Lecture 14 - Differentiation and Functions of CD8+ T cells Flashcards
(107 cards)
1
Q
All T lymphocytes have what marker?
A
CD3 (TCR)
2
Q
All T cells are derived from what?
A
Thymus
3
Q
Helper T cells have what marker?
A
CD4
4
Q
CTLs have what marker?
A
CD8
5
Q
What is the typical percentage of Th and CTLs in blood?
A
Th - 66%
CTLs - 33%
6
Q
T cells make up what percentage of all lymphocytes in the blood?
A
70%
B cells comprise the remaining 30%
7
Q
CD8+ T cells are activated where and by what cells?
A
In the LN and by dendritic cells loaded with Ags exactly as CD4+ T cells are.
8
Q
What do CTLs recognize?
A
Class I MHC-associated peptides
9
Q
Once CTLs are activated, what follows?
A
They proliferate and leave the LN
10
Q
CD8+ T cells are activated by mechanisms that involves what?
A
Cross-presentation of antigens to CD8+ T cells
11
Q
Cells infected with intracellular microbes, such as viruses, are ingested by what?
A
DCs
12
Q
CD8+ T cells are class ___ MHC- restricted
A
I
13
Q
Naive CD8+ T cells recognize what?
A
Peptide Ags presented by DCs in the lymph nodes
14
Q
CD*+ T cells are stimulated to do what?
A
Proliferate and differentiate into CTLs (and memory cells)
15
Q
Once CTLs are activated the enter what?
A
The circulation and migrate to the site of Ag
16
Q
CD8+ CTLs recognize the Ag at the site of Ag in the tissues and respond how?
A
By killing the target cells where the Ag is produced
17
Q
The naive CD8+ T cells, like all naive T cells, are activated by what?
A
Ags presented by DCs
18
Q
Ags recognized by CD8+ T cells may be from what?
A
Viruses or tumors derived from a variety of cell types
19
Q
The process of cross-presentation is critically important for what?
A
Ag presentation by professional APCs within class I MHC
20
Q
Exogenous Ags derived from ingested infected cells, tumor cells, or their proteins are transferred into the cytosol for processing, loading and presentation on what?
A
Class I MHC molecules
21
Q
What is the first signal for the activation of naive CD8+ cell?
A
Recognition of Ags
22
Q
What is the second signal for the proliferation and differentiation of CD8+ cells into effector CTLs?
A
CD28-CD80 costimulation
23
Q
Activated CTLs contain numerous amounts of what?
A
Granules called lysosomes
24
Q
What do granules contain?
A
Perforin and granzymes used by the cells to kill other cells
25
What do activated CTLs secrete?
Cytokines, mostly IFN-γ, that potently activate macrophages
26
Similar to the activation of Th1 cells, the molecular events in CTL differentiation involve what TF?
T-bet
27
What does T-bet regulate?
Transcription of genes encoding perforin, granzymes, and IFN-γ
28
What provides signal 3 in the form of cytokines which enhance activation of CTLs?
CD4+ helper T cells
29
Of particular importance, CD4+ helper T cells are required for CD8+ T cells responses when?
Relatively weak innate immune reactions are evoked by laten viral infections, organ transplants, and tumors
30
Evidence suggests that CD4+ helper T cells are more important for the generation of what ?
CD8+ memory T cells than for the differentiation of naive CD8+ T cells into effector CTLs
31
Licensing of the APC occurs when?
The CD4+ T cell recognizes Ag presented by an MHC class II+ APC
32
Licensing of APC delivers activating signals through what?
CD80/CD86 and CD40
33
Activated CD4+ Th cells express what?
CD40L
34
What does CD40L bind to?
To CD40 on Ag-loaded DCs
35
What does the CD40-CD40L interaction upregulates?
Expression of CD80/CD86 on professional APCs which makes them more efficient at sitmulating the differentiation of CD8+ T cells
36
True or False?
| IT is required for CD4+ and CD8+ T cells should come in contact with APC at the same time?
FALSE
37
What role does IL-2 play in the activation of CD8+ T cells into CTLs and memory cells?
It promotes the proliferation and differentiation
38
What may CD8+ T cells express at high levels after activation?
α subunit of IL-2R
39
The IL-2 shares a common receptor component (the γ chain) with what?
IL-15 and IL-21
40
IL-12 and Type I IFNs stimulate what?
The differentiation of naive CD8+ T cells into effector CTLs
41
Naive CD8 T cells proliferate in response to what? What is needed for survival and development for optinal effector functions?
TCR and CD28 signals, but require IL-12 or type I IFN for survival and development of optinal effector functions
42
IL-15 may be produced by what cells?
DCs and tissue Mo
43
What is IL-15 important for?
The survival of memory CD8+ T cells
44
Mice laking IL-15 showed what?
Significant loss of memory CD8 T cells
45
IL-21 produced by activated CD4 T cells play a role in what?
Induction of CD8 T cell memory and the prevention of CD8 T cell exhaustion
46
What was IL-2 originally known as?
T cell growth factor due to its effects on T lymphocyte activation and proliferation
47
What is a major feature of IL-2?
Autocrine loop through which it operates
| *15 kDa polypeptide
48
Local release of IL-2 can lead to what?
Activation of T cells which results in massive upregulation of production of both the cytokine and its receptors
And the activation of nearby CD8 T cells in a paracrine fashion
49
IL-2 shares a common receptor component with what other cytokines?
IL-4, 7, 9, 15, 21
50
What is a key cytokine produced by activated DCs and Mo?
IL-12
51
IL-12 has a profound effect on what?
Inducing naive CD4 T cells to differentiate into Th1 effector cells
52
The balance of IL-12 and IL-4 during naive CD4 T cell activation thus determines what?
Whether these cells become Th1 or Th2
53
IL-12 promotes the production of what cytokines?
Pro-inflammatory cytokines IFN-γ and TNF-β by CD4 and CD8 T cells
54
IL-12-stimulated CD8 T cells are more effective in what?
| What do they maintain?
Controlling tumor
| Maintain high numbers and function as compared to type I IFNs-stimulated cells
55
IL-12 assists in prevention of what?
CD8 T cell exhaustion
56
IL-12 also activates ___ cells
NK
57
The primary source of IL-15 is what?
Activated tissue Mo and Mature DCs
58
IL-15 has similar biologic properties with what cytokine?
IL-2, which is consistent with their shared receptor (R) signaling componets
59
IL-15 was first identified as what?
T-cell growth factor through its ability to promote the proliferation of CTL cells
60
Exogenous IL-15 favors what?
Human Th1 T-cell differentiation in vitro
61
IL-15 acts as a potent _________ for T cells isolated from human blood.
Chemoattractant
62
IL-15 stimulates proliferation of what?
memory CD4 and CD8 and naive CD8 T cells
63
IL-15 has been shown to costimulate what?
Innate immune IFN-γ production
64
IFN-γ is a homodimer composed of subunits of approximately ___ kDa
25
65
IFN-γ is released by what cells?
Th1, CTLs, activated NK cells
66
INF-γ is a potent activator of what?
Mo
| inducing an increase in metabolic, phagocytic and killing activity
67
INF-γ has the ability to increase expression of what?
```
MHC class I on a range of cell types
MHC class II on professional APCs
```
68
IFN-γ may be an important component of antiviral protection, since it does what?
Up-regulates Ag presentation of viral targets by infected cells
69
IFN-γ favors the development of what cells?
Th1 cells and B cell differentiation biasing the production of immunoglobulin in favor of IgG and away from IgE
70
In acute infections, CD8 T cells differentiate into what?
CTLs that eliminate the infected cells
71
Activated CTLs secrete what?
Pro-inflammatory TNF-β, IFN-γ, and cytotoxic perforin and granzymes
72
After viral clearance, the CD8 T cells undergo what?
Extensive contraction phase, mediated by apoptosis
73
In some chronic viral infections, the responses of CD8 T cells may be initiated but gradually extinguished. This phenomenon is called what?
Exhuastion
74
Exhaustion is an active ______ of immune responses first described in a chronic viral infection
suppression
75
Exhausted CD8 T cells show reduced production of what? What has its expression increased?
IFN-γ - reduced
| PD-1 inhibitory receptor - increased
76
Inhibitory signals from PD-1 block what?
The activation of CTLs
77
PD-1-mediated T cell exhaustion may contribute to what?
Chronicity of HIV and hep C virus
78
Anti-PD-1 Abs are effective in what?
immuno-therapy of tumors
79
CTL-mediated cytotoxicity involves what?
Specific TCR-dependent recognition and induction of apoptosis in target cells
80
Interaction of TCR with Class I MHC brings CTL and the target cell in close contact which results in what?
The formation of the immunologic synapse
81
The immunologic synapse ensure what?
That normal bystander cells are not injured by CTLs reacting against infected cells
82
What is secreted from CTLs into the synapse that performs the killing and cannot diffuse to other nearby cells?
Perforin and granzymes
83
True or False
| CTLs themselves are not injured during the killing of targets
True
84
How are target cells killed involving perforin and granzymes?
Complex of perforin and granzymes are released form the CTL by granule exocytosis and enter target cells
The granzymes are delievered into the cytoplasm of the target cells by a perforin-dependent mechanism, and they induce apoptosis
85
How are target cells killed by FasL?
FasL is exdpressed on activated CTLs, engages Fas on the surface of target cells, and induces apoptosis
86
Granzymes A, B and C are what?
Serine proteases
87
Which Granzyme is the only one shown to be required for CTL cytoctoxicity in vivo?
B
88
Describe perforin?
A membrane-perturbing molecule that is homologous to the C9 complement protein
89
The granules also contain a sulfated proteoglycan serglycin which serves to do what?
Assemble a complex containing granzymes and perforin
90
Perforin insertion into target cell membrane elicits what?
Membrane repair process, which leads to internalization of both the perforin and granzymes into endosomes
91
When in target cell, what does granzyme B do?
Activates caspase-3 that triggers apoptosis
92
Binding of FasL to Fas recruits what?
procaspase-8 .
93
What converts the procaspase-8 into caspase-8?
FADD adaptor
94
In type-I cells such as thymocytes, caspase-8 can directly cleave what?
Caspase-3
95
In type-II cells such as virus-infected hepatocytes, caspase-8 cleaved what? What results from this?
Cleaves Bid
| The truncated Bid stimulates the release of cytochrome c from mitochondria
96
Macrophage activation by Th1 cells is an important immune mechanisms for eliminating what?
Bacteria which can resist lysosomal degradation
97
Cytochrome c, togehter with apoptotic peptidase activating factor 1 (Apaf-1) and ATP goes on to activate what?
Caspase -9
98
What does caspase - 9 activate?
Caspase -3
99
What is one of the substrates of caspase-3?
ICAD (inhibitor of caspase-activated DNase)
100
Th1 cells make Il-3 and GM-CSF, which does what?
Stimulate macrophage production in the bone marrow
101
Cleavage of ICAD by caspase-3 activates what?
CAD, which causes DNA degradation in nuclei
102
HIV specific CD8+ effector T cells produce chemokines and cytokines in order to do what?
eliminate infected cells
103
CD4+ T helper cells help to stimulate both dendritic cells and CD8+ T cells to maintain what?
CD8 T cell memory response
104
CD8 T cells cooperate with what in the defense against intracellular microbes?
CD4 T cells
105
Intracellular bacteria such a L. monocytogenes are phagocytized by Mo but what may happen?
They may survive in phagosomes and escape into the cytoplasm
106
CD4 T cells respond to class II MHC-associated peptide Ag derived from the intravesicular bacteria produce what cytokines?
IFN-γ and IL-2
107
CD8 T cells respond to what?
Class I - associated peptides derived from cytosolic Ags and kill the infected cells
