Lecture 5/6: T Cells Flashcards
Phases of normal healthy T response
- Infection -> surveillance + Ag capture
- Activation + clonal expansion
- Contraction + memory
How do dendritic cells present Ags?
DCs capture Ags and migrate via lymphatics to lymph nodes where they can interact with T cells
DC activation processes
- Epithelial detachment
- Extravasation to lymphatics
- Upregulation of MHC II, ICAM-1, B7 co-stim., CCR-7 chemokine R
How do T cells enter and exit lymph nodes?
- Entry following chemokines from arteries
- Exit via High Endothelial Venules (L-selectin, LFA-1 integrin expression binds HEV L-selectin ligand + ICAM-1)
2 signal model of T cell activation
2 stimuli are both necessary for activation
1. Ag recognition via TCR::MHC
2. Co-stimulatory molecule engagement
-> 3rd differentiation signal for appropriate response
How do APCs co-stimulate T cells? What does this do?
APC activation -> B7 upregulation -> interaction w/ T cell CD28 -> T cell IL-2, LFA-1 upreg.
What does IL-2 do for T cells?
T cell activation -> T cell IL-2, IL-2R, IL-2 mRNA stabilization upreg. -> expansion
T cell immune synapse
- CD4 co-receptor + TCR -> MHC
- CD3 molecules assoc. w/ TCR
- ITAM signal transducers assoc. w/ CD3
- CD28 co-stim. w/ B7 -> T cell LFA-1 + APC ICAM-1 stabilize synapse
Ag recog. + co-stim. + cell-cell stabilization -> TCR complex cluster -> max signal transduction -> IL-2 upreg.
ITAMs
Immunoreceptor Tyr-based Activation Motifs
LCK kinase on T cell immune synapse
Assoc. w/ CD4/CD8 receptor; Pi of CD3 zeta domain ->->-> nuclear translocation signals to IL-2 promoter
Inhibitory signals of TCR synapse
e.g. CTLA-4, PD-1 on T cell (B7, PD-L1/L2)
Belatacept
Checkpoint inhibitor; CTLA-4 fusion protein that blocks B7 binding to CD28 -> immune suppression
S1P
Expressed on medullary lymphatics in LN; guides T cell exit (T cell upreg. S1PR over time)
CD4+ Th subsets
- Th1
- Th2
- Th17
- Tfh
Th1 cells
- vs IC microbes
- Recognize MHC II
- Produce cytokines for phagocyte activity + pro-inflam.
Th1 differentiation
- IC microbes recognized by APCs
- mφ/DC -> IL-12, NK cells -> IFN-gamma
- TBET, STAT1/4 transc. fact. -> Th1 phenotype, repress others
- Th1 IFN-gamma (mφ’s) + IL-2 (CTLs) secretion
CTLs
- vs IC microbes
- Recognize MHC I
- Kill infected cells
How do Th1s activate mφ’s?
IFN-gamma, CD40L expression engages activated mφ:
- mφ oxidative burst
- mφ TNF, IL-1, IL-12 release (inflam., mφ recruit.)
- mφ MHC, B7 upreg.
CTL activity process
- Ag recognition -> CTL binds target cell
- CTL activation + granule exocytosis (granzymes, perforin)
- Target cell apoptosis
- CTL detaches and searches for new target
Th cells for EC microbes
- Th2: helminths
- Th17: stim. defensin production, recruit neutrophils
- Tfh: promote high-affinity Ab production
Anti-helminth response
- IL-4 release by mast cells, eosinophils, Th2 cells
Th2 differentiation
- GATA3, STAT6 TFs -> Th2 differentiation -> IL-4/-5/-13 release
Th2 signaling effectors
- IL-4/-13 -> alt. mφ activation (M2)
- IL-4 -> B cell Ab production
-> mast cell degranul., GI mucus secretion, peristalsis, eosinophil activation
Th17 differentiation
vs EC bacteria + fungi
1. APCs release IL-1/-6, TGF-beta, IL-23
2. STAT3 -> RORγt TFs -> Th17 differentiation
3. Th17 IL-17/-22 release
Th17 cytokine effects
- Protects epihelial/mucosal barriers, pro-inflam.
IL-17: - Inflam. + neutrophil response
- Anti-microb. peptide release (defensins)
IL-22: - Increase barrier integrity via tight junctions
Treg functions
Limit CD4/CD8 T cell function
- CTLA-4 expression
- Absorb IL-2
IC microbe immune evasion
- Mycobacteria block phagolysosomes
- HSV, CMV, EBV inhibit MHC I Ag presentation
- EBV/CMV –| proteasome process.
- HSV –| TAP ER transporter
- CMV –| MHC 1::peptide ER export - EBV, pox virus cytokines inhib. T cell function
- EBV -> IL-10 release –| mφ activation
- Pox -> IL-1/IFN-gamma receptors –| effector cell cytokine actions
