T cell effector mechanism Flashcards
1
Q
naïve T cells require two activation stimuli. name them
A
1) binding of TCR to specific peptide antigen:MHC complex
2) co-stimulatory signal supplied by interaction between CD28 (on the T cell) with B7 molecules (expressed by antigen-presenting cells)
2
Q
What is the only cell that expresses B7 molecules?
A
professional APCs
3
Q
When is B7 expression upregulated in APCs?
A
in response to potential infection
4
Q
T/F armed effector T cells require only a single activation stimulus
A
true
5
Q
What is the only activation stimulus needed by armed effector T cells? what is the result?
A
Stimuli => binding of TCR to specific peptide antigen:MHC complex
- when armed effector T cells recognize their specific antigen, they are quickly activated to perform their effector function
6
Q
naïve T cells and effector T cells express a different array of what?
A
adhesion molecules
7
Q
What reflects and defines the roles of adhesion molecules in immune response?
A
expression by naive T cells and by effector T cells
8
Q
naïve T cells must enter the secondary lymphoid tissues via process? Describe this process
A
HEV
mediated by surface adhesion molecules (L-selectin) to have a chance to become stimulated by an antigen presenting cell
9
Q
What keeps naive T cells from entering into inflammatory sites?
A
they do not express the adhesion molecules (VLA-4) required for entry into inflammatory sites
10
Q
Why does it not make sense for naive T cells to be in inflammatory sites?
A
they have no effector functions and no role in the environment
11
Q
What allows armed effector T cells to perform their effector functions?
A
expression of a different array of adhesion molecules
12
Q
Why can effector CD8 T cells not enter secondary lymphoid tissue?
A
effector CD8+ T cells (CTLs) down-regulate expression of L-selectin
13
Q
What allows CTLs to bind to vascular endothelium at sites of inflammation?
A
upregulate expression of VLA-4
14
Q
Why is it important for CD8 T cells not to enter secondary lymphoid tissues?
A
1) they have no role there
2) if they entered secondary lymphoid tissues, they could attack antigen-presenting cells that present their specific peptide antigen
15
Q
What allows CD8 T cells to enter inflammatory sites so they can “target” cells?
A
down-regulation expression of L-selectin
upregulation expression of VLA-4
16
Q
How does effector CD8 T cells initiate interactions between the effector T cells with their potential “target” cells?
A
upregulate expression of cell adhesion molecules (LFA-1 and CD2)
17
Q
Which is not an effector molecule produced by helper T cells?
A
granzymes
18
Q
T/F Both CD4 and CD8 effectors can initiate apoptotic deal of host cells
A
true
19
Q
What promotes differentiation of CD4 Tcell into Th1 type cell?
A
high Ag concentration; IL-12 + IFN-y
20
Q
the effector molecules produced by T cells fall into 2 broad classifications. Describe each of them
A
-
cytotoxins- perforin, granzymes, Fas ligand
* cytotoxins are the principal effector molecules of CTLs -
cytokines - IFN-y, GM-CSF, TNF-a, LT, IL-3, IL-4, IL-5, IL-10, IL-13, TGF-B;
* cytokines are the primary effector molecules for CD4 T cells;
21
Q
What defines the Th1 and Th2 cells?
A
defined by the cytokine profiles they produce
22
Q
Th1 cells produce what type of cytokines?
A
cytokines that upregulate macrophage functions and generally promote cell-mediated immunity
23
Q
Th2 cells produce what type of cytokines?
A
generally promote humoral immune responses
24
Q
Define cytokine and their effects
A
small soluble proteins that can act on the secreting cell, or on a different cell
the effects many cytokines have on cells have been determined
25
What is the primary cytokine produced by CD8 cells? Name its function/role
IFN-y
anti-viral properties and inhibits TH2 cell development
26
TH1 CD4 cells produce what type of cytokines? and name their role/function
IL-2 and IFN-y
lymphotoxin and other inflammatory cytokines
27
Th2 CD4 cells produce what cytokines?
IL-4, IL-5 and IL-10
28
CD4 cells activated in presence of IL-12 and IFN-γ will become
Th1
29
CD4 cells activated in presence of IL-4 and IL-6 will become
TH2 cells
30
What does a Th1 use its cytokines for? name them and overall function
IL-2, IFN-y
* macrophage activation
* B cell activation
* production of opsonizing Abs such as IgG1
31
What does a Th2 use its cytokines for? name them and overall function
IL-4, IL-5
* General activation of B cells to make Abs
32
Describe the differentiation from Th0 cells to Threg cells
33
Describe the differentiation to Th1 cells
34
Describe the diffentiation to Th2 cells
35
antigen presented to TH0 cell influences differentiation pathway. What does low affinity or concentration go toward?
presentation of low affinity or low concentration of Ag \>\>\>\> **TH2**
36
antigen presented to TH0 cell influences differentiation pathway. What does high affinity or concentration go toward?
presentation of high affinity or high concentration of Ag \>\>\>\> **TH1**
37
What is the role of CTLs wrt infection?
destroy infected cells, thereby limiting the infection
38
How do CTLs know how to target the correct cell?
proteins from these **intracellular** parasites (viruses and intracellular bacteria) are **processed and presented on MHC class I molecules to CD8 T cells**
39
When can an effector CD8 T cell initiate killing of the infected cell?
effector CD8 T cell (CTL) recognizes its cognate peptide antigen:MHC complex presented on any cell
40
the 1st step of specific antigen recognition by a CTL (or a CD4 T cell for that matter) is what?
1. interaction of the T cell with the target cell (or APC for CD4 T-helper cells) mediated by cell surface adhesion molecules
2. once in close proximity, interaction between TCR and MHC:peptide complexes can occur
41
T/F TCR must recognize the specific peptide or will disengage
true
42
What does a CTL contain and express that help with the mechanism of cell killing by CTLs?
CTLs contain granules that contain perforin and granzymes;
CTLs also express Fas ligand
43
once a CTL recognizes its specific peptide antigen:MHC complex, what occurs?
it degranulates
44
What are molecules polymerize to form a pore in the membrane of the target cell?
perforins
45
What a detergent like protein that associates with cellular membranes?
granulysin
46
What are serine proteases that activate programmed cell death (apoptosis) of the target cell?
granzymes
47
How do granzymes gain access to the interior of the cell?
repairative endocytosis model via a cation-independent mannose-6-P receptor (CI-MPR)
48
What is the action on the target cells via perforin?
aids in delivering contents of granules into cytoplasm of target cell
49
What is the action on the target cells via granzymes?
Serine proteases, which activate apoptosis once in the cytoplasm of target cell
50
What is the action on the target cells via granulysin?
has antimicrobial actions and can induce apoptosis
51
What is the Fas ligand?
engages with Fas on the target cell, helping to induce apoptosis
52
What increases the chances that an infected cell will be recognized by an antigen-specific effector CTL?
CTLs also produce cytokines (IFN- , TNF- , and TNF- ) that stimulate cells to upregulate expression of proteins involved in antigen presentation to MHC I
53
What is a Th1 cytokine and CTL effector molecule?
IFN-y
54
Describe the process of apoptosis mediated by CD8 cells
1. Fas ligand binds to Fas
2. adaptor proteins recruit and activate caspase 8 which cleaves caspase 3
3. Activated caspase 3 cleaves I-CAD which inhibits CAD (caspase-activatible DNase) that is released into nucleus and cleaves DNA
55
CTLs, as well as T helper cells, become polarized when their TCR is bound to MHC:peptide complexes- why is this important?
this polarization focuses the effector molecules released by the T cell onto its specific target cell
56
How do the CTLs and T helper cells become polarized?
reorientation of the cytoskeleton of the T cell polarizes the T cell so that effector molecules are focused on the target cell
57
What is the most important function of CTLs wrt its mechanism of killing cells?
ability of T cells to focus their effector molecules onto their specific target cells is vital to their function
effector function only on cells that bear the cognate peptide antigen:MHC complex that binds to the TCR of the effector T cell
58
What is the fate of cells targeted by CTLs? What other cell is this similar to?
programmed cell death is the ultimate fate of cells killed by antigen-specific effector CTLs
NK cells
59
What are the 2 stimuli that can cause apoptosis?
mediated by granzymes, which are serine proteases that initiate the programmed cell death pathway
initiated by interaction of Fas on a target cell with Fas ligand (FasL) expressed on effector cells
60
regardless of the initiation signal, all apoptosis initiators lead to what?
activation of a series of cysteine proteases known as caspases
61
the inactive form of CAD (I-CAD) is present in all cells of the body. What inhibits I-CAD to allow for DNA cleaving?
cascade of caspase activity
62
activate macrophages to kill bacteria and other pathogens is an effector function of what cells?
Th1 CD4 cells
63
both signals required to activate macrophages can be delivered by Th1 Cells. What are they?
1. cytokine IFN-
2. CD40 ligand interacts with CD40 (on macrophage)
64
activation of a macrophage leads to a number of biochemical responses by the macrophage (5)
1. •• upregulation of phagosome-to-lysosome fusion which leads to destruction of ingested pathogen
2. •• production of NO and oxygen radicals, both of which have potent anti-bacterial activity
3. •• production of antibacterial peptides and proteases that are released and can attack extracellular parasites
4. •• upregulation of surface molecules; MHC class II molecules, B7 (costimulator for presenting antigen to T cells), CD40
5. •• production of IL-12 which stimulates differentiation of TH0 cells into TH1 T cells
65
What cells coordinate the host response to intracellular pathogens?
TH1 cells
66
How do T cells regulate the activities of
macrophages during a cellular immune response?
T cells produce a variety of cytokines and cell surface markers
67
in response to specific antigen recognition by an effector TH1 cell, the TH1 cell:
1. •• produces IFN- and CD40 ligand which are the signals for activation of macrophages; makes macrophages more bacteriocidal
2. •• produces TNF- apoptosis and Fas ligand; can induce a chronically-infected macrophage to undergo is the 1 required signal
3. •• produces IL-2 which is a growth factor for T cells; can also assist the activation of naïve CD8+ T cells
4. •• produces IL-3 and GM-CSF which induces macrophage differentiation in the bone marrow •• produces lymphotoxin and TNF- which facilitates macrophage binding to epithelium / exit from blood vessel at sites of infection
5. •• produces macrophage chemotactic factor which causes macrophages to accumulate at sites of infection
68
once naive CD4 T cells are activated to differentiate into _what_, they can serve as what?
armed effector TH cells (either TH1 or TH2)
the effector cell that stimulates B cell activation by supplying the 2nd signal of B cell activation
69
most TH2 effector cells reside where?
in the T cell zones of secondary lymphoid tissues
where they can perform their effector functions
70
as naïve B cells migrate thru the T cell zones, what occurs?
effector T cells sample the peptide:MHC class II complexes on their surface.
71
If a helper T cell recognizes its cognate peptide antigen:MHC complex displayed on the surface of a B cell, the effector T cell will do what?
will supply the **second signal of activation** (includes production of cytokines and CD40 ligand) to the B cell
72
the remaining effector TH1 cells recirculate thru secondary lymphoid tissues where they can do what?
can activate antigen-presenting B cells
73
many effector TH1 cells remain in the circulation where they do what?
they patrol and enter tissues at sites of inflammation where they serve as activators of phagocyte activity,
74
effector TH1 cells produce cytokines that stimulate B cell activation and differentiation into cells that produce what? Why are these important?
* antigen-specific antibodies of the IgG1 and IgG3 isotype;
* these isotypes are very important opsonizing antibodies (cell-mediated immunity)
75
Why are the antigen-specific antibodies of the IgG1 and IgG3 isotype important?
these isotypes are very important opsonizing antibodies (cell-mediated immunity)
76
effector TH2 cells produce cytokines that stimulate B cell activation and differentiation into cells that produce what?
antigen-specific antibodies of the IgG2, IgG4, IgA, and IgE isotypes
77
Why are the antigen-specific antibodies of the IgG2, IgG4, IgA, and IgE isotypes important?
neutralization and complement fixation, which are important effector mechanisms for clearing extracellular pathogens
78
T/F CTLs Release Granular Contents in
Polarized Fashion
True
79
TH1 Effector Cells Activate what? What is the ultimate result?
Infected Macrophages
killing of intravesicular bacteria
80
Activated Macrophages Become Better what?
APCs and More Bacteriocidal
81
What acts as the Maestro of Developing Immune Responses?
TH1 Effector Cells
82
If an activated Th1 cell secretes IFN-y and CD40L, what is the result?
activates macrophages to destroy engulfed bacteria
83
Th1 secretes FasL or LT, what is the result?
kills chronically infected macrophages, releasing bacteria to be destroyed by healthy macrophages
84
Th1 secretes IL-2, what is the result?
Induces T cell proliferation thus increasing the number of effector T cells
85
Th1 secretes IL-3 + GM-CSF, what is the result?
induces macrophage differentiation in the bone marrow
86
Th1 secretes TNF-a + LT, what is the result?
activates endothelium to induce macrophage adhesion and exit from blood vessel at site of infection
87
Th1 secretes CXCL2, what is the result?
causes macrophages to accumulate at site of infection
88
What is the effect of IL-2 on T cells?
growth
89
What is the effect of IFN-y on macrophages?
* activation
* increase MHC class I and class II
90
What is the effect of lymphotoxin(LT) and TNF-B on macrophages?
* activation
* induces NO production
91
What is the effect of IL-4 on B cells? T cells?
**B cells**
* activation
* growth of IgG1 and IgE
* increase MHC class II induction
**T cells**
* growth
* survival
92
hat is the effect of IL-3 on hematopoietic cells?
growth factor for progenitor hematopoietic cells (multi-CSF)
93
What is the effect of TNF-a on macrophages?
* activation
* induces NO production
94
What is the effect of GM-CSF on hematopoietic cells?
increase in production of granulocytes and macrophages and dendritic cells
95
How is Signaling Thru Cytokine Receptors done?
1. cytokine receptors consist of at least 2 chains that the cytoplasmic domains bind JAKs
2. cytokine binding dimerizes receptor to bring together JAKs which activate each other and phosphorylate receptor
3. transcription factors (STATs) bind to phosphorylated receptors and phosphorylated by activated JAKs
4. phosphorylated STATs form dimers that move into nucleus to initiate gene transcription
96
What occurs when a microbe resists destruciton by macrophages? What is the function of this?
granuloma
function is to prevent dissemination of microbe
97
Describe a granuloma
multinucleated giant cells that contain mycobacteria are walled of with T cells that cannot be removed
