19 - T cells II: CTLs & cytokine patterns Flashcards
Fas ligand & CD40 ligand Both expressed on
effector T cell surface
o Not expressed on naïve T cell
Ligands = crucial for
effector T cell function
Fas ligand & CD40 ligand are…. ligands, part of what family
Transmembrane ligands
TNF family
Cell-to-cell interaction
-CD40 ligand interact with CD40 on DC
Fas ligand: Expressed on
surface of effector CD8+ & TH1 cell
Used by CD8+ T cell cytotoxic effect
what does Fas ligand do?
Bind Fas on surface of infected cells in periphery (site of infection)
CD40 ligand, Expressed on
helpter T cells: TH1, TH2, TH17 & TFH cells
CD40 ligand bind to
o Binds CD40 on B cells & innate immune cells (DC)
CD40 ligand function:
o Used to activate target cells
o Allow for DC licensing (cross-presentation) & expression of more co-stimulatory molecules
naive CD8+ T cells become…
Cytotoxic T Lymphocytes
3 signals to activate CD8+ T cell
o Signal 1: TCR binds peptide presented by APC on MHC class I
o Signal 2: costimulatory signal transmitted by CD28-B7 (CD80/86) interaction between T cell and APC
o Signal 3: provided mainly by IL-2 & other cytokines (IL-12) induce proliferation & differentiation into CTL form
CD8+ specific considerations (4)
CD8+ cells require more co-stimulatory
IL-2 can be:
Autocrine
Paracrine from TH1 & TH17 cell
Require help of effector CD4 + T cells
Once CD8+ T cells receive all signals = CTLs, what do CTLs do?
CTLs recognize & kill infected/tumour cells by recognition with their TCR
CD8+ T cells can be activated in different ways to become CTLs (2)
Simplest & rarely:
-By activated DC that have high co-stimulatory activity (In some viral infections, DC becomes infected & sufficiently activated)
-it is rare because: virus don’t just infect any type of cell, Each virus has specific host cell & most don’t infect DC
Majority:
-Additional help with CD4 effector T cells & licensing DC to cross present
2 models to activating CD8+ T cells:
sequential & SIMULTANEOUSLY
Sequential
CD4+ T cell activated –> give permission through CD40 ligand binding –> activated CD8+ T cell
APC becomes further licensed following interaction with CD4+ cell
-Key part of licensing = signal APC receives through CD40 signaling
Interacts with CD8+ T cell independently
IL-2 produced by CD8+ T cells alone= induce proliferation (Autocrine fashion)
Simultaneous
CD4+ T cell activated –> effector T cell –> CD40 signaling –> DC licensing
APC interacts with both CD4+ and CD8+ T cells at same time
-A moment in time, the DC interact with both CD4+ & CD8+ T cell
-By chance
Important: CD40 signaling due to interaction with CD40L on CD4+ t cell
IL-2 secreted by both CD4+ & CD8+ T cell -> induce proliferation of CD8+ T cell (paracrine fashion)
CD40 signaling lead to …
DC licensing to cross-present& expression of more co-stimulatory molecules
What needs to happen to CD4+ T cells to activate CD8+ T cells?
o Find its p:MHC class II match
o All 3 signals received
o CD40 ligand gets expressed & binds to CD40 on APC
What needs to happen to DCs to allow them to present antigen to both CD4+ & CD8+ T cells?
o Encounter a PAMP
o Travels to secondary lymphoid organ (lymph node) as a mature DC
o Present antigen on MHC class II to CD43+ T cell
o Gets licensed through CD40 binding
o Presents antigen (from exogenous origin) on MHC class I to CD8+ T cell cross presentation
Activation of CD4+ T cell:
APC licensed by activated CD4+ T cells through CD40 binding:
o IL-2 secretion
o CD40L expression
o Presenting exogenous antigen via MHC class II
o Cross-presentation to present antigen via MHC class I
o Increased expression of CD80/86
o Induction of additional molecule that activates CD8+ T cells
-4-1BBL (bind to 4-1BB) & CD70(bind to CD27)
——-Provide costimulatory molecules along with B7
o Increased production of IL-12
CTL-mediated killing
Naïve CD8+ T cell (CTL precursors) gets activated & differentiates into CTL
CTL leaves lymph node -> travels to site of infection
CTL can kill infected cells in the periphery
-Interaction of TCR (+CD8 co-receptor) with pMHC class I
… cells express MHC class I
All nucleated
- Initial interaction via
nonspecific adhesion molecules
- If pMHC isn’t a match
CTL moves on
- When CTL recognizes pMHC (an infected/cancerous cell)
- Death of infected cell
how does CTL Induce apoptosis to kill infected cells? (2)
o Fas-FasL mediated killing
o Granules-mediated killing
CTL also Secrete cytokines direct immune response
Fas-FasL mediated killing
Effector CTL expresses FasL
Infected cells express Fas
Signaling cascade: cleavage of pro-caspases –>caspases –>apoptosis of target cell
Granules-mediated killing
CTL makes contact to target cell via nonspecific adhesion
Specific recognition via TCR:pMHC
Reorganization of cytoskeleton & cytoplasmic contents (granules & microtubules…)
Granules released at point of cell contact
Granules of CTLs (cytotoxins)
perforin deliver granzyme B
perforin role:
Aids in delivering contents of granules into cytoplasm of target cells
Delivers content of granules through forming pores
Form pores to let granzyme pass through cell
Granzymes – granzyme B role:
Serine proteases: activate apoptosis once in cytoplasm of target cell
Granzyme/perforin-mediated cytolysis
When stimulated CTLs release granule contents
-Perforin = pore-forming proteins
-Granzymes = serine proteases
Perforin punches holes in membranes & granzyme enters to induce apoptosis
steps in Granzyme/perforin-mediated cytolysis
TCR on CTL binds pMHC –> triggers intracellular signaling –> reorganization of intracellular structure & granule release –> perforin forms pores –> granzyme B enters cytoplasm of target cell –> initiates signaling through pro-caspases cleavage into caspases+other factors –> DNA fragmentation & cell death
Membrane blebbing:
cytoskeleton break & causes membrane to bulge outward
-Classic sign of apoptosis
Cell-mediated effector responses
CTLs recognize & kill infected/tumor cells via TCR activation:
-Perforin/granzyme pathways
Fast-acting
Primarily used by CTLs
-Fas/FasL pathways
Slow-acting
Both converge on various caspase 3 activation leading to apoptosis
CTL lytic action – enhances when
both mechanisms operate simultaneously
CTL kills-dissociates-restarts process
- nonspecific adhesion interaction
2.find its match - mediate killing
- dissociate
repeat for each cells
desnt want to kill cells they dont need to kill
Cytotoxic CD8 T cells can induce apoptosis infected target cells while sparing neighbouring uninfected cells
… required in CD8+ T cell activation
CD3
Type I IFN (a/b):
important anti-viral cytokines – can inhibit/slow viral replication
Natural killer cells:
recognize & kill infected/tumor cells by their absence of MHC class I
Virus-specific CTLs directly …
directly kill infected cells
CTLs secrete: … cytokine!
IFNy – Type II IFN
IFNy
o Increase MHC class I expression o infected cells
o Activates macrophages & stimulates production of chemokines - recruit additional macrophages & CD8+ T cells to sites of infection
Type I IFN
potent anticviral effects, effects of PRR activation
Type II IFN
role in immune response against intracellular pathogens - secreted mainly by T cells
