T Cell and B Cell Activation and Signaling

Question 1

To activate naive T cells

Answer 1

1. TCR
2. Costimulatory
3. Cytokine signaling

Question 2

CD4+ T helper cells antigen interaction

Answer 2

Via TCR with antigen peptide complexed with class II MHC on antigen presenting cell

Question 3

CD8+ T cytotoxic cells antigen interaction

Answer 3

TCR interaction with antigenic peptide bound to class I MHC on target cell

Question 4

CD4+ T helper cell activation

Answer 4

Essential for development of cell-mediated immunity and optimal humeral immunity

Question 5

TCR receptor signaling

Answer 5

Engagement by peptide/MHC initiates multiple pathways

Regulated by activation/inhibition of protein kinases/phosphatases and amplified by cascades

Question 6

Costimulatory signaling

Answer 6

CD28 interacting with B7 family members (CD80/CD86) on antigen presenting cells
Acts synergistically with TCR signaling to enhance gene transcription and stabilize cytokine mRNA

Question 7

Cytokine signaling

Answer 7

Antigen presenting cell makes cytokines or autocrine signaling (to provoke making of transcription factors)

Question 8

Immediate gene expression

Answer 8

Within 30 min of TCR signaling

ie. TF

Question 9

Early gene expression

Answer 9

1-6h of TCR signaling

ie. Cytokines

Question 10

Late gene expression

Answer 10

More than 2 days after TCR signaling

ie. Adhesion molecules

Question 11

IL-2

Answer 11

T cell growth factor

Allows autocrine growth, cell cycle progression and differentiation into memory and effector cells

Question 12

GM-CSF

Answer 12

Neutrophil production

First line of defence against bacteria

Question 13

Major events of TCR signaling

Answer 13

Phospholipase Cgamma activation
Increase in intracellular Ca concentrations
Protein kinase C activation
Nuclear translocation of NFkappaB
Activation of Ras/MAPK pathway

Question 14

Receptors/AP involved in TCR signaling

Answer 14

TCR/CD3 complex, CD4, CD8 coreceptors

Accessory molecules CD2, CD28, CD45

Question 15

CD45

Answer 15

(T cell signaling)
Cell surface phosphatase that catalyzes the dephosphorylation of inhibitory tyrosine residue on p56lck
Causes activation and phosphorylation of CD3 ITAMs and phospholipase Cgamma

Question 16

Calcium release

Answer 16

Ca released with 1 TCR

Max release with 10+ TCR

Question 17

p56lck

Answer 17

(T cell signaling)
CD4/CD8 associated protein tyrosine kinase
Sequestered into lipid rafts (that exclude TCR/CD3) in resting T cell
TCR engangement recruits TCR/CD3 complex into lipid rafts and CD4/CD8 coreceptors that interact with invariant regions of the MHC molecule form clusters
Phosphorylates the ITAMs located on 4 chains of CD3 complex

Question 18

SMAC

Answer 18

Central and peripheral
Immunological synapse formed by sequestering TCR/CD3 into lipid raft
TCR/CD3 complex molecules on the inside and adhesion molecules on the outside

Question 19

pSMAC

Answer 19

CD2 on T cell interacting with LFA-3

LFA-1 on T cell interacting with ICAM-1

Question 20

cSMAC

Answer 20

TCR/CD3 interacting with MHC
p56lck
CD4/CD8 interacting with MHC

Question 21

ITAMs (T cell)

Answer 21

Located on zeta, gamma, delta and epsilon chains of the CD3 complex

Question 22

zeta Chain of CD3

Answer 22

(T cell signaling)
Phosphorylated by p56lck
Homodimer forms docking sites for protein tyrosine kinase ZAP70, which memes activated

Question 23

ZAP70

Answer 23

(T cell signaling)
Associated with zeta chain of CD3 to become activated
Phosphorylates membrane associated adaptor proteins (Vav1, Shc, LAT, SLP76) that act as scaffolds for the recruitment of other molecules in signal transduction

Question 24

Vav1

Answer 24

(T cell signaling)
Membrane associated adaptor protein that acts as scaffold for recruitment of other molecules in signal transduction
Phosphorylated by ZAP70

Question 25

Shc

Answer 25

(T cell signaling) Membrane associated adaptor protein that acts as scaffold for recruitment of other molecules in signal transduction Phosphorylated by ZAP70

Question 26

LAT

Answer 26

(T cell signaling) Membrane associated adaptor protein that acs as scaffold for recruitment of other molecules in signal transduction Phosphorylated by ZAP70 Phospholipase Cgamma docks and becomes phosphorylated and activated

Question 27

SLP76

Answer 27

(T cell signaling) Membrane associated adaptor protein that acs as scaffold for recruitment of other molecules in signal transduction Phosphorylated by ZAP70

Question 28

Phospholipase Cgamma

Answer 28

(T cell signaling) Docks to LAT and becomes phosphorylated/activated Hydrolyzes membrane associated phosphoinotisol bisphosphate to generate IP3 and DAG

Question 29

Ionistol 1,4,5-triphosphate (IP3)

Answer 29

(T cell signaling) Result of hydrolysis of phosphoinotisol bisphophate by phospholipase Cgamma Causes Ca released from ER Causes opening of Ca channels in cell membrane

Question 30

NFAT

Answer 30

(T cell signaling) Dephosphorylated by calcineurin, which is activated by increase Ca levels caused by IP3 NFAT translocated to the nucleus where it causes transcription of cytokines including IL2 and IL4

Question 31

DAG

Answer 31

(T cell signaling) Byproduct of hydrolysis of phosphoinotisol bisphosphate by phospholipase Cgamma Activates PKC

Question 32

Protein kinase C

Answer 32

(T cell signaling) Activated by DAG Translocates to lipid rafts Phosphorylates serine and threonine residues Initiating cascade of signaling events that cause activation of NFkappaB

Question 33

NFkappa B

Answer 33

(T cell signaling) Usually kept inactive by IkappaB Activation of IKK allows phosphorylation of IkappaB causing NFkappaB Promotes transcription of IL2

Question 34

RAS

Answer 34

(T cell signaling) Small G protein Activated by GTP following TCR-CD3 signaling Leads to activation of MAPK pathway, including MAPK ERK

Question 35

ERK

Answer 35

(T cell signaling) Activated by Ras activated MAPK pathway Activates transcription factor Elk that induces Fos expression Phosphorylates Fos, which combines with Jun to form transcription factor AP1 involved in regulating IL2 gene transcription

Question 36

AP1

Answer 36

(T cell signaling) Phosphorylated Fos + Phosphorylated Jun Involved in regulating IL2 gene transcription

Question 37

CD28

Answer 37

Present on surface of resting and activated T cells as disulphide linked homodimer Interacts with B7 family members from APC

Question 38

B7 family

Answer 38

B7-1 (CD80) and B7-2 (CD86) | Found on dendritic cells, activated macrophages and activated B cells

Question 39

Cytokine mRNA

Answer 39

Usually very unstable to regulate inappropriate immune response and potential auto reactivity

Question 40

Negative Costimulatory signaling

Answer 40

``` Only in activated T cells Using CTLA4 (CD152) ```

Question 41

CTLA4

Answer 41

Found only on activated T cells Structurally similar to CD28, binds to B7 family members but provides inhibitory signal to down-regulate T cell activation Induced within 24h of TCR engagement and has a higher affinity for B7 molecules than CD28 Expression is proportional to strength of CD28 signalling, allowing for correct amount of regulatory braking

Question 42

PD-1

Answer 42

Interacts with PD-L1 and PD-L2 | Inhibits T cell activation

Question 43

B cell signaling

Answer 43

mIg engagement and cross linking by antigen Initiates Src kinase, which phosphorylates ITAMs of Ig-alpha and Ig-beta ITAMs are docking sites for Syk

Question 44

Src kinase

Answer 44

(B cell signaling) Initiated by cross linking of mIg of B cell with antigen Phosphorylates ITAMs of Ig-alpha and Ig-beta ITAMs are docking sites for Syk

Question 45

Syk

Answer 45

(B cell signaling) Phosphorylated by docking on ITAMs of Ig-alpha and Ig-beta Phosphorylates adaptor protein BLK

Question 46

BLK

Answer 46

(B cell signaling) Phosphorylated by Syk Docking site of PLCgamma2 and Bruton's tyrosine kinase (BtK) Causes induction of multiple signaling pathways that culminate in the activation of transcription factors

Question 47

B Cell coreceptors

Answer 47

Complex of CD19, CR2 and TAPA-1

Question 48

CD19

Answer 48

Part of B cell coreceptors | Long cytoplasmic tail that has docking sites of intracellular molecules, such as PTK lyn

Question 49

Lyn

Answer 49

Protein tyrosine kinase | Augments signals delivered by the BCR

Question 50

CR2

Answer 50

Part of BC coreceptors | Interacts with C3d

Question 51

C3d

Answer 51

Formed by C3b cleaved by Factor I

Question 52

CD22

Answer 52

Part of BC coreceptors Constitutively associated with BCR Following activation, delivers negative signal due to tyrosine phosphatase SHP-1 bound to ITIM

Question 53

SHP-1

Answer 53

Bound to ITIM on CD22 | Delivers negative signal following activation of BCR

Question 54

ITIM

Answer 54

On cytoplasmic tail of CD22 | Binds SHP-1

Question 55

Clonalanergy

Answer 55

State of unresponsiveness CD4+/CD8+ T cells that receive signal through TCR/CD3 complex that fail to receive costimulatory signal Unable to respond to antigenic peptide Alterations in key components of TCR signaling pathways