Lecture 1 Flashcards
(89 cards)
1
Q
T-cell recognize only ONE specific non-self peptide. However, there is a large TCR repertoire made up by many T-cells generated in the body so that we can recognize ANY antigens. When does this process occur?
A
This occurs during normal thymus development. T-cells are eliminated if they react with self-antigens or kept to survive if they do not.
2
Q
CD4+ T helper cells will recognize antigens to presented on MHC Class II molecules that are expressed on what cells?
A
- Dendritic cells 2. Macrophages 3. B-cells
3
Q
What are the two phenotypes of CD4+ T- helper cells?
A
Th1 Th2
4
Q
CD8+ cytotoxic T cells recognize peptides on MHC Class I molecules. What is their action?
A
They kill host cells that are infected with pathogens and then activate macrophages.
5
Q
What part of the MHC Class II and MHC Class I molecule for T cells bind to?
A
The non-polymorphic part.
6
Q
Where do naive T-cells circulate through?
A
The lymph node.
7
Q
When do naive T cells activate?
A
When they encounter a antigen.
8
Q
What transports antigens to the lymph nodes?
A
mature (activated) dendritic cells
9
Q
Naive T cells will interact how with antigens?
A
They will interact with many different DC’s until they find the antigen for their TCR.
10
Q
Once naive T-cells are activated, what do they do?
A
They become EFFECTOR CELLS and then: 1. Stay in the lymphoid organ and help B-cells. 2. Go to sites of infection and help activate macrophages.
11
Q
What are the phases of T-cells responses?
A
- Naive T-cells circulate throughout the LN.
- Dendritic cells bring antigens to the LN.
- Naive T-cells search through the DC until they find an antigen that they match with.
- Naive T cell is activated by [antigen+co-stimulatory signal]. What happens next depends on the type of T-cell.
- A. CD4+ Helper T-cell–> IL2–> Clonal expansion (proliferation) and differentiation–>
- CD4+ effector T helper cells will activate macrophages, B cells and other cells
- Memory CD4+ T cells
- B. CD8+ T-cells–> proliferate and differentiate –>
- CTL cells–> kill infected host and activate macrophages
- CTL Memory cells
12
Q
When a T cell recognizes the antigen+costimulatory signal, what responses do the T-cells make?
A
- Proliferation 2. Differentiation into effector and memory cells 3. Cytokines are secreted
13
Q
After the antigen is eliminated, does the number of effector T-cells increase, decrease or stay the same?
A
They will decrease. As a result, we will only be left with memory-T cells
14
Q
In order for T-cells to proliferate and differentiate into an effector signals, we need three signals. What are they?
A
First signal- Antigen Second signal- Costimulation Third signal- Cytokine ACC
15
Q
In order to activate a NAIVE T cell, it must recognize an antigen that is presented by what kind of cells?
A
ONLY a dendritic cell.
16
Q
In order to activate a EFFECTOR T-cell, it must recognize antigens that are presented by what kind of cells?
A
Tissue macrophages and B-cells
17
Q
When a TCR recognizes an antigen, there are inhibitory and activating signals. What is the inhibitory signal?
A
CTLA4: CD80/86 (B7-1, B7-2)
18
Q
When a TCR recognizes an antigen, there are inhibitory and activating signals. What is the activating signal?
A
CD28: CD80/86
19
Q
What is CD28?
Where it is located and what does it bind to?
A
CD28 is a co-stimulator involved in signal transduction.
Located on T-cells and binds to CD80/86 (B7-1/B7-2) that is located on APCs.
20
Q
How do T-cells adhere with APCs?
A
LFA-1: ICAM-1
ICAM-1 is located on APCs and endothelium.
21
Q
What do CD4 or CD8 co-receptors on the T-cells do?
A
CD4 co-receptor binds to class II MHC on APCs and helps with signal tranduction.
CD8 co-receptor is binds to class I MHC on all nucleated cells and helps with signal transduction.
22
Q
What is CD3?
A
T-cell signaling complex.
23
Q
What are ITAMs?
A
ITAMs (immunoreceptor tyrosine-based activation motifs) are parts of the signaling complex
- whose tyrosine residues get phosphorylated
- where [tyrosine kinases] attach.
24
Q
What are ITIMs?
A
ITIMs (Immunoreceptor tyrosine based inhibitory motifs) are part of the signaling complex where [tyrosine phosphotases] bind.
They are located on the cystolic tails of PD-1, which have an inhibitory function.
25
What are co-stimulatory molecules?
Co-stimulatory molecules are located on APCs after they encounter pathogens. They bind to the co-stimulatory receptor that is on the naive T-cell and help to promote the response of the pathogen.
26
What are adhesion molecules?
They help T-cells bind stronger with APCs.
27
What are superantigens (SAgs)?
(SAgs) made by some bacteria are the most powerful T-cell mitogens. They are **not peptides**. Only **0.1pg/ml** of the SAg needs to bind to the T-cell in an uncontrolled manner and it will result in fever, shock and death due to toxic shock syndrome.
28
Where do SAgs bind?
1. SAgs glue both the [MHC class II molecules] and SOME [V-region of the B subunit] of the TCR at the same time. This activates T-cells. Because SAgs are not peptides, they do not bind to the peptide binding groove.
2. When the SAg bind, this causes the T-cells to make a massive amount of pro-inflammatory cytokines (TNF, IL-1 and IL-2)
3. Can cause shock
29
30
Example of bacterial SAg?
Staphylococcal enterotoxins (SE)- causes food postening
Toxic Shock Syndrome Toxin (TSST)
31
Signal 2 is costimulation. Explain this process.
1. Immature DC's have ____ levels of co-stimulatory molecules.
2. What happens when an antigen is recognized, but there is no co-stimatulation?
3. What causes DC's to express co-stimulator molecules?
1. Immature DC's have a low levesl of co-stimulatory molecules. Pathogens or cytokines in the innate immune system will trigger DC's to make co-stimulatory molecules
2. When an antigen is recognized without co-stimulation, it may make the T-cell unresponsive or anergic (tolerant)
32
Activated APC's have increased expression of co-stimulators and secrete cytokines.What is an example of the cytokine secreted? (signal 3)
IL-12- causes naive T-cells--\> Th1 type of effector T-helper cells.
33
Example of co-stimulators molexules
CD80/CD86
34
T-cell co-stimulation by CD-28
The best characterized costimulatory pathway in T-cell acitvation is when T-cell surface receptor CD28 binds to the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) that are on activated APCs.
This makes sure that T-cells only respond when they need to.
35
Many receptors like CD28 and ligands like B7 have been identified. How do they regulate T-cell responses?
They regulate them positively and negatively. As a result, **T-cell activation is influenced by a balance between activating and inhibitory receptors of the CD28 family.**
36
What co-stimulator LIGANDS do only [**DC's, macrophages and B-cells]** express and receptors on the T-cell do they bind to?
1. B7-1 (CD80) bind to CD28 or CTLA-4
2. B7-2 (CD-86) bind to CD28 or CTLA-4
37
CD28?
Expression:
Major function:
Expression: T-cell; **constituitive**
Major function: co-stimulates naive T cells and generates regulatory T cells
38
CTLA-4
## Footnote
Expression:
Major function:
A co-stimulatory receptor
Expression: T-cells; inducible
Major function: negatively regulates immune responses and self-tolerance
39
What ligands to [DCs, macrophages B-cell and OTHER cells] express and what receptor do they bind to?
ICOS-L (CD275).
**I**nducible T-cell **Cost**imulator
Binds to ICOS.
40
ICOS
## Footnote
Expression:
Major function:
ICOS-L (CD275)
Expression: **T cells (induced)**
Major function:
1. A *costimulator* for **effector and regulatory T-cells**
2. Generates follicular helper T-cell
41
What ligands are expressed on [macrophages, B-cells, endothelial, epithelial and tumor cells] and what receptor do they bind to?
1. PD-L1 (program death-L1)
2. PD-L2 (not expressed on tumor cells)
They both bind to the PD-1 receptor.
42
PD-1
## Footnote
Expression:
Major function:
Co-stimatory receptor
Expression: Induced receptor on **T-cells, B-cells, myeloid cells**
Major function: negatively regulates T-cells
43
What are the inhibitory co-receptors on T-cells?
1. CTLA4
2. PD1
They are structurally similar to CD-28.
44
CTLA4 and PD1 are both inhibitor co-stimulator receptors on T-cells that serve as \_\_\_\_\_\_\_\_\_\_\_\_\_
checkpoints that regulate T-cell responses.
45
CTLA-4 is an inhibitory co-stimulator that regulates the T-cell immune response. Tell me about it.
**Naive and memory T-cells** have high levels of CD28 located on the surface. But, they do not express CTLA-4; it is stored in intracellular vesicles.
When naive T-cells respond to an antigen, the CTLA-4 receptor is transported to the surface. The stronger the stimulation, the more CTLA-4 that goes to the surface.
Thus, it regulates the amount of T-cells activated by damping the sigal.
46
PD1 is an inhibitory co-stimulator that regulates the T-cell immune response. Tell me about it.
PD-1 regulates inflammatory responses in tissues by effector T-cells recognizing Ag in peripheral tissues.
1. When a T-cell is activated, it increases the amount of **PD1 receptors and expresses it IN TISSUES**.
2. Inflammatory signals in the tissue will induce the expression of PD1L due to IFN-y released from Th1 cells.
3. When PD1-L binds to PD1, it downregulates the activity of T-cells and limits tissue damage.
**If too many PD1 receptors are made, it can induce an exhausted or anergic state in T-cells.**
47
\_\_\_\_\_\_ is a rheostat for immune responses.
PD-1
48
Cytokines that are released from the T-cell will determine the outcome of antigen recognition with regards to effector T-cell differentiation.
What does IL-12 cause?
IL12--\> *STAT4 -*-\> *T-bet*--\> **Th1 cells**
49
Cytokines that are released from the T-cell will determine the outcome of antigen recognition with regards to effector T-cell differentiation.
What does IL-4 cause?
IL4--\> *STAT-6*--\> *GATA-3*--\> **Th2 cells**
50
Cytokines that are released from the T-cell will determine the outcome of antigen recognition with regards to effector T-cell differentiation.
What does IL-6 cause?
IL-6--\> *STAT3*--\> *RORyt (retinoic acid receptor-related orphan receptor-yt)*--\> **Th17 molecules**
51
Cytokines that are released from the T-cell will determine the outcome of antigen recognition with regards to effector T-cell differentiation.
What does TGF-BR cause?
TGF-BR--\> *SMAD2-SMAD4*--\> *FOXP3*--\> **Regulatory T-cells**
52
CD8+ T cells recognize antigens that are presented on class 1 MHC-cells. What happens when an antigen is presented to it?
1. Naive T-cells recognize antigens and are co-stimulated by **CD28-CD80** on DCs in the lymph nodes.
2. CD8+ T-cells proliferate and differentiate into [CTLs and memory cells].
3. CD8+ CTLs are released into circulation and go to the site of the antigen.
4. CTLs recognize antigens in the tissue and release lysosome granules, which have perforin and granzymes. This kills the target cells that are making the antigen.
5. CTLs will release IFN-y, which activates macrophages.
53
What is the role of T-bet in that CD8+ T-cells?
T-bet is a **transcription factor for perforin, granzymes and IFN-y** involved in CTL differentiation.
54
Describe the signaling cascade in the activation of T-cells
1. TCR recognizes the antigen
2. The LCK that is associated with CD4/CD8 moves near the CD3 Complex.
3. LCK will doubly phosphorylate ITAMS on their __ chains.
4. ZAP 70 binds to the SH2 domain of ITAM
5. LCH will phosphorylate and activate ZAP70.
6. ZAP-70 will then phosphorylate LAT and SLP-76, which function as scaffolds to recruitother signaling molecules
7. Phosphorylated Lat will then recruit: GADS and GRB2.
8. GRB2 will then phosphorylate and activate PLC1.
9. PLC1 will then make [IP3 and DAG].
10. IP3 will then increase Ca2+ in the cytosol and activate NFAT.
11. DAG will activate PKC, which activates NF-kB and RAS, which activates MAPK and AP-1.
55
After the CD4+ T cell is activated, what is the first change in protein we will see?
An **increase in c-Fos** (a transcription factor) 0-3 hours after activation.
56
What are the 5 biological actions of IL-2 in the adaptive immune response?
1. IL-2 is an autocrine growth factor for T-cells.
2. It increases cytotoxicity of NK cells and CD8+ T-cells.
3. Co-stimulates T-cells to make--\> [**IL4, IL5 and IFN-y**].
4. Promotes the development of T-regulatory cells.
5. Induces a autocrine activation-induced death in T-cells.
57
IL-2 will stimulate the survival, proliferation and differentiation of antigen-activated T-cells. How does it do so?
1. Induce anti-apoptotic protein, **Bcl-2**
2. Helps the cell cycle progress by degrading **p27**, which inhibits the cell cycle.
58
What is required for the survival and function of Tregg cells?
IL-2.
IL2 is the **ONLY** cytokine that can maintain Treg cells.
59
What causes proliferation and differentiation of NK cells and B cells **in vitro**?
IL-2
60
When T-cells are activated, CD69 expression is altered. How and what happens?
S1PR1 (sphingosine 1- phosphate receptor 1) on T cells and S1P concentrations between [lymph organs] and the circulatory system play a big role T-cells leaving the LN.
1. CD69 binds to CD69L, which reduces the amount of S1PR1 that is expressed on the surface.
2. As a result, activated T-cells remain in the LN long enough to cause them to proliferate and differentiate into [effector and memory cells].
3. Once the cell divides, CD69 decrease, the activated T-cell re-expressed high levels of S1PR1; allowing effector and memory cells to exit lymphoid organs.
61
Explain the expression of CD25 (IL-2Ralpha) in activated T-cells
1. A resting naive cell expresses IL-2RByc complex, which has low affinity for IL-2.
2. When IL-2 is released, this causes the IL-2Ralpha (CD25) to come from within the cell and combine with the IR-2RByc complex and form--\> IL-2RalphaByc complex (which has high affinity for IL-2).
Now the complete IL-2 receptor is able to bind IL-2 strongly. Thus, IL-2 binds to the same T-cell that it was made from and acts as an autocrine cytokine.
62
Explain the expression of CD40L in activated T-cells
- CD40L (CD154) expression on the T-cell increases 24-48 hours after it recognizes the antigen.
- CD40L will bind to CD40 on the APC--\> Increase in B7 molecules & secretion of cytokines that activate T-cells.
-
63
Describe clonal expansion of T-cells.
1-2 days after the T-cell is activated by the [antigen + costimulatory molecule], we see an increase in antigen-specific clones (clonal expansion). S/O to IL-2.
A majority of the clones are specific for a few, less than 5 immunodominant peptides. Effector cells can use these to fight infections.
The expansion of CD4+ T cells appears to be 100-fold --\> 1000-fold less than that of CD8+ cells. This may be because of the difference between the two cells:
CTL kill infected cells via direct contact. Thus, may are needed to kill are large number of infected cell. CD4+, on the other hand, release cytokines and activate other effector cells, so we will need a small number of them.
64
How do we get T-cells to decline their response?
When the antigen is eliminated, the T-cells responses decline, allowing us to maintain homeostasis.
1. As the level of co-stimulation and IL-2 decrease, the levels of anti-apoptotic proteins drop.
2. IL-2 starvation causes the intrinsic pathway of the mitochondria to begin apoptosis.
3. Inhibitory receptors: CTLA4 and PD
4. Apoptosis due to death receptors TNFRI and Fas
5. Treg cell products are inhibited.
65
What makes up the most abundant lymphocyte population in the body during the lifetime?
Memory T cells
66
Where do a majority of memory T-cells live?
Tissue sites
67
What influences the fate between the development of effector and memory cells?
Transcription factors
68
What causes effector cells to differentiate into CD4 T-cells?
T-bet
69
What TF promotes the generation of memory cells?
Blimp-1
70
What determines the function and status among the three types of T cells: naive, effector and memory?
DNA methylation.
**Effector and T memory cells** have similar methylation patterns. Naive cells, on the other hand, have more methyl group.
Thus, this proves that memory T-cells are made from effector T-cells via epigenetic changes.
71
Properities of Memory cells.
- What may help them survive for a while?
- In terms of initating a response, how to memory cells compare to naive T-cells?
- Do we have more memory T-cells specific for an antigen or naive T cells for the same antigen?
When an antigen is not present, memory cells are dormant.
1. They have increased levels of anti-apoptic proteins and they undergo slow self-renewing, which may cause them to live longer.
2. They initate a larger and quicker response: responding in 1-3 days compared to the 5-7 days naive cells take.
3. We have a 10-100 fold more memory cells than naive.
72
What is the maintenance of memory cells dependent on?
Cytokines, but it does not require antigens
73
Memory T-cells express antipoptic proteins, helping them live for a while. What cytokines cause these to be expressed?
IL-7
IL-15
74
What are the three phases that memory T-cells go through?
1. Memory generation
2. Memory homeostasis
3. Immunosenescence
75
Memory T-cell generation
1. Memory T-cells are mostly made after the exposure to an antigen during [0-20 years].
2. At ages 30-65, their levels plateau and are maitained via homeostasis.
3. After 65, they show senescent changes (remain the same)
76
How are **CD4+ and CD8+ memory T cells** subsubdivided into subsets?
Based on where they live and their function
77
Central memory T-cells (Tcm cells)
Live?
Function?
- Live in **LN**, **spleen** and in the **blood**.
- They proliferate (due to high IL-2) and make many effector cells on antigen
78
Effector memory T-cells (TEM cells)
- Located in **blood**.
- Do **not** proliferate. Instead, they
1. Make **IFN-y** and **TNF**
2. Become **cytotoxic**
79
Resident tissue memory T cells (TRM Cells)
- Located in **epithelial barrier**.
- Make **IFN-y and TNF**; they are *specific* for pathogens that have been *encountered previously* through that barrier epithelium.
80
Naive T lymphocytes home to lymph nodes as a result of L-selectin, integrin, and chemokine receptor CCR7 binding to their ligands on high endothelial ve- nules (HEVs). Chemokines expressed in lymph nodes bind to CCR7 on naive T cells, enhancing integrin-dependent adhesion and migration through the HEV. The phospholipid, sphingosine 1-phosphate (S1P), plays a role in the exit of T cells from lymph nodes, by binding to the receptor, called S1PR1 (type 1 sphingosine 1-phosphate receptor). Activated T lymphocytes, including the majority of effector cells, home to sites of infection in peripheral tissues, and this migration is mediated by E-selectin and P-selectin, integrins, and chemokines secreted at inflammatory sites. Follicular helper T (Tfh) cells (not shown) are effector cells that remain in lymphoid organs, because they express a chemokine receptor (CXCR5) that draws them into lymphoid follicles, where they can interact with resident B lymphocytes. B, This table summarizes the functions of the principal T cell homing receptors and chemokine receptors and their ligands. ICAM-1, Intercellular adhesion molecule 1; LFA-1, leukocyte function– associated antigen 1; VCAM-1, vascular cell adhesion molecule 1; VLA-4, very late antigen 4.
Naive T-cells live in LN, as a result of [**L-selectin, integrin and chemokine receptor CCR7**] binding to ligands on HEV.
1. Chemokines in the LN bind to CCR7 on naive T-cells and move through the HEV.
2. SLP binds to S1PR1 causes T-cells to leave the LN.
3. E-selectine, P-selectin integrins and chemokines at the site of infection will cause the activated T-lymphocyte to go to the site of infection.
81
What are the 3 T-cell homing receptors located on naive- T cells?
1. L-selectin
2. LFA-1
3. CCR7
82
L-selectin is a naive T-cell receptor. What does it bind to and what does it do?
Binds [L-selectin ligans].
Function: Causes naive T-cells to weakly adhere to HEV in lymph node.
83
LFA-1 is a naive T-cell receptor. What does it bind to and what does it do?
Binds to ICAM-1.
Causes the naive-Tcell to firmly adhere on HEV.
84
CCR7 is a naive T-cell receptor. What does it bind to and what does it do?
- binds to CCL19 or CCL21.
- activates integrins and chemotaxis.
85
What are the receptors/ligands on activated (effector and memory) T cells?
1. **Ligands** for E and P selectin.
2. **LFA-1 or VLA-4**
3. **CXCR3**
86
Ligands for E and P-selectin
Activated T-cells express ligands for E and P selectin.
This allows them to weakly adhere effector and memory T cells to the activated endothelium
87
LFA-1 and VLA-4
What does it bind to? What is the function?
Receptors on the T-cell.
Bind to ICAM-1 or VCAM-1.
Cause the T-cell to firmly adhere to the endothelium
88
CXCR3 is a activated T-cell receptor. What does it bind to and what does it do?
Binds to the CXCL10 ligand.
Activates integrins and chemotaxis.
89
