T Cell Signalling

Question 1

T or F. Each TCR is specific for combination of peptide and at least two MHCs

Answer 1

F! only in the context of one MHC

Question 2

T helper cell activation steps

Answer 2

1. TCR + antigen bound to MHC
2. costimulation and survival signals
3. IL-2 and IL-2R = poliferation

Question 3

when is costimulatory interaction important

Answer 3

signal #2 needs to happen if cell has never seen antigen before

Question 4

TCR two main problems

Answer 4

exceptionally low affinity for MHC + Ag; don’t adhere very well without accessory molecules

TCR and CD3 have no intrinsic kinase activity

Question 5

ITAM

Answer 5

immunoreceptor tyrosine-based activation motif
allows different kinases to phosphorylate CD3 tyrosines ?

important for downstream signalling

Question 6

CD28 binding to this costimulates the T cell

Answer 6

CD80/86

Question 7

this increases T cell response in conjunction with TCR

Answer 7

costimulatory molecule
= cannot act unless TCR is engaged

Question 8

co-inhibitoy receptors in T cells

Answer 8

CTLA-4
PD-1

Question 9

CTLA-4 is expressed ____ after a naive cell is activated

Answer 9

24 hrs

Question 10

T or F. CTLA-4 expressed at lower levels than CD28

Answer 10

T, but binds to CD80/86 with greater affinity than CD28

Question 11

diseases when T cell signalling is defective

Answer 11

SCID (severe combined immunodeficiency)

leukocyte-adhesion defect (LAD)

Question 12

SCID

Answer 12

ZAP70 defect

defective signal from TCR

Question 13

LAD

Answer 13

LFA-1

defective T-APC adhesion

Question 14

T or F. Coreceptors are required for TCR signal

Answer 14

T

Question 15

coreceptors

Answer 15

CD4 and CD8

Question 16

T or F. TCR and CD3 hav no intrinsic kinase activity

Answer 16

T, utilize ITAMs

Question 17

how does tyrosine phosphorylation of a protein modify its function?

Answer 17

1. regulate a protein’s enzymatic activity
2. regulate interactions bw proteins
   - Src homology 2 (SH2) and protein binding domains bind phosphorylated tyrosines
3. regulate a protein’s subcellular localization

Question 18

T cell immune checkpoints co-inhibitory receptors

Answer 18

CTLA-4 and PD-1

Question 19

CTLA-4 ligand

Answer 19

CD80/86 or B7
- expressed by professional APCs

Question 20

what does CTLA-4 and CD80/86 do?

Answer 20

negative regulation of the immune response
= maintaining peripheral T-cell tolerance; reducing inflamation; contracting T-cell pool after infection is cleared

Question 21

PD-1 ligand

Answer 21

PD-L1 or PD-L2
- expressed by professional APCs, some T and B cells, and tumor cells

Question 22

activity of PD-1 and PD-L1/PD-L2

Answer 22

negative regulation of the immune response, regulation of Treg differentiation

Question 23

T or F. CTLA-4 is expressed 18 hrs after naive cells are activated

Answer 23

F! 24 hrs

Question 24

T or F. CTLA-4 is expressed at lower levels than CD28

Answer 24

T! BUT it binds to CD80/86 with greater affinity than CD28

Question 25

Ipilimumab

Answer 25

An anti-cancer drug that block CTLA-4 from binding to 80/86 = can increase T cell response to kill tumor cells

Question 26

T or F. CTLA-4 and PD-1 both have ITIM sequences

Answer 26

F! CTLA-4 does not but PD-1 does

Question 27

how have tumor cells adaptive to use PD-1 for their own good?

Answer 27

Tumor cells express PD-L1 to shut down T cell response

BUT our counter = we have also developed immune checkpt inhibitors to block that rxn = T cell remains active = recognizes antigen on tumor cell and kill It

Question 28

what mechanisms do T cells use for activation induced cell death?

Answer 28

Fas/FasL

Question 29

Describe activation induced cell death

Answer 29

1. naive cell does not express Fas/FasL until it recognizes Ag
2. in presence of repeated activation (antigen not being dealt with) = identical T cells express separated Fas receptors and ligand
3. high Bcl-XL = anti-apoptotic
4. when lack of Ag stimulation = Bcl-XL low so FasL and Fas bind to make T cell apoptotic

Question 30

patients with defective Fas-FasL

Answer 30

• important for peripheral deletion of autoreactive T cells, limiting T cell expansion and shutting down T cell response
• clinical relevance for lymphoproliferative diseases

Question 31

what happens when ZAP70 is defective?

Answer 31

SCID = defective signal from TCR

Question 32

what happens when LFA-1 is defective?

Answer 32

leukocyte-adhesion defect (LAD) = defective T-APC adhesion