T cells: cytotoxic T lymphocytes

Question 1

Describe fas ligand and cd40 Ligand

Answer 1

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

Question 2

Why are fas ligand and cd40 ligand important

Answer 2

Crucial for effector T cell function

Question 3

Describe cd40L AND fasL

Answer 3

Transmemrane ligands, part of tnf fam
Cell to cell interaction

Question 4

What expresses fas ligand

Answer 4

Surface of effector cd8+ cells and Th1 cells

Question 5

What does fas ligand do

Answer 5

Used by cd8+ T cells to exert cytotoxic effect
Bind fas on surface of infected cells in periphery-site infection

Question 6

What expresses cd40 ligand

Answer 6

Expressed by th1, th2, th17, tfh cells

Question 7

What does cd40 ligand do

Answer 7

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

Question 8

Describe effector ctl generating

Answer 8

From naive cd8+ precursors
Signal 1, 2 and 3

Question 9

Describe signal 1 cd8+ T cells

Answer 9

Tcr binds peptide presented by apc on Mhc. Class.1

Question 10

Describe signal 2 cd8+ T cells

Answer 10

Co stimulatory signal transmitted by cd28-b7(cd80/86) interaction between T cell and apc

Question 11

Describe signal 3 cd8+ T cells

Answer 11

Il-2 = mostly
Other cytokines to some extent - il-12
Induces proliferation and differentiation into ctl form

Question 12

What do cd8+ T cells require more of

Answer 12

More co stimulation

Question 13

Describe cytokines for cd8+

Answer 13

Il-2 can be autocrine (mostly) and paracrine from th1 or th17 cell

Question 14

Cd8+ cells need help of

Answer 14

Often require help fo effector cd4+ T cells

Question 15

What do ctls do

Answer 15

Reorganize and kill infected/tumour cells via recognition with their tcr - has to bind match

Question 16

Name the 2 ways cd8+ T cells can be activated

Answer 16

Simplest and rarely
Majority

Question 17

Describe simplest and rarest way of cd8+ T cell activation

Answer 17

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

Question 18

Describe the way majority of cd8+ T cells activated

Answer 18

Additional help with cd4 effector T cells and licence dcs to Cross present - dcs take up = exogenous
Sequential or simultaneous activation

Question 19

Describe sequential activation - gen

Answer 19

Apc becomes further licensed following interaction with cd4+ T cell
Interacts with cd8+ T cell independently
Th1 expressed cd40L which binds cd40 on dc

Question 20

Describe sequential activation - specifics

Answer 20

Key part listening = signal apc receives through cd40 singling
Il-2 produced by cd8+ T cells alone induces proliferation - autocrine

Question 21

Describe simultaneous activation - gen

Answer 21

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

Question 22

Describe simultaneous activation - specifics

Answer 22

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

Question 23

What does cd40 signalling lead to

Answer 23

Dc licensing and expression of more co stimulatory molecules

Question 24

What needs to happen to cd4+ T cells in order for cd8+ T cells activation to occur

Answer 24

To find its p:mhc class 2 match
All 3 signals received
Cd40 ligand gets expressed and binds to cd40 on apc

Question 25

What needs to happen to dendritic cells to allow them to present antigens to both cd4+ T cells and cd8+ T cells

Answer 25

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

Question 26

Describe activation of cd4+ T cell

Answer 26

Il-2 secretion Cd40L expression, expressed on immature dc but increases when mature

Question 27

How is apc licensed

Answer 27

By activated T cells through cd40 binding Presenting exogenous antigen via mhc class 2 Cross presentation to present antigen via mhc class 1

Question 28

Describe effects - 2 of licensing

Answer 28

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

Question 29

What are cd4+ T cells critical for

Answer 29

Critical to generate memory cd8+ T cells (Thought to be due to other cytokines secreted by cd4+ T cells)

Question 30

Describe ctl

Answer 30

Naive cd8+ T cells - ctl precursors get activated and differentiate into ctls Ctl leaves lymph node and travels to site of infection

Question 31

What can ctls do

Answer 31

Kill infected cells in periphery Interact of tcr + cd8 coreceptor worry pmhc class 1

Question 32

How does ctl recognize infected cells

Answer 32

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

Question 33

Name and describe ctl effector functions

Answer 33

Induces apoptosis to kill infected cells = fas-fasL and granules Secrete cytokines to direct immune response

Question 34

Describe fas-fasl mediated killing

Answer 34

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

Question 35

Describe granule mediated killing - contact

Answer 35

Ctl first makes contact to target cell via nonspecific adhesion - anchors ctl

Question 36

Describe granule mediated killing - after contact

Answer 36

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)

Question 37

Name granules - cytotoxins of ctls

Answer 37

Perforin Granzymes - granzyme B

Question 38

Describe perforin

Answer 38

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

Question 39

Describe whole process of granule mediated killling

Answer 39

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

Question 40

Describe granzyme

Answer 40

Granzyme b = serine proteases= activated apoptosis once in cytoplasm of target cell Needs to enter cell to activate caspase 3 SERINE PROTEASE

Question 41

Describe granules - specifically

Answer 41

Movement of granules towards target cell Target cell displays membrane blebbing - cytoskeleton break and causes membrane to bulge outwards = classic sign of apoptosis

Question 42

Describe cell mediated effector responses

Answer 42

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

Question 43

Do ctls use granule or fas-fasL mediated killing

Answer 43

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

Question 44

What happens after ctl kills infected cell

Answer 44

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

Question 45

Describe reponse to a viral infection

Answer 45

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

Question 46

What do ctls secrete - effect via cytokines

Answer 46

Ifny - type 2 ifn

Question 47

What can ifny do

Answer 47

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

Question 48

What’s difference between type 1 and 2 ifn

Answer 48

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