Ch5: T Cells Flashcards
1
Q
T-cell precursoWrs are made where?
A
Bone marrow
2
Q
T-cell precursors from bone marrow travel where?
A
Thymus to develop
3
Q
Mature T cells leave what?
Where do they go?
A
Thymus
Secondary lymphoid tissues
4
Q
Upon entering the thymus cortex what do T cells do?
A
Begin positive and negative gene selection
5
Q
What cells are immature thymocytes next to? 2
A
Branched cortical epithelial cells
Macrophages
6
Q
The thymus medulla contains what? 4
A
- Mature thymocytes
- medullary epithelial cells
- dendritic cells
macrophages
7
Q
What happens at Hassali’s corpuscles?
A
Cellular destruction
8
Q
Function of macrophages in thymus?
A
Remove T cells that failed to mature
9
Q
A birth, what happens to T-cell producing area of thymus?
A
Replaced with fatty tissue (Involution)
10
Q
3 categories of mature peripheral T cells
A
Long-lived
Self-renewing
Both
11
Q
What receptors do T cells display in the bone marrow? 2
A
CD34
CD44
12
Q
What receptors do T cells display outside of bone marrow? 4
A
CD2, CD5, IL-7, CD1A
13
Q
Can immature T cells outside of bone marrow recognize antigens?
A
No
14
Q
T cell gene rearrangement occurs where?
A
Thymus
15
Q
Why is T cell diversity greater?
A
T cells aren’t replenished throughout life
16
Q
The Fab fragment of an antibody is similar to what?
How so? (2)
A
TCR
- 2 chains with variable and constant regions
- Antigen recognition occurs at tip of variable region
17
Q
Major differences of Ab and TCR?
A
- Antibody monomers can bind 2 antigens simultaneously
- Antibodies recognize antigen in their native conformation
- Antibody recognition does not require processing and presentation of antigen
- MHC restriction is not required for antibodies
- Antibodies function as effector molecules while TCR is a receptor that activates an effector cell
18
Q
What is the signaling that initiation maturation upon a T cell arriving in thymus?
A
Notch-1 Signaling
19
Q
Describe Notch-1 signaling 4
A
- Notch-1 on thymocytes interact with Notch ligand on thymic epithelial cells
- Transcription repressors removed from thymocyte DNA
- Transcription co-activators attracted
- Transcription and maturation of T Cells occurs in thymus
20
Q
Upon T cells arriving in Thymus, what rearrangement can occur?
A
Beta, Gamma and delta
21
Q
Two possibilities of t cell rearrangement?
A
- Gamma and delta chains rearrange forming gamma:delta mature T cell that leaves the thymus
- Beta chain rearranges forming a pre-TCR. Induced expression of CD4 and CD8. Rearrangement resumes of alpha, gamma, and Beta genes
22
Q
The pre-T cell Beta chain is tested where?
Using what?
A
Cell surface
Surrogate alpha chain known as pTalpha
23
Q
The pre-T cell receptor is expressed when?
A
In context of signaling molecules that are required for T cell activation (CD3 complex)
24
Q
Once an appropriate Beta chain has been identified in pre-T cell receptor, what occurs?
A
Removed from cell surface and rearrangement of alpha chian is induced
25
What are genes specific to T cells? 4
Zap-70, CD3, CD4, CD8
26
Positive selection of alpha:beta T cells is done by what cells? Where?
Cortical epithelial cells
| Thymus
27
alpha:beta t cells are positively selected by recognition of what?
Self-MHC
28
Upon being positively selected, what is status of T cell?
Double positive: Has both CD4 and CD8 expressed
29
What aids in the formation of double-positive T cells?
Cells in thymus that express both MHC-I and MHC-II
30
What determines whether the T cells will commit to CD8 or CD4 type cell?
If the TCR expressed by the double-positive thymocyte interacts with MHC-I or MHC-II
31
Negative selection is what?
Removal of T cells that recognize self peptide
32
What TF turns on expression of non-thymic self antigens in thymus?
What does this allow for?
```
Autoimmune Regulator (AIRE)
Negative selection based on reactivity toward self tissue-specific antigens from tissues they might not otherwise see
```
33
Central tolerance is derived from what?
Negative selection of T Cells
34
Do self-reactive T cells exist in circulation?
Small amounts in ALL individuals
35
Self-reactive T cells recognize what?
| What does this allow them to become?
Self antigens expressed by self MHC
| Regulatory T Cells (Tregs)
36
Do Tregs proliferate?
| What do they produce?
No
Produce cytokines that suppress activity of other self-reactive T cells that have bound to the same MHC:peptide complex on the same APC
37
Steps in T cell maturation in thymus 5
1. Double-negative CD3 thymocytes in subcapsular zone proliferate and differentiate into double positive CD3 thymocytes
2. In the cortex, positive selection occurs
3. In the cortex, negative selection occurs to form mature, self-restricted, self-tolerant, single-positive CD4 or CD8 T cells
5. Leave the thymus through the blood
38
Naive mature T cells enter what?
Lymph nodes
39
If the T cell encounters its specific antigen, what happens?
T cell activates leading to proliferation and differentiation
40
T cells that do not recognize their specific peptide travel where?
Other lymph nodes and eventually re-enter circulation via efferent lymphatics
41
How are T cells attracted to lymph node?
Chemokines CCL21 and CCL19 are secreted by stromal and dendritic cells in lymph node cortex
42
What receptor must T-cells have to use the cytokines expressed by cortical lymph node cells?
CCR7
43
The initial interaction associated with the homing of T cells to the lymph node is between what?
Mucin-like vascular addressins (CD34 and GlyCAM-1) which bind L-selectin on T cells
44
L-selectin has what function?
Homes mature, unactivated T cells to lymph nodes
45
Steps of T cell entering lymph node? 5
1. Circulating T cell enters high endothelial venule
2. L-selectin on T cell binds to endothelial CD34 and GlyCAM-1 and starts rolling interaction
3. LFA-1 on T Cell activated by chemokines bound to ECM.
4. Activated LFA-1 binds to ICAM-1
5. Diapedesis occurs and T cell enters lymph node
46
After T cell enters the lymph node, it interacts with what?
Professional APC's
47
Initial interactions between T cells and DC's are mediated by what? 4
1. CD2 of T cell binds to LFA-3
2. LFA-1 of T cell binds to ICAM-1
3. LFA-1 of T cell binds to ICAM-2
4. ICAM-3 of T cell binds to DC-SIGN
48
Are APC and T cell interactions transient?
Yes so the T cell can move through lymph node
49
T cells scan APC's for what?
MHC expressing peptide that it recognizes
50
When the TCR and CD4 bind to the MHC, what happens?
Signal transduced to LFA-1 changing its conformation resulting in greater affinity for ICAM-1 that prolongs cell-cell contact
51
What is the immunological synapse?
Gathering of receptors on surface of an APC and a T Cell that work in coordinated effort to prolong their interaction and strengthen the signals associated with activation of T cell by APC
52
What induces expression of MHC-II peptide and B7 co-stimulatory molecule by the APC?
Phagocytosis of a pathogen
53
What is the first signal required for T cell activation?
TCR activation with peptide:MHC
54
Second signal required for T cell activation?
B7 co-stimulatory molecule interaction with CD28
55
B7 co-stimulatory molecules are known as what?
CD80 and CD86
56
What else can activated T cells express that will bind B7?
| Result of this?
CTLA4
CTLA4 acts as antagonist that dampens activation and limits proliferation of activated T cells
57
When an antigen binds the antigen-specific B- cell receptor, the B cell expresses what?
Why?
B7 on the surface
| To interact with CD28 on T cells
58
The T cell receptor recognizes what on the B cell?
| And then expresses what?
Peptide:MHC complex
CD40 ligand
59
CD40 ligand on the T cell binds to what?
| Which provides what?
CD40 on the APC
| Second signal of activation of the APC
60
Activation of a B cell by foreign antigen can provide signals for T cell activation which leads to what?
further APC activation and induction of a cellular
| response (antibody production).
61
How do co-stimulatory molecules differ between APC's when interacting with T Cells?
They don't
62
Do cytokines produced and cellular functions differ between APC's when interacting with T cells?
No
63
The T cell receptor is similar to the B cell receptor in what respect?
too weak to signal by itself
64
The complete TCR has acessory proteins called what?
CD3 complex
65
The CD3 complex is made up of what chains? 4
2 ε chains
one δ chain
one γ chain
2 ζ (zeta) chains
66
Each signal chain of CD3 complex has what?
| Which have what action done to them?
ITAM's (immunoreceptor tyrosine-based activation motifs)
phosphorylated by kinases
67
Helper T cells express which Co-Receptor?
CD4
68
Cytotoxic T cells express which co-receptor?
CD8
69
Both CD4 and CD8 T cells express what? (2)
TCR and CD3 on their surface
70
Uptake of antigen by a professional APC induces expression of what?
Co-stimulatory molecule B7
71
What leads to T cell activation?
TCR and its co-receptor recognize specific peptide:MHC
72
What keeps T cell and APC in close proximity?
LFA-1:ICAM-1
73
What signals survival of T cell
CD28 of the T cell interacting with B7 of APC
74
The IL-2 receptor on naive T cells is made up of what? (2)
Gamma and Beta chain
75
The IL-2 receptor on naive T cells has a low affinity for what?
IL-2
76
Upon activation, T cells express what? (2)
IL-2
| IL-2 receptor alpha subunit
77
What does the IL-2 receptor alpha subunit do upon synthesis?
binds with the b and g chains to increase the affinity of the IL-2 receptor for IL-2.
78
What is signaled when IL-2 binds to IL-2 receptor?
signals the antigen-specific T cells to proliferate to produce multiple clones.
79
Activated, effector T cell clones no longer require what?
costimulatory molecules to act on cells they recognize.
80
What are 3 possibilites of results of interaction between APC and T cell?
1. Activation of T cell
2. Anergization of T cell
3. No effect on T cell
81
What must happen for T cell to activate?
Co-stimulatory signal and specific signal are both encountered by the T cell
82
What causes a T cell to anergize?
Specific signal alone is encountered
83
Why does a T cell anergize in response to specific signal only?
so that it does not respond to a potential self antigen
84
What would APC-T cell interaction would have no effect on T cell
If only co-stimulatory signal is encountered. (no antigen = no attack)
85
What do activated T cells turn off at their surface? 2
L-selectin
| CD45RA
86
What do activated T cell turn on at their surface or increase expression of? 5
```
VLA-4
LFA-1
CD2
CD44
CD45RO
```
87
After encountering an antigen in the lymph node, what must effector T cells do?
Move to site of infection
88
What integrin does a T cell have to help it more out of node?
VLA-4
89
VLA-4 of T cells interacts with what?
VCAM-1
90
Where is VCAM-1 expressed?
activated endothelium around inflamed tissue
91
Two types of effector T cells?
CD4 Helper
| CD8 CTL
92
Two types of memory T cells?
CD4
| CD8
93
CD4 cells do what
Activate other cells like macrophages and B cells
94
CD8 cells do what? 2
Kill infected cells
| Activate macrophages
95
Two phases in the kinetics of T cell responses?
1. Clonal expansion
| 2. Contraction
96
7 Main steps of T cell activation starting with antigen recognition?
1. Antigen recognition in lymphoid organs
2. T cell expansion and differentiation
3. Differentiated effector T cells enter circulation
4. Migration of effector T cells and other leukocytes to site of infection
5. Effector T cells encounter
97
Cytokine receptors use what pathway of signaling?
JAK/STAT
98
Explain the steps of cytokine receptor actions
1. Cytokine receptors of at least two chain bind JAK's
2. Cytokine binding dimerizes the receptor bringing together the cytoplasmic JAK's
3. Cytoplasmic JAK's activate each other and phosphorylate the receptor
4. STAT's bind to the phosphorylated receptors
5. STAT's are then phosphorylated by activated JAK's
6. Phosphoarylated STAT's form dimers
7. STAT dimers move to nucleus to initiate gene transcription
99
What tells T cells what lineage they will commit to?
APC's
100
What allows T cells that are specific for a pathogen to be flexible in the type of effect that they will induce?
The ability to change phenotypes
101
Signature cytokines of Th1 cells
IFN gamma
102
Signature cytokines of Th2 cells? 3
IL-4
IL-5
IL-13
103
Signature cytokines of Th17 cells? 3
IL-17A
IL-17F
IL-22
104
Immune reactions of Th1 cells? (2)
1. Macrophage activation
| 2. IgG production
105
Host defense of Th1 cells?
Intracellular microbes
106
What diseases do Th1 cells play a part? (2)
1. Autoimmune disease
| 2. Chronic infections
107
Immune reaction of Th2 cells? (3)
1. Mast and eosinophil activation
2. IgE production
3. Alternative macrophage activation
108
Host defense of Th2 cells?
Helminthic parasites
109
Th2 have role in what diseases?
Allergic diseases
110
Immune reactions of Th17 cells?
1. Neutrophilic
| 2. Monocytic inflammation
111
Host defense role of Th17 cells?
Extracelular bacteria
| Fungi
112
Th17 have a role in what types of diseases?
Autoimmune and inflammatory diseases
113
Cytokiens produced during Th1 have what effect on Th2 response?
Inhibit it
114
Cytokines produced during Th2 have what effect on Th1 response?
Inhibit it
115
A macrophage infected with an intracellular bacteria expresses what on its surface?
And produces what cytokine?
Bacterial peptides bound to MHC-II
IL-12
116
IL-12 induces what?
Th1 response
117
The Th1 cell expresses what ligand on its surface?
CD40
118
Th1 responds to IL-12 how?
| Which then has what effect?
Produces IFN-gamma
Tells macrophage to kill bacteria in its vesicles
119
Two things that tell an APC to kill whatever bacteria it has inside it?
1. CD40 of T cell binding to CD40L of APC
| 2. IFN-gamma produced by CD40 binding
120
Mycobacteria can survive in macrophages for what reason?
resisting the killing activity of Th1 cells
121
Mycobacteria living in a macrophage cause formation of what?
multi-nucleated giant cell made up of
| multiple fused macrophages that contain mycobacteria
122
What defines a granuloma?
presence of these multi-nucleated giant cells surrounded by T cells, many of which are CD4
123
Th1 cell releases what cytokines and ligands?
1. IFN-gamma and CD40
2. Fas ligand or LT
3. IL-2
4. IL-3 and GM-CSF
5. TNF-alpha and LT
6. CXCL2
124
Effect of Th1 releasing IFN-gamma and CD40?
Activate macrophage to destroy engulfed bacteria
125
Effect of Th1 releasing Fas ligand or LT?
Kills chronically infected macrophages
126
Effect of Th1 releasing IL-2
Induces T-cell proliferation which increases the number of effector T cells
127
Effect of Th1 releasing IL-3 and GM-CSF
Induces macrophage differentiation in bone marrow
128
Effect of Th1 releasing TNF-alpha and LT?
Activates endothelium to induce macrophage adhesion and exit from blood vessel
129
Effect of Th1 releasing CXCL2?
Causes macrophages to accumulate at site of infection
130
Antigen recognition of a Th2 cell results in what being expressed? (4)
1. CD40 ligand
2. IL-4
3. IL-5
4. IL-6
131
Can polysaccharides be presented to T cells?
No
132
How do we get immunity to polysaccharides in steps?
1. B cell binds bacterial polysaccharide component of vaccine conjugate
2. Conjugate is internalized and degraded
3. Peptides from the toxoid are presented to the T cell which activates the B cell
4. Activated B cell differentiates into a plasma cell that produces anti-polysaccharide antibodies that bind to bacteria
133
At the end of B and T cell interaction with a polysaccharide what is each cell specific for?
B cell: Polysaccharide
| T-cell: the toxoid
134
What is needed for activation of CD8 T cells? 2
1. APC or tissue cell with microbe infection
| 2. Co-stimulation from cytokines
135
3 general steps of CD8 T cell action?
1. Antigen binding and recognition of CTL to target cell
2. CTL activation and granule exocytosis
3. Apoptosis of target cell
136
3 main cytotoxins released by CD8 T cells?
1. Perforin
2. Granzymes
3. Granulysin
137
What does perforin do?
Forms pores in cell membranes of target cells
138
What do granzymes do?
Serine esterases that enter the cytoplasm of target cells inducing apoptosis
139
What does granulysin do?
Membrane-perturbing protein that works with perforin and serglycin to form pores in target cells.
140
How do CD4 and CD8 cells work together?
CD4 cells activate killing of microbes in phagolysosomes
| CD8 then kills the infected cell
141
4 steps in T cell development from bone marrow to thymus to periphery
1. T-cell precursor rearranges its T cell receptor genes in thymus
2. Immature T cells that recognize self MHC receive signals for survival (too strong of recognition and cells are also removed)
3. Mature T cells encounter foreign antigens in peripheral lymphoid organs and are activated
4. Activated T cells proliferate and migrate to peripheral sites to eliminate infection
142
```
If a thymocyte has weak recognition of class II MHC + peptide it undergoes what?
To become what?
```
Positive selection
| Mature CD4 T cell
143
```
If a thymocyte has weak recognition of class I MHC + peptide it undergoes what?
To become what?
```
Positive selection
| CD8 T cell
144
```
If a thymocyte has no recognition of class I MHC or class II + peptide it undergoes what?
To become what?
```
Fails to go through positive selection
| Apoptosis
145
```
If a thymocyte has strong recognition of class I MHC or class II + peptide it undergoes what?
To become what?
```
Negative selection
| Apoptosis
146
Naive T cells use L-selectin to bind to what on endothelial cell?
Function of this?
L-selectin ligand
| Adhesion of naive T cells to HEV in lymph node
147
Naive T cells use LFA-1 to bind to what on endothelial cell?
| Function of this?
ICAM-1
| Stable arrest on HEV
148
Naive T cells use CCR7 to bind to what on endothelial cell?
| Function of this?
CCL19 or CCL2
| Activation of integrins and chemotaxis
149
Activated T cells use E and P selectin ligands to bind to what on endothelial cell?
Function of this?
E or P selectin
Weak adhesion of effector and memory T cells to cytokine-activated endothelium at peripheral site of infection
150
Activated T cells use LFA-1 or VLA-4 ligands to bind to what on endothelial cell?
Function of this?
ICAM-1 or VCAM-1
| Stable arrest on cytokine activated endothelium
151
Activated T cells use CXCR3 to bind to what on endothelial cell?
Function of this?
CXCL10
Activated of integrins and chemotaxis
152
Cytokines that CD8 cells release at target cell? (2)
IFN-gamma
| LT
153
Cytokines that Th1 cells release at target cell? (5)
```
IFN-gamma
GM-CSF
TNF-alpha
LT
IL-3
```
154
Cytokines that Th2 cells release at target cell? (5)
```
IL-4
IL-5
IL-10
IL-13
TGF-beta
```
155
Action of IL-2?
Survival, proliferation, and differentiation of effector and regulatory T cells
156
Effect of IL-4?
B cell switching to IgE
157
Effect of IL-5
Activation of eosinophils
158
Effect of IFN-gamma?
Activate macrophages
159
Effect of TGF-Beta?
Inhibition of T cell activation
| Differentiation of regulatory T cells
160
Two main Th1 cell responses to antigen?
1. Classical macrophage activation (IFN-gamma)
| 2. Complement binding and opsonizing IgG antibodies (IFN-gamma)
161
5 main responses of Th2 cells to antigen?
1. Antibody production (IL-4)
2. Mast cell degranulation (IL-4)
3. Intestinal mucus secretion and peristalsis (IL4 and IL13)
4. Eosinophil activation (IL-5)
5. Alternative macrophage activation (IL4, IL13)
162
3 main responses of Th17 cells to antigen?
1. Inflammation neutrophil response (IL-17)
2. Antimicrobial peptides (IL-17 and IL-22)
3. Increased barrier function (IL-22)
