Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

BI405 (ii) > T-Cell Exhaustion > Flashcards

T-Cell Exhaustion Flashcards

1
Q

Name the viral immune evasion mechanisms

A

*Shielding of antigens
*Delayed induction/inhibition of IFN
*Inhibition of PRR signaling
*Decoy receptors
*Defective antigen presentation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Molluscum contagiosum

A
  • Human poxvirus
  • Persistent infections (3-6 months)
  • This virus contains hundreds of proteins
    involved in immune evasion
  • This virus hides!
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Influenza

A
  • Seasonal infections
  • This virus can undergo reassortment
    (antigenic shift)
  • This virus changes!
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

HBV, HCV and HIV

A
  • Hepatitis B virus, hepatitis C virus and human
    immunodeficiency virus (and severe COVID-19)
  • Failure to rapidly clear the virus
  • Persistent infections with high viral loads
  • No shortage of antigen and no antigen clearance
  • T Cell Exhaustion
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Hepatitis B Virus

A
  • Prevalence ranges from 6% in Western Pacific to 1% in Western Europe/North America
  • Double-stranded, DNA genome of ∼3.2 kilobases
  • Early high viral load which eventually declines, with
    90% adults spontaneously clearing the virus
  • Chronic infection more likely to occur in children
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Hepatitis C Virus (HCV)

A
  • Global prevalence 1.6%
  • Positive-strand RNA genome of approximately 9.6 kb
  • 25% spontaneous clear infection
  • Chronic infection – virus persistence >6 months
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Human Immunodeficiency virus (HIV)

A
  • Causative agent of AIDS
  • Single-stranded, positive-sense, enveloped RNA
    retroviruses
  • Estimated to be 37 million infected worldwide
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

True or False T cell Exhaustion is not restricted to viruses..?

A

True. e.g. Malaria & Cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What is T cell exhaustion characterised by?

A

Characterised by chronic antigen persistence and high antigen levels.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is exhaustion?

A
  • Exhaustion is a state of dysfunction that occurs in CD8+ T cell
  • Characterized by the lack of effector functions associated with typical effector and memory T cells
  • Altered proliferative abilities and maintenance requirements
    *TCF1+ cells include both memory precursors and
    exhaustion precursors (TPEX)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are the 3 main states of dysfunction in T cells?

A

Anergy, Exhaustion and Senescence

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Anergy

A

Defective activation resulting in non-responsiveness and apoptosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Senescence

A

A stress response resulting in non-proliferation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

T cell senescence

A
  • Non-proliferative cell state induced in response to cell stress
    – ROS, telomere shortening due to proliferation,
    chromosome damage
  • Expression of cell cycle inhibitors - p53, p16,p14
  • Secrete inflammatory mediators – activate and recruit other immune cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

The benefits of exhaustion

A
  • CD8+ T cell effector function is associated with cytolysis of target cells and pro-inflammatory cytokines
  • Too much activation is bad
  • Immunopathology – pathology caused by excessive immune system activation
  • Exhaustion may have evolved as a mechanism to
    limit immunopathology
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What induces? T cell anergy

A

*Induced due to lack of co-stimulation via CD28 and insufficient growth signals from cytokines

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is T cell anergy characterised by?

A

It is characterised by diminished Ras/MAPK signalling and reduced AP1.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

In T cell Angery what do NFAT signals induce?

A
  • NFAT signals induce transcription factors
    (EGR2, EGR3) and E3 ubiquitin ligases (Itch)
  • Itch can target PLCɣ for proteosome
    degradation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Describe T cell senescence

A
  • Non-proliferative cell state induced in
    response to cell stress
    – ROS, telomere shortening due to proliferation,
    chromosome damage
  • Expression of cell cycle inhibitors - p53, p16,
    p14
  • Secrete inflammatory mediators – activate
    and recruit other immune cells
20
Q

Are HCV, HBV and Mtb directly cytotoxic?

A

No, the infected cells survive for extended periods of time

21
Q

Old model of CD8 T cell exhaustion

A

Antigen presentation to naive CD8 T cells - Effector CD8 T cells + persistent antigen - CD8 T cell exhaustion

22
Q

New model of CD8 T cell exhaustion

A

Antigen presentation to naive CD8 T cells - Effector and precursor CD8 T cells develop - precursors give rise to memory and exhausted CD8 T cells

23
Q

What is the Key T Cell Factor (TF) involved in CD8 memory cell formation?

A

Transcriptional regulator T cell factor 1 (TCF1)

24
Q

Which T cells display self-renewing capacity?

A

TCF1+ display self-renewing capacity

25
Q

What can naive CD8 differentiate into?

A
  • Naïve CD8 can differentiate into either:
    Effector T cells + TCF1+ central memory T cells
    Exhausted T cells + TCF1+ precursor exhausted T cells
  • This differentiation process is influenced by antigen levels (i.e. high antigen&raquo_space; more TEX and TPEX)
  • In the presence of continuous antigenic stimulation TEX and TPEX cells have a survival advantage
26
Q

Functional Changes of CD8

A

slide 30-31

27
Q

What does Src-homology 2 domain (SH2) contain?

A

Src-homology 2 domain
(SH2)-containing protein
tyrosine phosphatases (PTPs)

28
Q

What does SHP-1 and SHP-2 oppose the function of?

A

Oppose the function of protein tyrosine kinases (PTKs)

29
Q

What is Lck

A

Lck is a protein tyrosine kinase (PTK) that phosphorylates CD3z

30
Q

What do SHP-1 and SHP-2 act to reduce?

A

SHP-1 and SHP-2 acts to reduce CD3z phosphorylation and thereby limit TCR signalling

31
Q

What do exhausted T cells expressand what do these ____ ____ do?

A
  • Exhausted T cells express a range of inhibitory receptors
  • Act to reduce TCR signals
  • A number lead to the activation of SHP-1 and SHP-2
    via ITIMs and ITSMs (switch motifs)
32
Q

LAG3 (also known as CD223)

A

negative regulator of cell cycle progression

33
Q

What is therapeutic targeting of inhibitory receptors referred to as?

A

*Checkpoint inhibition

34
Q

What are targeting inhibitory receptors used for ?

A
  • Used clinically in cancer patients
  • Aims to reinvigorate TEX cells
  • Approved for treatment of melanoma, non-small cell lung carcinoma, head-and-neck cancer,
    urothelial carcinoma, and more
35
Q

What does CTLA-4 do?

A
  • Inhibitory receptor that
    binds CD80 and CD86
  • Competes with CD28 for
    ligands blocking costimulation
  • ectodomain
    competition
  • Limits PI3K and AKT signalling
  • Sequesters target ligands and prevents the optimal
    formation of TCR microclusters and lipid rafts
36
Q

What does Ipilimumab target?

A
  • Targets CTLA-4 blocking the ability of CTLA-4 to
    bind CD80 and CD86
  • Enables signalling via CD28
  • Acts in tumor-draining lymph nodes allowing tumor antigens to be cross-presented by APCs to prime tumorreactive T cells
37
Q

What does Ipilimumab enhance?

A
  • Enhances activation of existing exhausted CD8+ T cells
  • Enhances activation of naïve tumour-specific CD8 and CD4 T cells (lower affinity?)
  • Leads to depletion of CTLA-4+ Treg cells
38
Q

What is PD-1?

A
  • Inhibitory receptor that binds PD-L1 and PD-L2
39
Q

What does the intracellular domain of PD1 contain?

A
  • The intracellular domain of PD1 contains an immunoreceptor tyrosine-based inhibitory motif
    (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM)

*Motifs recruit the tyrosine-protein phosphatases
SHP1 and SHP2

  • SHP1 and SHP2 act to dephosphorylate proximal
    signalling elements following TCR activation
40
Q

Function of Pembrolizumab and Atezolizumab?

A
  • Target PD-1 binding to PD-L1 and PD-L2
  • Restores exhausted CD8 T cell proliferation ability and IL-2
  • Alters metabolic profile of exhausted CD8 T cells and enhances IFNγ
41
Q

Describe LAG-3

A
  • LAG-3 binds to MHC class II
  • Evolutionary related to CD4
  • LAG-3 inhibits TCR signalling
  • Lacks well-defined ITIM or ITSM motifs
  • Inhibitors currently in phase I and II clinical trials to be used in combination with CTLA4/PD1 inhibitors.
42
Q

What is the intracellular domain of LAG-3 essential for?

A

Intracellular domain of LAG-3 is essential for
inhibitory signaling but specific mechanisms are unknown.

43
Q

TIGIT

A
  • T cell immunoreceptor with immunoglobulin and
    ITIM domain (TIGIT)
  • Binds to two ligands, CD155 (PVR) and CD112
    (PVRL2, nectin-2)
  • Limits TCR signalling via ITIM
  • Binds CD155 on DC inducing immunoregulatory DC
    phenotype
  • Competes for CD155 against the activating receptor
    DNAM-1 (CD226)
44
Q

What does the TIGIT blockade directly enhance?

A
  • TIGIT blockade directly enhances CD8 T cell and NK
    cell responses
  • Results in Treg depletion
  • Directs target TIGIT+ cancers, e.g. triple-negative
    breast cancer
  • Currently in phase I and II clinical trials as a monotherapy and as combination therapy
45
Q

What happens when the antigen is removed?

A
  • HCV – Direct acting antivirals can eliminate the virus in >95%
    of patients
  • HIV – Antiretrovirals can suppress viral replication to
    undetectable levels
46
Q

What happens in epigenetic
scarring’?

A
  • Exhausted CD8 T cells no longer have persistent
    signaling via the TCR
  • TEX cell frequencies typically decreased after viral
    control
  • Frequencies of T cells targeting escaped epitopes
    remained stable or even slightly increased after therapy
  • TEX cell maintain PD-1, TIGIT and Eomes expression after antigen removal
  • Function improves but a defect in cytokine expression and cytotoxic functions remains
47
Q

CD4 exhaustion?

A
  • Exhaustion is less defined in CD4 T cells
  • PD1, CTLA4, LAG3, TIM3, TIGIT have all been
    identified on CD4 T cells
  • Associated with reduced cytokine production
  • CD39 is a potential marker of exhausted CD4 T cells
  • CD39+ CD4 T cells express highest levels of TOX

BI405 (ii) (4 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions