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23
Q

How does ignorance of self peptides work?

A
  1. Naive T cells are excluded from non-lymphoid peripheral tissue.
  2. This means there is a low likelihood of a self reactive T cell from finding the antigen.
  3. TCR affinity could be too low to find the antigen.
  4. Self-antigen abundance may also be too low.
  5. The self-antigen is behind a physical barrier like the blood brain barrier
  6. The antigen could be in an area of poor lymphatic drainage so the antigen never gets presented to the T cells.
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24
Q

What happens if an ignorant T cell encounters its antigen?

A
  1. It is activated.
  2. Antigen-experienced T cells can traffic through most tissues.
  3. Activated T cells home to the sites of inflammation
  4. Once activated, self-reactive T cells are dangerous.
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25
Q

How do we control self-reactive T cells once the self-antigen is recognise via the TCR?

A
  1. Deletion
  2. Anergy
  3. Negative co-stimulation
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26
Q

What is apoptosis important for?

A
  1. T cell homeostasis and tolerance.
  2. Generally helps control T cell numbers.
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27
Q

What are the different types of apoptosis that occur in T cells?

A
  1. BIM mediate which mostly happens in the thymus.
  2. Fas/FasL mediated cell death that mostly happens in the periphery.
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28
Q

What is BIM mediated apoptosis?

A

Bcl-2 interacting mediator of cell death

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29
Q

What does activation of BIM or Fas pathway lead to?

A
  1. Caspase activation
  2. Cleavage of essential intracellular proteins.
  3. Apoptosis
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30
Q

What is the intrinsic method of apoptosis?

A

BIM

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31
Q

How does the BIM apoptosis pathway work?

A
  1. Developmental signal or extracellular stress.
  2. Activation of BIM
  3. release of cytochrome C from the mitochondria.
  4. Formation of the apoptosome with APAF1, pro-caspase 9 and cytochrome C.
  5. Cleavage of pro-caspase 9 then pro-caspase 3.
  6. Cell death
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32
Q

What is the extrinsic method of apoptosis?

A

Fas/FasL pathway

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33
Q

How does the Fas/FasL apoptosis pathway work?

A
  1. External signals via the engagement of the death receptor Fas with Fas Ligand.
  2. Formation of Fas associated death domain protein (FADD)
  3. Pro-caspase 8 cleavage then pro-caspase 3.
  4. Cell death
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34
Q

What does disruption of Fas/FasL cause?

A
  1. Leads to accumulation of self reactive T cells and autoimmune disease.
  2. Systemic autoimmunity like neutropenia, haemolytic anaemia, thrombocytopenia, and uveitis.
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35
Q

What humans disorder is caused by a Fas or FasL mutation?

A

Autoimmune lymphoproliferative syndrome (ALPS)

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36
Q

What is Activation induced cell death?

A
  1. Cell death triggered by TCR engagement
  2. Fas-mediated apoptosis
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37
Q

What can induce activation induced cell death?

A
  1. High levels of self antigen
  2. Chronic self-antigenic stimulation
  3. TCR engagement without co-stimulation.
38
Q

How is Fas mediated apoptosis a check and balance for T cell expansion?

A
  1. Fas is always expressed on T cells
  2. FasL expression is induced by TCR engagement.
  3. Engagement of Fas with FasL triggers formation of death-inducing signalling complex (DISC).
  4. This occurs at T cell activation
  5. If the correct signals for T cell expansion are present the Fas pathway is inhibited.
  6. FLIP protein inhibit caspase 8 and DISC formation
  7. FasL expression is downregulated by CD28 signalling.
39
Q

What are immune privileged sites?

A
  1. Places in the body which are not subject to normal immune surveillance.
  2. They are places were damage and inflammation is too risky.
  3. Like the brain, testis and the eye.
40
Q

Why is FasL expressed at immune-privileged sites?

A
  1. To induce apoptosis in T cells that interact with these tissues.
  2. this protects these sites and contributes to the privileged status.
41
Q

How can dendritic cells promote T cell tolerance?

A
  1. Absence of co-stimulation with anergy.
  2. Negative co-stimulatory signals.
  3. Induction of Treg cells
42
Q

What are immature dendritic cells?

A
  1. They reside in parenchymal tissues to monitor for infection or injury.
  2. High levels of endocytic and antigen processing activity to sample the environment.
  3. Low MHC expression
  4. Low co-stimulatory molecule expression.
43
Q

How do dendritic cells change during maturation?

A
  1. They encounter microbial products/necrosis/ pro-inflammatory cytokines.
  2. Massively reduced endocytosis and antigen processing activity.
  3. High MHC expression
  4. High co-stimulatory molecule expression
  5. Traffic to lymph node to access naive T cells.
44
Q

How are mature dendritic cells immunogenic?

A
  1. They are good at activating T cells due to high levels of MHC and co-stimulatory molecule expression.
  2. NF-kB signalling causes upregulation of MHC2, CD40, CD80/86, CRR7 and pro-inflammatory cytokines.
  3. They can deliver signal 1 and 2.
  4. They migrate to T cell areas of the lymph node
45
Q

What are tolerogenic dendritic cells?

A
  1. They are a subset of dendritic cells that go through a different kind of maturation.
  2. They are not unique and are induced and maintained by different conditions.
  3. Characterised by low levels of MHC and costimulatory molecule expression.
46
Q

How do tolerogenic dendritic cells arise?

A
  1. In the presence of apoptotic cells.
  2. So they are induced by the normal turnover of our tissues.
  3. Apoptotic cells don’t trigger dendritic cells in the same way as neurotic cells.
  4. Apoptotic cells express ligands for MerTK which triggers SOCS 1 and 3 expression
  5. SOCS shut down NF-kB activation so there is no up regulation of MHC2 and co-stimulation
47
Q

What signals from the APC are needed for T cell activation?

A

Signal 1: TCR MHC2 engagement
Signal 2: Co-stimulation
Signal 3: Differentiation via cytokines

48
Q

What is T cell anergy?

A

A state of unresponsiveness is induced in antigen-specific T cells.

49
Q

What are anergic T cells?

A
  1. Potentially dangerous but not right now.
  2. Not proliferating
  3. Altered metabolism that keeps them anergic
50
Q

What are anergic T cells characterised by?

A
  1. Lack of proliferation
  2. Significant reduction in IL-2 secretion and effector cytokine production.
  3. Inhibitory receptor expression
51
Q

Can T cell anergy be lost?

A
  1. Yes
  2. It needs to be maintained by signalling from the antigen without co-stimulation.
  3. Anergy can be reversed and anergic cells can die.
52
Q

What does T cell activation lead to?

A
  1. TCR + co-stimulation causes NFkB, NFAT, AP-1 and CREB activation.
  2. This activated IL-2 transcription.
53
Q

What does IL-2 expression do?

A
  1. Growth factor for T cells
  2. Promotes CD8+ T cell memory.
  3. Drives IFNy and IL-4 during TH1/Th2 differentiation
54
Q

Why is the expression of IL-2 tightly regulated?

A
  1. To ensure T cell expansion only occurs under the correct conditions
  2. This is signal 1 and signal 2.
55
Q

What happens during T cell activation in the absence of co-stimulation?

A
  1. An alternative signalling pathway is triggered.
  2. Without co-stimulation from CD28 no AP-1 is generated.
  3. Without AP-1 NFAT can’t induce IL-2 expression.
  4. Instead, NFAT activates anergy-associated genes.
56
Q

What is NFAT?

A
  1. A transcription factor
  2. Acts as a biological switch between anergy and activation.
57
Q

How do we know NFAT is essential for anergy?

A

If you treat T cells with cyclosporin which inhibits NFAT cells are resistant to anergy induction.

58
Q

What types of anergy-associated genes does NFAT activate?

A
  1. Inhibitors of TCR proximal signalling.
  2. Inhibitors of gene transcription.
59
Q

What inhibitors of TCR proximal signalling are activated in anergy?

A
  1. E3 ubiquitin ligases like Cbl-b, GRAIL, itch
  2. Diacylglycerol kinase alpha
  3. These normally lead to blocked activation of Ras, ERK and JNK.
  4. Even if the TCR later get co-stimulation the cell remains anergic
60
Q

What do E3 ubiquitin ligases do?

A
  1. Target key signalling components for degradation by the proteasome.
  2. Like PKC theta and PLCy-1 which inhibits downstream signalling
61
Q

What does Diacylglycerol kinase a do?

A
  1. Depletes DAG to inhibit Ras activation
62
Q

what inhibitors of transcription are activated in T cell anergy?

A
  1. Ikaros
  2. CREM
  3. Egr2 and Egr3
63
Q

what does Ikaros do?

A
  1. It is a transcription factor that is normally expressed in naive T cells.
  2. It represses IL-2 production.
  3. Expression of Ikaros increases in anergic cells
64
Q

What does CREM do?

A
  1. It is induced by TCR engagement.
  2. Without AP1, CREM and NFAT bind to the IL2 promoter to repress transcription.
65
Q

What do Egr2 and Egr3 do?

A
  1. Increased expression in anergic cells
  2. Inhibits expression of il2
66
Q

What happens in mice with a deletion in Egr2 and Egr3?

A
  1. They develop fatal autoimmune syndrome.
  2. lymphocytic infiltration of multiple organs.
  3. Anti-self antibodies
  4. High levels of T and B cell activation causing splenomegaly and super enlarged lymph nodes.
  5. High levels of inflammatory cytokines in serum/
67
Q

How does gene expression change in mice without Egr2 and Egr3?

A
  1. Decreased SOCS1 and SOCS3 expression
  2. Decreased inhibition of STAT-1 and STAT-3
  3. Hyper activation of STAT-1 and STAT-3.
  4. Dysregulation of cytokine expression
  5. Excessive Th1 and Th17 cytokines leading to autoimmunity
68
Q

What is SOCS?

A

Suppressor of cytokine signalling

69
Q

What co-stimulatory molecules do T cells express?

A
  1. CD28
  2. ICOS
  3. CD40L
70
Q

Why is co-stimulation on T cells important?

A
  1. Important for activation
  2. Enhances immune responses
71
Q

What does CD40L do?

A

Gives positive signals to APCs to make them better at activating T cells.

72
Q

What other molecules are expressed by T cells?

A

Co-inhibitory molecules

73
Q

Why do T cells express co-inhibitory molecules?

A
  1. To limit T cell responses
  2. To reduce pathology associated with responses to self and foreign antigens.
74
Q

What co-inhibitory molecules do T cells express?

A
  1. CLTA-4
  2. PD-1
  3. LAG-3
75
Q

What balance do T cells need to strike?

A
  1. Between co-stimulatory and co-inhibitory to regulate responses to antigens
  2. If the balance isn’t right, there are implications for immunotherapy of cancer or autoimmune disease.
76
Q

What can contribute to autoimmune disease?

A

Dysregulation of co-stimulatory and co-inhibitory molecules

77
Q

What is CTLA-4?

A
  1. An inhibitory CD28 homologue
  2. Competitively binds to CD80/86 at higher affinities then CD28.
  3. CTLA-4 exists in vesicles in naive and memory cells
  4. Expression is up-regulated on T cell activation.
78
Q

Where is CTLA-4 constitutively expressed?

A

on Treg cells

79
Q

What is PD-1?

A
  1. An inhibitory molecule
  2. Expressed by activated T cells
  3. highly expressed by several Treg subsets
  4. Important for regulation of tolerance
80
Q

Where are PD-1 ligand up regulated?

A
  1. Inflammatory signals causing up regulation of PD-L1 and PD-L2.
  2. Expressed in tissue with inflammation
81
Q

What is LAG-3?

A
  1. An inhibitory CD4 homologue
  2. Binds to MHC2 with high affinity but away from the peptide binding groove.
  3. Upregulation several days after T-cell activation.
  4. Also expressed in NK and myeloid cells.
  5. Upregulated on various Treg populations and anergic cells.
  6. LAG-3 deficiencies accelerates Diabetes in NOD mice
82
Q

What does expression of co-inhibitory molecules do in autoimmunity?

A
  1. Dampen pro-inflammatory responses.
  2. Limit local and systemic inflammation to promote tissue tolerance.
  3. Correlate with favourable clinical outcomes
  4. Expression of inhibitors gets down-regulated in autoimmunity
83
Q

What does expression of co-inhibitory molecules do in cancer?

A
  1. Dampen anti-tumour effector functions
  2. Promote tumour evasion
  3. Correlate with poor clinical outcomes.
  4. Expression of inhibitors gets up-regulated in cancer.
84
Q

What is pembrolizumab?

A
  1. A PD-1 blocking antibody
  2. It induces tumour regression in patients with metastatic melanoma.
85
Q

What can blocking co-inhibitory signals do?

A

Release the inhibition of T cells that recognise tumour-associated antigens

86
Q

What is the problem with blocking co-inhibitory molecules to treat cancer?

A
  1. It stops the inhibition on all T cells.
  2. This often results in immune-mediated pathologies.
  3. This can include things like vitiligo where T cells attack melanocytes.
87
Q

What are the 4 main mechanisms of peripheral tolerance?

A
  1. Ignorance
  2. Deletion
  3. Anergy
  4. Co-inhibition
88
Q

Extra: Can Fas activate non-apoptotic pathways?

A

It can induce proliferation through NF-kB signalling.

89
Q

Extra: What is sFasL?

A
  1. Soluble FasL
  2. It is FasL cleaved off the membrane and released.
90
Q

Extra: What does sFasL do?

A
  1. Can induce apoptosis in Fas+ T cells to evade immune surveillance. This has been seen in some cancers like NK cell lymphoma
  2. Can also inhibit apoptosis as it doesn’t oligomerise with it binds Fas in other T cells.
91
Q

Extra: How can apoptotic cells promote tolerogenic dendritic cells?

A

Uptake of apoptotic debris can inhibit MyD88 and NF-kB mediated proinflammatory cytokine synthesis.

92
Q

Extra: Why does lack of co stimulation reduce AP-1 production?

A
  1. AP-1 is made up of 2 proteins fos and jun.
  2. CD28, PI3K, AKT, and JNK cascade produces Jun.
  3. TCR induced Ras signalling induces fos.
  4. Without CD28 co stimulation limited AP-1 is formed

Cellular and Molecular Immunology (17 decks)

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