Immunology (Test Ii): Chapter 9 & 10: T-Cell Receptors: Structure, Signaling, Maturation, Activation, & Differentiation

Front 1

Each T-cell has how many TCRs? What is their purpose?

Back 1

Each T-cell has thousands of TCRs to increase the odds of binding to an Ag.

Front 2

Are TCRs membrane bound, soluble, or both?

Back 2

TCRs are always membrane bound. They are never soluble.

Front 3

Which binding is weaker, Ag or that of Abs?

Back 3

Ag binding is weaker than that of Abs. TCR binding is pretty weak so it depends on accessory molecules to "lock" it.

Front 4

Each T-cell has specific TCRs. Where are these derived from?

Back 4

Each T-cell has specific TCRs derived from genetic recombination during maturation in the thymus before it has even encountered a complementary Ag!

Front 5

What kind of dimer is the TCR?

Back 5

It is a heterodimer.

Front 6

The TCR is a what?

Back 6

TCRs are Abs.

Front 7

TCRs are usually ? and ? chains with short ?.

Back 7

TCRs are usually alpha and beta chains with short cytoplasmic tails.

Front 8

TCRs are a member of what family?

Back 8

They are a member of Ig superfamily.

Front 9

The majority of TCRs have alpha and beta chains. However, a minority of TCRs also have what kind of chains?

Back 9

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.

Front 10

What is autoimmunity?

Back 10

The failure of an organism to recognize it's own constituent parts. Results in autoimmune disease.

Front 11

Are the variable regions of a TCR alpha or beta? What about the constant regions?

Back 11

There are alpha and beta chains in both the variable and the constant regions of a TCR.

Front 12

TCRs have short cytoplasmic tails. What does this mean for signal transduction?

Back 12

The TCRs need another way to transduce signals intracellularly.

Front 13

What are the short cytoplasmic tails of TCRs composed of?

Back 13

Amino Acid residues. About 21-22 amino acids in length.

Front 14

What is TCR-CD3?

Back 14

It is a TCR complex.

Front 15

The accessory molecule, CD3, participates in what?

Back 15

It participates in signal transduction. Without CD3 the TCR will not have signal transduction.

Front 16

What is CD3 not involved in?

Back 16

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.

Front 17

The TCR-CD3 complex includes which homodimer?

Back 17

Zeta-Zeta homodimer.

Front 18

The TCR-CD3 complex includes which two heterodimers?

Back 18

1. Delta-Epsilon

2. Gamma-Epsilon

Front 19

The zeta-zeta homodimer may occasionally (about 10% of the time) be observed as this heterodimer instead?

Back 19

Zeta-Mu

Front 20

What is a critical part of the Zeta-Zeta homodimer of the CD3 complex?

Back 20

ITAM.

Front 21

What does ITAM stand for?

Back 21

Immunoreceptor tyrosine-based activation motif.

Front 22

CD3 and ? actually signal the cell via ?.

Back 22

CD3 and zeta actually signal the cell via ITAM.

Front 23

The homodimers and heterodimers that compose CD3 are members of what family?

Back 23

The Ig superfamily.

Front 24

What is a key signaling motif seen in both BCRs and TCRs?

Back 24

CD3

Front 25

What are CD4 and CD8 molecules?

Back 25

They are accesory membrane molecules of TCRS. They are co-receptors.

Front 26

What are two of the various roles of the CD4 and CD8 co-receptors of TCRs?

Back 26

1. Strengthen the binding interaction between T-cells and APCs

2. Signal Transduction

Front 27

The extracellular domains of CD4 and CD8 have high variability among species. True or False?

Back 27

False. The extracellular domains are highly conserved across species.

Front 28

Remember, TCR binding to Ag is loose. What helps them 'stick'?

Back 28

T-cell accessory molecules.

Front 29

List the 8 T-cell accessory molecules that helps the TCRs bind to Ags?

Back 29

1. CD4

2. CD8

3. CD2 (LFA-2)

4. LFA-1 (CD11a/CD18)

5. CD28

6. CTLA-4

7. CD45R

8. CD5

Front 30

Most of the T-cell accessory molecules have these two functions?

Back 30

1. Adhesion

2. Signal Transduction

Front 31

Most of the T-cell accessory molecules are members of this family?

Back 31

Most are members of Ig superfamily.

Front 32

The Kd of TCRs is relatively ? compared to Ag-Ab complexes.

Back 32

They are relatively weak compared to Ag-Ab complexes (which are tight).

Front 33

Are T-cell interactions solely dependent on binding by the TCR?

Back 33

No, T-cell interactions are not solely dependent on binding by the TCR.

Front 34

What do cell adhesion molecules strengthen?

Back 34

They strengthen the bond between a T-cell and an APC or a target cell.

Front 35

Co-receptors enhance what?

Back 35

Co-receptors enhance binding affinity.

Front 36

Accessory membrane molecules bind ? to other ligands on APCs or target cells.

Back 36

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.

Front 37

What happens next after the accessory membrane molecules bind to other ligands on APCs or target cells?

Back 37

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.

Front 38

What does CD4 stabilize?

Back 38

T-cell and APC interaction.

Front 39

Describe the 'two-point' attachment that occurs in T-cell and APC interactions?

Back 39

A two-point attachment occurs between:

1. Extracellular part of CD4 and MHC II

and

2. Intracellular part of CD4
and P56ick with the zeta chain of the CD3 complex.

Front 40

CD4 stabilizes T-cell and APC interaction and it also may be responsible for the recruitment of what?

Back 40

Recruitment of molecules for signal transduction.

Front 41

What does the maturation of T-cells begin with?

Back 41

A thymocyte from the bone marrow.

Front 42

There is a slow proliferation of T-cells in the cortex of the thymus, where apoptosis takes place. What does this allow?

Back 42

This allows only T-cells that are capable of MHC recognition to survive. This is known as positive selection.

Front 43

What percentage of thymocytes die of apoptosis in the thymus?

Back 43

98% never see maturity.

Front 44

What does negative selection eliminate?

Back 44

It eliminates T-cells that react too strongly with self-MHC or with self-MHC + self-peptides (self tolerance).

Front 45

T-cell activation is aka what?

Back 45

"Signal Transduction"

Front 46

What is clonal expansion very important to?

Back 46

They are very important to immunity.

Front 47

What is T-cell activation initiated by?

Back 47

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.

Front 48

After activation what does T-cell proliferate into?

Back 48

After activation T-cell goes from Go (resting phase) through the cell cycle proliferating into memory and effector cells.

Front 49

The synthesis of what very important products occurs as a result of signal transduction?

Back 49

The synthesis of gene products.

Front 50

List the 3 types of gene products that are synthesized as a result of signal transduction. Also include the roles of each.

Back 50

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)

Front 51

How long after signal transduction before we see the immediate genes? What about the early or late genes?

Back 51

1. Immediate genes : Within a half-hour

2. Early genes : 1-2 hours

3. Late genes : About 2 days

Front 52

List 5 immediate genes?

Back 52

1. c-Fos

2. c-Myc

3. c-Jun

4. NFAT

5. NF-kB

Front 53

List 4 early genes?

Back 53

1. IL-2

2. IL-2R

3. IL-6

4. IFN-gamma

Front 54

Signal transduction starts in the ? and terminates in the ?.

Back 54

Signal transduction starts in the plasma membrane and terminates in the nucleus.

Front 55

What is the initiation step of signal transduction?

Back 55

The engagement of MHC-peptide initiates processes that lead to assembly of signaling complex.

Front 56

Do the TCRs and the ClassI/II MHC complexes actually have contact?

Back 56

No, there is a space. They do not need to touch to transduce. There is an immunological synapse.

Front 57

What is the 2nd step of signal transduction?

Back 57

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.

Front 58

Why is the lipid raft that contains P56lck different than lipid in most plasma membranes?

Back 58

Because it is very rich in sphingomycin, cholesterol, and glycosphingolipids (these are detergent resistant lipids).

Front 59

Once ZAP-70 is phosphorylated what does it do?

Back 59

Once phosphorylated it becomes activated and phosphorylates other molecules. Starts a cascade. (see slide on page 7 of class notes)

Front 60

IP3 always facilitates the release of what?

Back 60

The release of Ca2+ from stores (ie, SER)

Front 61

What is PLC-gamma aka?

Back 61

Phospholipase C-gamma.

Front 62

Phospholipase is inactive until what occurs?

Back 62

Inactive until it is phosphorylated. It is phosphorylated by LAT and activation depends upon this phosphoyrlation as well as subsequent hydrolysis of PIP2.

Front 63

What do all phosporylation reactions involve?

Back 63

ATP

Front 64

Ca2+ could be described as a ? ion.

Back 64

It is a promiscous ion.

Front 65

What is the result of PLC-gamma activation?

Back 65

NF-kB and NFAT, which is an important transription factor.

Front 66

What is Ras activated by?

Back 66

Ras is activated by GTP-->GDP. Not by ATP.

Front 67

What does activated Ras go on to activate?

Back 67

Ras is a small G-protein whose activation initiates MAP kinase (aka Mitogen-Activated PK)

Front 68

Ras is ? ? across eukaryotes.

Back 68

It is highly conserved across eukaryotes.

Front 69

Ras is a pivotal point in what?

Back 69

Ras is a pivotal point in signal transduction.

Front 70

What does GEF stand for?

Back 70

Guanine-Nucleotide Exchange Factors.

Front 71

What does MAP-kinase go on to activate?

Back 71

It activates Fos.

Front 72

Once activated, what does Fos do?

Back 72

It binds with Jun.

Front 73

Once bound what is the product of the Fos-Jun linkage?

Back 73

AP-1. This allows transcriptional activation of several genes.

Front 74

Without the formation of AP-1 what can not be made?

Back 74

Without AP-1 you cannot make some very important cytokines (IL-2).

Front 75

Full T-cell activation requires what?

Back 75

Co-stimulators.

Front 76

What is Signal 1 of Full T-cell activation?

Back 76

The initial signal, generated by Ag-peptide with TCR-CD3.

Front 77

What is Signal 2 of Full T-cell activation?

Back 77

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.

Front 78

CTLA-4 is ? and ? T-cell activity.

Back 78

CTLA-4 is inhibitory and counter regulates T-cell activity. It is a way to turn it off.

Front 79

Name two B7 ligands?

Back 79

1. CD28

2. CTLA-4

Front 80

What is CTLA-4 aka?

Back 80

CD152

Front 81

What is CD28 expressed by? What does the term 'expressed' mean?

Back 81

CD28 is expressed by both resting and activated T cells. 'Expressed' means you see it on the plasma membrane.

Front 82

CD28 and CTLA-4 do what to one another?

Back 82

CD28 and CTLA-4 antagonize one another.

Front 83

CD28 sends what kind of signal?

Back 83

It sends a positive signal.

Front 84

CTLA-4 is inhibitory and down-regulates what?

Back 84

It down-regulates T-cell activity.

Front 85

What is CTLA-4 expressed on?

Back 85

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.

Front 86

The B7 molecules (the ligands of CD28 and CTLA-4) are expressed on what?

Back 86

They are present on almost all APCs. (Dendritic cells, activated macrophages, and activated B-cells)

Front 87

What is clonal anergy?

Back 87

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.

Front 88

What can a superantigen induce?

Back 88

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.

Front 89

Are superantigens viral or bacterial proteins? Are they endogenous or exogenous?

Back 89

Superantigens can be either VIRAL or BACTERIAL proteins and either EXOGENOUS or ENDOGENOUS.

Front 90

Describe EXOGENOUS superAgs?

Back 90

They are SOLUBLE proteins secreted by BACTERIA or toxoids. (ex. tetanus food poison)

Front 91

Describe ENDOGENOUS superAgs?

Back 91

They are cell MEMBRANE proteins encoded by VIRUSES (MIs).

Front 92

Superantigens bind what part of TCRs to what part of the MHC II?

Back 92

It binds to the V-beta region of TCR and alpha-chain of MHC II.

Front 93

What can superAgs influence in the thymus?

Back 93

They can influence T-cell maturation in the thymus. (SuperAgs are very dangerous)

Front 94

List two exogenous superAgs?

Back 94

1. Toxic Shock Syndrome Toxin (TSST1)(from tampons)

2. Exfoliative Dermatitis Toxin (ExFT)(Looks like 2nd degree burns)

Front 95

Are you likely to see Ag in the thymus?

Back 95

No, it is not likely, EXCEPT for superantigen.

Front 96

Do CD4 and CD8 leave the thymus in the Go stage of the cell cycle?

Back 96

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.

Front 97

Cells in the Go stage (that have not seen Ag) have ? chromatin and ? ? cytoplasm.

Back 97

Cells in the Go stage have condensed chromatin and very little cytoplasm.

Front 98

What is the ratio of CD4 to CD8 cells?

Back 98

There is always 2X more CD4 than CD8 cells.

Front 99

When does activation of T-cells occur?

Back 99

ONLY when it encounters a processed Ag on an APC.

Front 100

What two things does the primary response require?

Back 100

CD28 and B7.

Front 101

How long does it take after activation to see a primary response?

Back 101

It takes 48 hours post-activation.

Front 102

During the primary response the Naive T-cell enlarges into a ? ? and undergoes repeated ? ?.

Back 102

During the primary response the naive T-cell enlarges into a BLAST CELL and undergoes repeated CELL DIVISIONS.

Front 103

Name three specialized functions that effector cells carry out?

Back 103

1. Cytokine Secretion

2. B-cell help

3. Cytotoxic killing

Front 104

How many repeated cell divisions do T-cells undergo once they enlarge into a blast cell?

Back 104

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.

Front 105

How can an initial exposure to an immunogen be differentiated from a secondary exposure to the same immunogen?

Back 105

1. The level of Abs produced

2. Isotype change (IgA, IgB)

3. Response time

Front 106

How long are effector cells around?

Back 106

Effector cells are short-lived. Only from a few days to a few weeks.

Front 107

Effector and Naive cells express different what? What does this contribute to?

Back 107

Effector and naive cells express different cell membrane molecules. (ex. CD28, CTLA-24). This contributes to different recirculation patterns.

Front 108

How many subpopulations do effector T-cells form? List them. What are these subpopulations derived from?

Back 108

Effector T-cells form two subpopulations derived from CD4.

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

2. TH2 (Helper-2s)

Front 109

What does the TH-1 subpopulation of Effector T-cells secrete?

Back 109

IL-2, IFN-gamma, and TNF-beta

Front 110

What is the TH-1 subpopulation of effector T-cells responsible for?

Back 110

They are responsible for classic cell mediated functions

1. Delayed type hypersensitivity (ie, allergies)

2. Activation of Tc cells (responsible for cytotoxic killing)

Front 111

What does the TH-2 subpopulation of effector T-cells secrete?

Back 111

IL-4, IL-5, IL-6, IL-10

Front 112

What is the TH-2 subpopulation of effector T-cells responsible for?

Back 112

They are a helper for B-cell activation.

Front 113

Memory T-cells are ? lived.

Back 113

Memory T-cells are long-lived.

Front 114

Memory T-cells respond with a larger ? response.

Back 114

A larger secondary response.

Front 115

Memory T-cells express similar ? ? ? as effector T-cells?

Back 115

They express similar cell surface markers as effector T-cells.

Front 116

Most memory T-cells are in what stage until they encounter the Ag they have memory for?

Back 116

Most are in Go (resting) until they encounter the Ag they have memory for.

Front 117

What is meant by the fact that Memory T-cells have different recirculation patterns?

Back 117

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)

Front 118

What is a Ts?

Back 118

Suppressor T-cells. These were once believed to be CD8 cells originally but really they are a type of CD4.

Front 119

Ts cells are aka what?

Back 119

Treg cells.

Front 120

What can Ts (ie, Treg) cells inhibit?

Back 120

They can inhibit proliferation of other T-cells in vitro. (so it dampens the immune response)

Front 121

What markers are on the Ts cells?

Back 121

CD4/CD25 (may inhibit experimentally induced autoimmune disease)

Front 122

List two different principal co-stimulatory molecules characteristic of APCs.

Back 122

B7-1(CD80) and B7-2(CD86).

Front 123

Resting APCs have never been exposed to an ? and can not activate a ?.

Back 123

Resting APCs have never been exposed to Ag and can not activate a T-cell.

Front 124

APCs differ in their ability to display ? and in their ? signals.

Back 124

APCs differ in their ability to display Ag and in their co-stimulatory signals.

Front 125

Why is the dendritic cell so important in activating naive T-cells?

Back 125

Because B7 is constitutive (ie, the co-stim. cells are ready to act quickly).

Front 126

Cell death (apoptosis) is a highly conserved process among ? and ?.

Back 126

Cell death is a highly conserved process among vertebrates and invertebrates.

Front 127

What is apoptosis responsible for in utero?

Back 127

It is responsible for the separation of hands and fingers.

Front 128

What does cell death require?

Back 128

Cell death requires caspases.

Front 129

What is a caspase?

Back 129

It is required in cell death. They are specialized proteases with specificity for aspartic acid residues.

Front 130

What cells produce caspase proteins? When are they active?

Back 130

Every body cell produces caspase proteins which are normally in inactive form. They have their highest level of activity in utero.

Front 131

How many different pathways do T-cells use to activate caspases?

Back 131

Two different pathways.

Front 132

Describe the activation of a caspase?

Back 132

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.

Front 133

Fas and FasL (ie, Fas ligand) are members of what family?

Back 133

TNF family (tumor necrosis family).

Front 134

If TCR joins a T-cell what does it express that will prevent cell death?

Back 134

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.