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134 Cards in this Set

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  • Back
Each T-cell has how many TCRs? What is their purpose?
Each T-cell has thousands of TCRs to increase the odds of binding to an Ag.
Are TCRs membrane bound, soluble, or both?
TCRs are always membrane bound. They are never soluble.
Which binding is weaker, Ag or that of Abs?
Ag binding is weaker than that of Abs. TCR binding is pretty weak so it depends on accessory molecules to "lock" it.
Each T-cell has specific TCRs. Where are these derived from?
Each T-cell has specific TCRs derived from genetic recombination during maturation in the thymus before it has even encountered a complementary Ag!
What kind of dimer is the TCR?
It is a heterodimer.
The TCR is a what?
TCRs are Abs.
TCRs are usually ? and ? chains with short ?.
TCRs are usually alpha and beta chains with short cytoplasmic tails.
TCRs are a member of what family?
They are a member of Ig superfamily.
The majority of TCRs have alpha and beta chains. However, a minority of TCRs also have what kind of chains?
A minority of TCRs have gamma and lambda chains. No one is sure what they do. Their significance and function is unknown.

They do not recognize MHC processing or presentation of Ag (so there is no MHC requirement). They may be involved in autoimmunity.
What is autoimmunity?
The failure of an organism to recognize it's own constituent parts. Results in autoimmune disease.
Are the variable regions of a TCR alpha or beta? What about the constant regions?
There are alpha and beta chains in both the variable and the constant regions of a TCR.
TCRs have short cytoplasmic tails. What does this mean for signal transduction?
The TCRs need another way to transduce signals intracellularly.
What are the short cytoplasmic tails of TCRs composed of?
Amino Acid residues. About 21-22 amino acids in length.
What is TCR-CD3?
It is a TCR complex.
The accessory molecule, CD3, participates in what?
It participates in signal transduction. Without CD3 the TCR will not have signal transduction.
What is CD3 not involved in?
It does not influence interaction with Ag. The TCR can bind to Ag without CD3. However, it can not signal without CD3. Also CD3 will not signal until there is binding.
The TCR-CD3 complex includes which homodimer?
Zeta-Zeta homodimer.
The TCR-CD3 complex includes which two heterodimers?
1. Delta-Epsilon

2. Gamma-Epsilon
The zeta-zeta homodimer may occasionally (about 10% of the time) be observed as this heterodimer instead?
What is a critical part of the Zeta-Zeta homodimer of the CD3 complex?
What does ITAM stand for?
Immunoreceptor tyrosine-based activation motif.
CD3 and ? actually signal the cell via ?.
CD3 and zeta actually signal the cell via ITAM.
The homodimers and heterodimers that compose CD3 are members of what family?
The Ig superfamily.
What is a key signaling motif seen in both BCRs and TCRs?
What are CD4 and CD8 molecules?
They are accesory membrane molecules of TCRS. They are co-receptors.
What are two of the various roles of the CD4 and CD8 co-receptors of TCRs?
1. Strengthen the binding interaction between T-cells and APCs

2. Signal Transduction
The extracellular domains of CD4 and CD8 have high variability among species. True or False?
False. The extracellular domains are highly conserved across species.
Remember, TCR binding to Ag is loose. What helps them 'stick'?
T-cell accessory molecules.
List the 8 T-cell accessory molecules that helps the TCRs bind to Ags?
1. CD4

2. CD8

3. CD2 (LFA-2)

4. LFA-1 (CD11a/CD18)

5. CD28

6. CTLA-4

7. CD45R

8. CD5
Most of the T-cell accessory molecules have these two functions?
1. Adhesion

2. Signal Transduction
Most of the T-cell accessory molecules are members of this family?
Most are members of Ig superfamily.
The Kd of TCRs is relatively ? compared to Ag-Ab complexes.
They are relatively weak compared to Ag-Ab complexes (which are tight).
Are T-cell interactions solely dependent on binding by the TCR?
No, T-cell interactions are not solely dependent on binding by the TCR.
What do cell adhesion molecules strengthen?
They strengthen the bond between a T-cell and an APC or a target cell.
Co-receptors enhance what?
Co-receptors enhance binding affinity.
Accessory membrane molecules bind ? to other ligands on APCs or target cells.
Accessory membrane molecules (CD2, LFA-1, CD28, CD45R) bind INDEPENDENTLY to other ligands on APCs or target cells. They help the rxn between the TCR and MHC.
What happens next after the accessory membrane molecules bind to other ligands on APCs or target cells?
Next, TCRs scan the membrane for peptide-MHC complexes. Cell-adhesion molecules upregulate making for closer contact allowing cytokines or cytotoxic chemicals to transfer more efficiently. After activation, detachment occurs.
What does CD4 stabilize?
T-cell and APC interaction.
Describe the 'two-point' attachment that occurs in T-cell and APC interactions?
A two-point attachment occurs between:

1. Extracellular part of CD4 and MHC II


2. Intracellular part of CD4
and P56ick with the zeta chain of the CD3 complex.
CD4 stabilizes T-cell and APC interaction and it also may be responsible for the recruitment of what?
Recruitment of molecules for signal transduction.
What does the maturation of T-cells begin with?
A thymocyte from the bone marrow.
There is a slow proliferation of T-cells in the cortex of the thymus, where apoptosis takes place. What does this allow?
This allows only T-cells that are capable of MHC recognition to survive. This is known as positive selection.
What percentage of thymocytes die of apoptosis in the thymus?
98% never see maturity.
What does negative selection eliminate?
It eliminates T-cells that react too strongly with self-MHC or with self-MHC + self-peptides (self tolerance).
T-cell activation is aka what?
"Signal Transduction"
What is clonal expansion very important to?
They are very important to immunity.
What is T-cell activation initiated by?
T-cell activation is initiated by the interaction of TCR-CD3 with a processed Ag bound to either MHC I or MHC II on an APC.
After activation what does T-cell proliferate into?
After activation T-cell goes from Go (resting phase) through the cell cycle proliferating into memory and effector cells.
The synthesis of what very important products occurs as a result of signal transduction?
The synthesis of gene products.
List the 3 types of gene products that are synthesized as a result of signal transduction. Also include the roles of each.
1. Immediate genes (Role in phosphorylation to keep signal paths going)

2. Early genes (code for very important cytokines)

3. Late genes (code for various adhesion molecules)
How long after signal transduction before we see the immediate genes? What about the early or late genes?
1. Immediate genes : Within a half-hour

2. Early genes : 1-2 hours

3. Late genes : About 2 days
List 5 immediate genes?
1. c-Fos

2. c-Myc

3. c-Jun


5. NF-kB
List 4 early genes?
1. IL-2

2. IL-2R

3. IL-6

4. IFN-gamma
Signal transduction starts in the ? and terminates in the ?.
Signal transduction starts in the plasma membrane and terminates in the nucleus.
What is the initiation step of signal transduction?
The engagement of MHC-peptide initiates processes that lead to assembly of signaling complex.
Do the TCRs and the ClassI/II MHC complexes actually have contact?
No, there is a space. They do not need to touch to transduce. There is an immunological synapse.
What is the 2nd step of signal transduction?
Because the short tails of the TCR need help signaling the CD4 or CD8 intracellularly associates with P56LCK (which is normally bound up in a lipid raft). The associated P56LCK then phosphorylates ITAMs of zeta chains. This creates docking sites for ZAP-70.

If there is no phosporylation then there is no docking and there is no signal transduction.
Why is the lipid raft that contains P56lck different than lipid in most plasma membranes?
Because it is very rich in sphingomycin, cholesterol, and glycosphingolipids (these are detergent resistant lipids).
Once ZAP-70 is phosphorylated what does it do?
Once phosphorylated it becomes activated and phosphorylates other molecules. Starts a cascade. (see slide on page 7 of class notes)
IP3 always facilitates the release of what?
The release of Ca2+ from stores (ie, SER)
What is PLC-gamma aka?
Phospholipase C-gamma.
Phospholipase is inactive until what occurs?
Inactive until it is phosphorylated. It is phosphorylated by LAT and activation depends upon this phosphoyrlation as well as subsequent hydrolysis of PIP2.
What do all phosporylation reactions involve?
Ca2+ could be described as a ? ion.
It is a promiscous ion.
What is the result of PLC-gamma activation?
NF-kB and NFAT, which is an important transription factor.
What is Ras activated by?
Ras is activated by GTP-->GDP. Not by ATP.
What does activated Ras go on to activate?
Ras is a small G-protein whose activation initiates MAP kinase (aka Mitogen-Activated PK)
Ras is ? ? across eukaryotes.
It is highly conserved across eukaryotes.
Ras is a pivotal point in what?
Ras is a pivotal point in signal transduction.
What does GEF stand for?
Guanine-Nucleotide Exchange Factors.
What does MAP-kinase go on to activate?
It activates Fos.
Once activated, what does Fos do?
It binds with Jun.
Once bound what is the product of the Fos-Jun linkage?
AP-1. This allows transcriptional activation of several genes.
Without the formation of AP-1 what can not be made?
Without AP-1 you cannot make some very important cytokines (IL-2).
Full T-cell activation requires what?
What is Signal 1 of Full T-cell activation?
The initial signal, generated by Ag-peptide with TCR-CD3.
What is Signal 2 of Full T-cell activation?
Signal 2 is not specific for Ag.

It is generated by an interaction between CD28 (T-cell) and members of the B-7 family (B7-1 and B7-2members of the Ig superfamily) on the APC.
CTLA-4 is ? and ? T-cell activity.
CTLA-4 is inhibitory and counter regulates T-cell activity. It is a way to turn it off.
Name two B7 ligands?
1. CD28

2. CTLA-4
What is CTLA-4 aka?
What is CD28 expressed by? What does the term 'expressed' mean?
CD28 is expressed by both resting and activated T cells. 'Expressed' means you see it on the plasma membrane.
CD28 and CTLA-4 do what to one another?
CD28 and CTLA-4 antagonize one another.
CD28 sends what kind of signal?
It sends a positive signal.
CTLA-4 is inhibitory and down-regulates what?
It down-regulates T-cell activity.
What is CTLA-4 expressed on?
CTLA-4 is expressed on activated T cells. They are expressed within 24 hours of T-cell receptor and Ag coming in contact. But they are not at their max until 2-3 days.
The B7 molecules (the ligands of CD28 and CTLA-4) are expressed on what?
They are present on almost all APCs. (Dendritic cells, activated macrophages, and activated B-cells)
What is clonal anergy?
It is a state of nonresponsiveness. It occurs if a costimulatory signal is absent. So T-cells are unable to clone out and be active. The precise biochemical mxm of this is not well understood.
What can a superantigen induce?
A superantigen can induce T-cell activation by binding the TCR and MHC II simultaneously. It is important because it can grab hold of and bind up the whole area.
Are superantigens viral or bacterial proteins? Are they endogenous or exogenous?
Superantigens can be either VIRAL or BACTERIAL proteins and either EXOGENOUS or ENDOGENOUS.
Describe EXOGENOUS superAgs?
They are SOLUBLE proteins secreted by BACTERIA or toxoids. (ex. tetanus food poison)
Describe ENDOGENOUS superAgs?
They are cell MEMBRANE proteins encoded by VIRUSES (MIs).
Superantigens bind what part of TCRs to what part of the MHC II?
It binds to the V-beta region of TCR and alpha-chain of MHC II.
What can superAgs influence in the thymus?
They can influence T-cell maturation in the thymus. (SuperAgs are very dangerous)
List two exogenous superAgs?
1. Toxic Shock Syndrome Toxin (TSST1)(from tampons)

2. Exfoliative Dermatitis Toxin (ExFT)(Looks like 2nd degree burns)
Are you likely to see Ag in the thymus?
No, it is not likely, EXCEPT for superantigen.
Do CD4 and CD8 leave the thymus in the Go stage of the cell cycle?
Yes, the naive T-cells (that have never seen Ag) continually recirculate between blood and lymph nodes every 12-24 hours. They do this so frequently so they can look for Ag (it's surveillance). This becomes more frequent once they encounter Ag.
Cells in the Go stage (that have not seen Ag) have ? chromatin and ? ? cytoplasm.
Cells in the Go stage have condensed chromatin and very little cytoplasm.
What is the ratio of CD4 to CD8 cells?
There is always 2X more CD4 than CD8 cells.
When does activation of T-cells occur?
ONLY when it encounters a processed Ag on an APC.
What two things does the primary response require?
CD28 and B7.
How long does it take after activation to see a primary response?
It takes 48 hours post-activation.
During the primary response the Naive T-cell enlarges into a ? ? and undergoes repeated ? ?.
During the primary response the naive T-cell enlarges into a BLAST CELL and undergoes repeated CELL DIVISIONS.
Name three specialized functions that effector cells carry out?
1. Cytokine Secretion

2. B-cell help

3. Cytotoxic killing
How many repeated cell divisions do T-cells undergo once they enlarge into a blast cell?
Two or 3 times per day for 4-5 days. This creates a population of memory and effector cells. The effector cells help B-cells by making cytokines.
How can an initial exposure to an immunogen be differentiated from a secondary exposure to the same immunogen?
1. The level of Abs produced

2. Isotype change (IgA, IgB)

3. Response time
How long are effector cells around?
Effector cells are short-lived. Only from a few days to a few weeks.
Effector and Naive cells express different what? What does this contribute to?
Effector and naive cells express different cell membrane molecules. (ex. CD28, CTLA-24). This contributes to different recirculation patterns.
How many subpopulations do effector T-cells form? List them. What are these subpopulations derived from?
Effector T-cells form two subpopulations derived from CD4.

1. TH1 (Helper-1s)(Most common)

2. TH2 (Helper-2s)
What does the TH-1 subpopulation of Effector T-cells secrete?
IL-2, IFN-gamma, and TNF-beta
What is the TH-1 subpopulation of effector T-cells responsible for?
They are responsible for classic cell mediated functions

1. Delayed type hypersensitivity (ie, allergies)

2. Activation of Tc cells (responsible for cytotoxic killing)
What does the TH-2 subpopulation of effector T-cells secrete?
IL-4, IL-5, IL-6, IL-10
What is the TH-2 subpopulation of effector T-cells responsible for?
They are a helper for B-cell activation.
Memory T-cells are ? lived.
Memory T-cells are long-lived.
Memory T-cells respond with a larger ? response.
A larger secondary response.
Memory T-cells express similar ? ? ? as effector T-cells?
They express similar cell surface markers as effector T-cells.
Most memory T-cells are in what stage until they encounter the Ag they have memory for?
Most are in Go (resting) until they encounter the Ag they have memory for.
What is meant by the fact that Memory T-cells have different recirculation patterns?
Most Naive T-cells are activated by dendritic APC cells BUT memory cells are more promiscous any can be activated by and APC (ie, Dendritic, Macrophage, and B-lymphocytes)
What is a Ts?
Suppressor T-cells. These were once believed to be CD8 cells originally but really they are a type of CD4.
Ts cells are aka what?
Treg cells.
What can Ts (ie, Treg) cells inhibit?
They can inhibit proliferation of other T-cells in vitro. (so it dampens the immune response)
What markers are on the Ts cells?
CD4/CD25 (may inhibit experimentally induced autoimmune disease)
List two different principal co-stimulatory molecules characteristic of APCs.
B7-1(CD80) and B7-2(CD86).
Resting APCs have never been exposed to an ? and can not activate a ?.
Resting APCs have never been exposed to Ag and can not activate a T-cell.
APCs differ in their ability to display ? and in their ? signals.
APCs differ in their ability to display Ag and in their co-stimulatory signals.
Why is the dendritic cell so important in activating naive T-cells?
Because B7 is constitutive (ie, the co-stim. cells are ready to act quickly).
Cell death (apoptosis) is a highly conserved process among ? and ?.
Cell death is a highly conserved process among vertebrates and invertebrates.
What is apoptosis responsible for in utero?
It is responsible for the separation of hands and fingers.
What does cell death require?
Cell death requires caspases.
What is a caspase?
It is required in cell death. They are specialized proteases with specificity for aspartic acid residues.
What cells produce caspase proteins? When are they active?
Every body cell produces caspase proteins which are normally in inactive form. They have their highest level of activity in utero.
How many different pathways do T-cells use to activate caspases?
Two different pathways.
Describe the activation of a caspase?
Fas ligand binds to Fas and then FADD ('death domain') binds. This then recruits procaspase-8 to make active Caspase-8 and then the rest of the cascade goes on and cell death occurs. Once the cascade begins the cell will die within 2-4 hours.
Fas and FasL (ie, Fas ligand) are members of what family?
TNF family (tumor necrosis family).
If TCR joins a T-cell what does it express that will prevent cell death?
If TCR joins it is important for the T-cell not to die. BCL-2 will be expressed and apoptosis will not occur. BCL-2 is a very strong inhibitor of apoptosis.