T cells: cytotoxic T lymphocytes Flashcards
Describe fas ligand and cd40 Ligand
Important for cd8 and some cd4 T cells
Expressed on surface of effector T cells - not expressed on naive T cells
Included in genes induced following signals 1,2,3
Why are fas ligand and cd40 ligand important
Crucial for effector T cell function
Describe cd40L AND fasL
Transmemrane ligands, part of tnf fam
Cell to cell interaction
What expresses fas ligand
Surface of effector cd8+ cells and Th1 cells
What does fas ligand do
Used by cd8+ T cells to exert cytotoxic effect
Bind fas on surface of infected cells in periphery-site infection
What expresses cd40 ligand
Expressed by th1, th2, th17, tfh cells
What does cd40 ligand do
Binds cd40 on B cells and innate immune cells (dcs)
Used to activate target cells
Allows for dc licensing - cross presentation and of more co stimulatory molecules
Describe effector ctl generating
From naive cd8+ precursors
Signal 1, 2 and 3
Describe signal 1 cd8+ T cells
Tcr binds peptide presented by apc on Mhc. Class.1
Describe signal 2 cd8+ T cells
Co stimulatory signal transmitted by cd28-b7(cd80/86) interaction between T cell and apc
Describe signal 3 cd8+ T cells
Il-2 = mostly
Other cytokines to some extent - il-12
Induces proliferation and differentiation into ctl form
What do cd8+ T cells require more of
More co stimulation
Describe cytokines for cd8+
Il-2 can be autocrine (mostly) and paracrine from th1 or th17 cell
Cd8+ cells need help of
Often require help fo effector cd4+ T cells
What do ctls do
Reorganize and kill infected/tumour cells via recognition with their tcr - has to bind match
Name the 2 ways cd8+ T cells can be activated
Simplest and rarely
Majority
Describe simplest and rarest way of cd8+ T cell activation
By activated dcs that have high co stimulatory activity - in some viral infections, dc becomes infected and sufficiently activated (endogenous then presented on mhc1)
Rare = bc each virus has their specific host cell - unlikely to infect immune cells, especially dcs
Describe the way majority of cd8+ T cells activated
Additional help with cd4 effector T cells and licence dcs to Cross present - dcs take up = exogenous
Sequential or simultaneous activation
Describe sequential activation - gen
Apc becomes further licensed following interaction with cd4+ T cell
Interacts with cd8+ T cell independently
Th1 expressed cd40L which binds cd40 on dc
Describe sequential activation - specifics
Key part listening = signal apc receives through cd40 singling
Il-2 produced by cd8+ T cells alone induces proliferation - autocrine
Describe simultaneous activation - gen
Apc interacts with both cd4+ and cd8+ T cells at same time
Th1= has to be activated first, also secreted Il-2 = paracrine bc binds to cd8+
For some point in time = dc interacts with cd4+ and cd8+ t cells at same time
Describe simultaneous activation - specifics
Cd40 signalling due to interaction with cd40L on cd4+ T cell important
Il-2 secreted by both cd4+ (paracrine) and cd8+ T cell = induce proliferation of cd8+ cell
What does cd40 signalling lead to
Dc licensing and expression of more co stimulatory molecules
What needs to happen to cd4+ T cells in order for cd8+ T cells activation to occur
To find its p:mhc class 2 match
All 3 signals received
Cd40 ligand gets expressed and binds to cd40 on apc
What needs to happen to dendritic cells to allow them to present antigens to both cd4+ T cells and cd8+ T cells
Encounter a pamp
Travels to secondary lymphoid organ - lymph node as mature dc
Present antigen on Mhc class 2 to cd4+ T cell
Get licensed through cd40 binding
Present antigen (from exogenous origin) on mhc class 1 to cd8+ T cell —> cross presentation
Describe activation of cd4+ T cell
Il-2 secretion
Cd40L expression, expressed on immature dc but increases when mature
How is apc licensed
By activated T cells through cd40 binding
Presenting exogenous antigen via mhc class 2
Cross presentation to present antigen via mhc class 1
Describe effects - 2 of licensing
Increases expression of cd60/86 - costimulation
Induction of additional molecule that activates cd8+ T cells - 4-1BBL binds to 4-1BB and cd70 -binds to cd27
= provides costimulatory molecules along with b7
Increased expression of Il-12
What are cd4+ T cells critical for
Critical to generate memory cd8+ T cells
(Thought to be due to other cytokines secreted by cd4+ T cells)
Describe ctl
Naive cd8+ T cells - ctl precursors get activated and differentiate into ctls
Ctl leaves lymph node and travels to site of infection
What can ctls do
Kill infected cells in periphery
Interact of tcr + cd8 coreceptor worry pmhc class 1
How does ctl recognize infected cells
Initial interaction via nonspecific adhesion molecules - anchor down ctl so can scan for peptide
If pmhc isn’t match= ctl moves on
(all nucleated cells express mhc class 1)
If recognize pmhc —> an infected/cancerous cell
= death of infected cell
Name and describe ctl effector functions
Induces apoptosis to kill infected cells = fas-fasL and granules
Secrete cytokines to direct immune response
Describe fas-fasl mediated killing
Effector ctl expresses fasL
Infected cells expresss fas
Signalling cascade involves cleavage of pro caspases —> caspases, = leads to apoptosis of target cell
Procaspase 3 cleaved to active caspase 3 = activates apoptotic enzymes = leads to cell death
Describe granule mediated killing - contact
Ctl first makes contact to target cell via nonspecific adhesion - anchors ctl
Describe granule mediated killing - after contact
After match = specific recognition via tcr:pmhc
Leads to reorganization of cytoskeleton and cytoplasmic contents
Granules at edge of cell - contact area
Granules released at point of cell contact (site of cell contact)
Name granules - cytotoxins of ctls
Perforin
Granzymes - granzyme B
Describe perforin
Deliver enzymes
AIDS in delivering contents of granules into cytoplasm of target cell —> delivers content of granules through forming pores, so granzyme can pass through
PORE FORMING PROTEIN
Describe whole process of granule mediated killling
WHEN tcr on ctl binds pmhc —> triggers intracellualr signalling
Leads to reorganization of intracellular structure
Perforin forms pores
Granzyme b enters cytoplasm of target cell
—> initiates signalling through pro-caspases cleavage into caspases + other factors
—> dna fragmentation and cell death
Destroys outer membrane mitochondria
Describe granzyme
Granzyme b = serine proteases= activated apoptosis once in cytoplasm of target cell
Needs to enter cell to activate caspase 3
SERINE PROTEASE
Describe granules - specifically
Movement of granules towards target cell
Target cell displays membrane blebbing - cytoskeleton break and causes membrane to bulge outwards = classic sign of apoptosis
Describe cell mediated effector responses
Ctls recognize and kill infected or tumour cells via tcr activation
Perforin/granzyme pathways
Fas/fasL pathways
= BOTH CONVERGE ON CASPASE 3 activation leading to apoptosis
Do ctls use granule or fas-fasL mediated killing
Perforin/granzyme = fast acting and ctls primarily use this
Fas-fasL = know as slow acting mechanism, only some cells express this when v stressed
Ctl lytic action enhanced when both mechanisms operate simultaneously
What happens after ctl kills infected cell
Dissociates and restarts process
Has to refind match - do whole cycle, to make sure killing right cell
Induce apoptosis in infected target cells while sparing neighbouring un infected cells
Describe reponse to a viral infection
Type 1 ifn - alpha/beta are important anti viral cytokines - can inhibit or slow viral rep = produced early on
Natural killer cells recognize and kill infected cells and tumour cells by their absence mhc class 1 = later a bit
Virus specific ctls directly kill infected cells = large and latest
- but need cell mediated immunity to clear infection
What do ctls secrete - effect via cytokines
Ifny - type 2 ifn
What can ifny do
Increase mhc class 1 expression in neighbouring cells - higher chance of ctls finding match and killing infected cells
Activated macrophages (with persisting infection- need boost) & stimulates the production of chemokiens that can recruit additional macrophages and cd8+ T cells to sites of infection
What’s difference between type 1 and 2 ifn
Type 1 ifn = potent antiviral effects, effect of prr activation
Type 2 ifn = role in immune response against intracellualr pathogens, secreted by T cells - mainly
