T Cell Signalling Flashcards
T or F. Each TCR is specific for combination of peptide and at least two MHCs
F! only in the context of one MHC
T helper cell activation steps
- TCR + antigen bound to MHC
- costimulation and survival signals
- IL-2 and IL-2R = poliferation
when is costimulatory interaction important
signal #2 needs to happen if cell has never seen antigen before
TCR two main problems
exceptionally low affinity for MHC + Ag; don’t adhere very well without accessory molecules
TCR and CD3 have no intrinsic kinase activity
ITAM
immunoreceptor tyrosine-based activation motif
allows different kinases to phosphorylate CD3 tyrosines ?
important for downstream signalling
CD28 binding to this costimulates the T cell
CD80/86
this increases T cell response in conjunction with TCR
costimulatory molecule
= cannot act unless TCR is engaged
co-inhibitoy receptors in T cells
CTLA-4
PD-1
CTLA-4 is expressed ____ after a naive cell is activated
24 hrs
T or F. CTLA-4 expressed at lower levels than CD28
T, but binds to CD80/86 with greater affinity than CD28
diseases when T cell signalling is defective
SCID (severe combined immunodeficiency)
leukocyte-adhesion defect (LAD)
SCID
ZAP70 defect
defective signal from TCR
LAD
LFA-1
defective T-APC adhesion
T or F. Coreceptors are required for TCR signal
T
coreceptors
CD4 and CD8
T or F. TCR and CD3 hav no intrinsic kinase activity
T, utilize ITAMs
how does tyrosine phosphorylation of a protein modify its function?
- regulate a protein’s enzymatic activity
- regulate interactions bw proteins
- Src homology 2 (SH2) and protein binding domains bind phosphorylated tyrosines - regulate a protein’s subcellular localization
T cell immune checkpoints co-inhibitory receptors
CTLA-4 and PD-1
CTLA-4 ligand
CD80/86 or B7
- expressed by professional APCs
what does CTLA-4 and CD80/86 do?
negative regulation of the immune response
= maintaining peripheral T-cell tolerance; reducing inflamation; contracting T-cell pool after infection is cleared
PD-1 ligand
PD-L1 or PD-L2
- expressed by professional APCs, some T and B cells, and tumor cells
activity of PD-1 and PD-L1/PD-L2
negative regulation of the immune response, regulation of Treg differentiation
T or F. CTLA-4 is expressed 18 hrs after naive cells are activated
F! 24 hrs
T or F. CTLA-4 is expressed at lower levels than CD28
T! BUT it binds to CD80/86 with greater affinity than CD28
Ipilimumab
An anti-cancer drug that block CTLA-4 from binding to 80/86 = can increase T cell response to kill tumor cells
T or F. CTLA-4 and PD-1 both have ITIM sequences
F! CTLA-4 does not but PD-1 does
how have tumor cells adaptive to use PD-1 for their own good?
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
what mechanisms do T cells use for activation induced cell death?
Fas/FasL
Describe activation induced cell death
- naive cell does not express Fas/FasL until it recognizes Ag
- in presence of repeated activation (antigen not being dealt with) = identical T cells express separated Fas receptors and ligand
- high Bcl-XL = anti-apoptotic
- when lack of Ag stimulation = Bcl-XL low so FasL and Fas bind to make T cell apoptotic
patients with defective Fas-FasL
- important for peripheral deletion of autoreactive T cells, limiting T cell expansion and shutting down T cell response
- clinical relevance for lymphoproliferative diseases
what happens when ZAP70 is defective?
SCID = defective signal from TCR
what happens when LFA-1 is defective?
leukocyte-adhesion defect (LAD) = defective T-APC adhesion
