Block 1 Lecture 8 -- T Cells Flashcards
Where is Class I MHC/HLA presented?
to CD8
Describe structure of MHC/HLA Class I.
2 units; 3 disulfides
- alpha + beta2 microglobulin
- peptide-binding cleft (peptide needed for alpha stability)
- transmembrane region
Describe structure of MHC/HLA Class II
2 units; 3 disulfides
- alpha + beta
- peptide binding cleft
- transmembrane region
How is Class I p-MHC associated?
infected cell’s Ag is transported into ER by TAP
- Transporter of Ag Peptides
- MHC I is intra-ER, binds Ag and vesicle goes to PM
How is Class II MHC associated?
ER vesicle containing MHC Class II fuses with phagocytosed vesicle
Where are Class I MHC’s located?
all nucleated cells
Where are Class II MHC’s located?
traditional APCs
What happens when cell presents Ag to CD8?
effector T cell kills Ag-expressing target
What happens when APC present Ag in MHC II to CD4?
effector T cell activates macrophages
effector T cell looks for B partner to stimulate Abs
Describe T cell development
stem – pro – pre – double positive – single positive/immature – mature
from cortex to medulla, to periphery (when naive!)
When do T cells begin expressing CD3?
double positive
Characteristics of Pre-T?
VDJ recombination has occurred
pre-T receptor (single chain)
Characteristics of Double Positive T?
alpha-beta TCR is finished;
undergoing +/- selection
Where are T cells activated?
in medulla of lymph nodes … they circulate through periphery to find Ag in lymph nodes
Describe T-cell requirements for activation?
- TCR-MHC
- CD28–APC costimulatory molecule (B7)
- adhesion interaction with LFA-1
- cytokines (usually IL-12)
How do T cells proliferate?
autocrine IL-2
What proteins are involved in signal transduction for the T-cell when activated?
CD4
CTLA4 and PD1 inhibit!
Waht proteins are involved in Ag recognition for the T-cell during activation?
TCR, CD3 (+ITAM), CD28
What proteins are involved in adhesion during the T cell activation?
LFA-1 (T cell) with ICAM-1 of APC
With what ligand does CTLA 4 interact?
B7
With what ligand does PD-1 interact?
PD-L1
Describe signal transduction during T-cell activation?
TCR lipid raft complex
- Lck phosphorylation pathways
- activation of PLCy1, Ras/MAPK
What are the signature cytokines of Th1 cells?
IFN-y
IgG, macrophage activation
What are the signature cytokines of Th2 cells?
IL-4, IL13, IL5
Th2 amplification, IgE (mast degranulation), gut motility, eosinophils
What are the signature cytokines of Th17 cells?
IL-22
IL-17
(stimulate WBC to release chemokines)
– inflammation, tissue response, anti-microbial peptides
How are Th1’s activated?
**microbes
NK (IFN-y);
DCs and macrophages (IL12)
How are Th2’s activated?
**Helminths, allergy
DCs (MHC2)
mast and eosinophils (IL-4)
How are Th17’s activated?
**bacteria
APCs (MHC2, IL6,1, TGF-beta)
What are the 2 mechanisms of CD8 killing?
1) perforin/granzyme
2) Fas/FasL-mediated
Describe perforin-granzyme killing
perforin induces uptake of granzymes into endosome
caspases are released into cytosol to activate apoptosis
Describe Fas-FasL killing
FasL on CTL binds Fas on target
apoptosis
Describe T-cell exhaustion
chronic infection
pathogens induce B7, PD1L
– no cytokines, reduced proliferation, no target killing
What is the function of Tregs?
prevent self-activation and over-activation
- important in gut flora
- inhibit T, B, NK
What are the anti-cancer immunotherapies acting with T-cells?
Anti-CTLA4 mAb (targets T-cell inhibitory protein)
Anti-PD1/PDL1
– PD1 on T cell
