Mimm 314: T-Cell Mediated Immunity Iv

Front 1

What happesn if naive T-cells are activated by IL-12 (probly from a DC) after APC?

Back 1

differentiate into Th1 IFN-γ producing phenotype

Front 2

What is Th1 important for?

Back 2

Cell mediated immunity
(protecion vs intracellular antigens)
Intracell bact: Mycobacterium
Important of autoimmune disease or delayed-type hypersensitivity

Front 3

What do naive T cells become if expoed to IL-4 (from basophils)?

Back 3

Differetiate into Th2 cells

Front 4

What do Th2 cells secrete?

Back 4

IL-4,5,13

Front 5

What do Th2 protect against?

Back 5

Extracellular pathogens
-parasites
-some bacteria

Front 6

Why are Th2 so good s extracell path?

Back 6

Th2 have the intrinsic capacity to sustain optimal B cell activation, Ab production and isotype switching of the Ag specific Ig

Front 7

What inflammatory conditions are Th2 cells important in?

Back 7

Allergic response
Asthma

Front 8

Why are cellular and humoral activity mutually exclusive?

Back 8

Their 2 cell divergent lineages are mutually exclusive
->Th1 secretes IFN-γ which inhibits differentiation of Th2 cell, counteracting the effects of IL-4
(opposite is true, IL-4 inhibits Th1 cell differentiations)

Front 9

Which extracelullar signalling motifs are reqired for transduction of IL-12 and IFN-γ?

Back 9

Stat1 and Stat4

Front 10

Which extracelullar signalling motifs are reqired for transduction of IL-4 inducing Th2 cells?

Back 10

Stat3

Front 11

How is the Th17 cell lineage created?

Back 11

Needs to be in the presence of:
-TGF-β1 (Transforming growth factor beta1)
-IL-6

Front 12

What does Th17 protect against?

Back 12

Extracellular pathogens
->Fungi
->Bacteria

Front 13

What kind of autoimmne diseases does Th17 trigger?

Back 13

Autoimmune diseases (MS)
Gut ass't diseases

Front 14

Which cytokines, in addition to TGF-β1 and IL-6 are required to sustain Th17 after its differentiation?

Back 14

IL-21: important for susaining imprtant TF: RAR-related orphan receptor gamma T (RORγT)
IL23: Important for sustaining memory and survival of the Th17 lineage

Front 15

What kind of responses are Th cells responsible for?

Back 15

Inflammatory responses

Front 16

What happens if a naive T ell is in the presence of cytokine TGF-β alone or other cmpds like retinoic acid or immature DC?

Back 16

The transcription factor FoxP3 can be induced

Front 17

What type of T cell does Fox3P induce?

Back 17

Regulatory T cell: immunosuppressive and anti-inflammatory cells

Front 18

What do T-reg cells secrete?

Back 18

TGF-β
cytokine IL-10

Front 19

Do all T cells in the body that are immunosuppressive express Fox3P?

Back 19

Not necessarily
But they can still secrete the very same cytokines that arae used by regulatory T cells (TGF-β and IL-10)

Front 20

Are the molecular signatures to ID T-regand Tr1 and Th3 the same?

Back 20

No, the molec signatures needed for their development are distinct, despite the fact that they produce the same cytokines and are all regulatory cells

Front 21

What is the transcription factor T-bet induced by? Which T cell requires T-bet for its development?

Back 21

Induced by IL-12 and IFN-gamma
Needed for Th1 dev'l

Front 22

What induces GATA-3?
What does GATA-3 help develop?

Back 22

Induced by IL-4
Needed for Th2 dev'l

Front 23

Can Th2 trigger CMI?

Back 23

No, only humoral immunity

Front 24

What do regulatory cells?

Back 24

Important in controlling any of the immune responses specific to the suppression of a variety of self and non-self Ag responses

Front 25

What are Tr1/Th3 cells important for?

Back 25

Gut immunology and mucosal ass't lymphoid tssues (MALT) when we need to tolerate foreign Ag

Front 26

What are some examples of foreign Ag against which responses must be tolerated?

Back 26

Bacteria in the gut
Food

Front 27

Which T cells are used for CMI?

Back 27

Th1 and CD8+

Front 28

Which MHC preent to CD8+ and Th1?

Back 28

CD8+: MHC I
Th1: MHC II

Front 29

What is the point of CMI?

Back 29

Cellular activation to kill off the infected cell
->could also have enough cell activation to enable the macrophage to release the necessary inflammatory mediators intracellularly, which would kill the bugs that are inside cellular vesicles

Front 30

What happens in humoral immunity?

Back 30

Enable Ag-specific Th2 cells to activate the requisite B cells to release the Ag-specific Ig to bind to the bug present in the extracellular env't

Front 31

How can Th1 cells be required in HI?

Back 31

Sometimes the release of IFN-γ by Th1 is required to establish some Ab production

Front 32

What determines the nature of a response?

Back 32

The dominance of one cell type

Front 33

What is the main role of Th1 cells?

Back 33

Activate APCs
->use a variety of cytokines: IFN-γ. TNF

Front 34

What are Th2 cells mostly for?

Back 34

B-cell activation. B cell survval, Ig production and isotype switching (in fomr of cytokines IL4/5/13)

Front 35

What happens if you infect an animal with Citrobacter rodentium (pathogenic form of E. coli)?

Back 35

Prominetn Th17 rewsponse
.: IL-17 is a primary neutrophil recruiter
->allows for inflammation before the pathogen dominates the host

Front 36

Diversity of effector cells.
Th1 exclusively

Back 36

IFN-γ prominent cytokine here
Ass't with co-production of IL-2 and TNF-β
Activation of APCs

Front 37

Diversity of effector cells.
Th2 exclusively

Back 37

IL-4: prominent cytokine
Also make IL-5
Some Th2 make IL-10: this helps Th2 control Th1 (through action of IL-10) and in a way makes it a regulatory/immunomodulatory T-cell pop'n
(Th1 also serve to regulate Th2 cell population)

Front 38

Diversity of effector cells.
Combination of Th1 and Th2

Back 38

Cytokines shared with both lineages: IL-3, TNF-α and GM-CSF (granulocyte-macrophage colony stimulating factor)

Front 39

What can GM-CSF do?

Back 39

specifially induce the production of a variety of granulocytes, myeloid cells and dendritic cells to support the necessary response

Front 40

Diversity of effector cells.
T-reg cells.

Back 40

Many produce TGF-β1: prominent cytokine
->certain tumour cells release excessive amounts of this factor
->TGF-β1 has mostly inhibitory fcts
->Has immunostimulatory effects in the form of production of certain Ab (ex: IgA in the gut)

Front 41

Diversity effector function.
Th17 cells

Back 41

-Make IL-17
->can make IFN-γ (like Th1 can make IL-17)
Th17 might just be a transition from Th1 ince it makes similar cytokines

Front 42

How can Th2 supress Th1?

Back 42

Use IL10 to:
-directly inhibit activation and growth of Th1 cells
-acting directly on APCs in order to supress co-stimulation of HLA-B71 and HLA-B72 (ultimately suppresses the dev'l of Th1 cells)

Front 43

What does IFN-γ do to Th2?

Back 43

Acts directly pm Th2 to inhibit their proliferation, as well as the activity of TF GATA3

Front 44

How can regulatory cells suppress immune responses by Th1 and Th2?

Back 44

It makes TGF-β

Front 45

Why are Th1 important for CMI?

Back 45

Can potentially activate infected macrophages/APCs through the activity of CD40L and the secretion of IFN-γ

Front 46

What does IFN do to macrophages?

Back 46

-Act on mac to enable it to secrete the necessary O2 radicals and nitric oxide
-IFN-γ also allows the mac to secrete the req'd TNF-α
->TNF-α acts in an autocrine way, directly triggering its own reeptor on the macrophage surface
->TNF can also come from the Th1 cells: it can be a product of activated T cells that can also act in an autocrine manner

Front 47

What would happen if the activity of TNF-α was blocked?

Back 47

Block the autocrine mechanism

Front 48

What does the activation of TNF-α do?

Back 48

Activates the killing mechanisms intracellularly
->also helps the immune response by feeding back on the T cells so as to increase the magnitutde/quality of Ag presentation

Front 49

What happens when a macrophage is activated?

Back 49

Gets the capacity to wipe out the infected vesicles within the cells
->also instructs the macrophage to sustain its own activation by virtue of the secretion of TNF-α

Front 50

What can Th1 synthesize?

Back 50

CD40L: sensitizes the APC
Direct secretion de novo of IFN-γ

Front 51

Why are Th2 ineffective at activating macrophages?

Back 51

Secrete Il-10 or Il-4 that deactivates macrophages
->Th2 can help an infecting microbe to survive in the cell body

Front 52

Why can activated infected macrophages be damaging to tissus and extracellular pathogens?

Back 52

They secrete O2 radicals, nitric oxide, proteases, antimicrobial peptides that can damage things

Front 53

What are granulomas?

Back 53

Anatomicl structures:
-At the centre of the core, have multi-nucleated giant cells, which are a variety of infected macrophages infefcted with a bact (Mycobac)
-Epithelioid cells are larger structures outside the core
-On periphery of granuloma (infected site) have ring of T-cells

Front 54

What are granulomas a sign f?

Back 54

Immune attack

Front 55

How can Th1 cells support CMI?

Back 55

-Cellular activation with CD40L and the likes
-support killing of infected cells directly through Fas ligand or LT-α
-production of IL-2: support prolif of other Ag-specific cells in a clonal manner
-secretion of IL-3 and GM-CSF support differentiation of the requisite stem cells and progenitors in the bone marrow
-Homing and accumulatio directly in the infected site by activating the endothelium to induce macrophage binding and exit from the blood vessel to get into the non-lymphoid infcted sites ->done through secretion of TNF-α and LT-β

Front 56

What can CCL2 do?

Back 56

Chemokine important in the accumulation of the immune cells at the site of infection (made by Th1 to support CMI)

Front 57

What does the capacity of Th2 to support Ag-specific Ig depend on?

Back 57

Capacity to get specific physical cellular interactions with the B cells to enable the B cell to make necessary Ig to neutralize the virus

Front 58

What conditions the B cells to produce Ig?

Back 58

IL-4 (produced by Th2)

Front 59

What is absolutley req'd for B cells to make Ig?

Back 59

CD40/CD40L path to sustain a response

Front 60

What do CD8 cells depend on to go from infected to non-infected cells to decide if it should ct on the cell or not?

Back 60

LFA-1

Front 61

What happens when Cd8 encounters an unifected cell?

Back 61

CD8 bond with adhesion molec LFA-1
If cell uninfected, then the CD8 will be released and go to another cell type

Front 62

What happens when CD8 detects an infected cell?

Back 62

Binds LFA-1
MHC I presentation occurs
TCR signalling will occur, as will co-stimulation
Instruction for the target cell to die
Death of target cell
Release of CD8 cell follows
CD8 free to go onto another cell type

Front 63

What is this mechanism by CD8?

Back 63

Ag-specific induction of apoptosis in target cells by CTL

Front 64

What does this killing process depend on?

Back 64

Capacityof CD8 clls to secrete certain mediators which let the cell die
->ptns in the ganules of CTLs that le it kill infected target cells

Front 65

What are these mediators?

Back 65

Perforin: helps delvery of contents of granules into the cytoplasm of the target cell
Granzymes: secreted through vesicles created i the TARGET cell
->perforins make holes in the target cells through which products like granzymes can travel through
Granulysin: anti-microbial actions, can induce apoptosis

Front 66

What are the steps of apoptosis?

Back 66

Engagement of TCR by the specific MHC/peptide combination
Results in specific release of perforin/granzyme combination on the virally infected cell
Granzyme delivered in the cytosol of the infected cell and targets a variety of vell mediators:
->BID
->Inactive form of caspase 4: procaspase 3
Granzymes truncate BID, which disrupt mito activity, activate caspase 3 and initiate the downstream cleaving events of the target cell DNA to target the cell for apoptosis
->this sequence of events happens in sec-min after cognate recognition of the Ag-specific CD8 cell

Front 67

What is needed for optimal Ag-specific CD8?

Back 67

Efficient Th1

Front 68

What nduces secretion of IL-12 by DC?

Back 68

Viruses and some bacteria

Front 69

What does this IL-12 act on?

Back 69

NK cells (activates them)
->sensitization of NK cells by IL-12 coming from the infected DC can result in copious production of IFN-γ, which can support th dev'l of Th1
-Th1 can in turn act on DC to make it kill the intracellular microbe

Front 70

What do extracelluar pathogens do?

Back 70

Make NK T cells secrete cytokines like IL-4 (can support activities and development of Th2 cells)
->these Th2 cells can produce Ig that can neutralize the worm before it can get into the cell

Front 71

Can the smae APC induce either Th1 or Th2?

Back 71

Yes, depending on the condition
(same for Th17/T-reg)

Front 72

What does CD4 cell express when no infection?

Back 72

A lot of TGF-β1, very little IL-6
->CD4 T cells are activated to express FoxP3 and show regulatory phenotype (can supress any one of the 2 primary T helper cells)
->get immune control of immunity and pathology of a pre-existing immune response)

Front 73

What happens when there is an infection?

Back 73

Signals from pathogen condition the Ag-presenting cell to make IL-6, which in conjunction with TGF-β1 can conditon the same CD4 as before to:
-Induce expression of RORγT
-Synthesize IL-17
-Play an important role in neurophil or immune cell recruitment
-->Infection results in release of immunosuppresion to allow the system to counteract the infection
->do this by letting infection modify cytokine env't to get right cytokine cocktail
->this deactivated T-reg cells and lets one dev'l immunity vs specific Ag

Front 74

What can induce bystander CD8 T cells to make IFN-γ?

Back 74

IL-12 and IL-18

Front 75

What happens in cytokine mediated bystander resistance to infection?

Back 75

Activation that conditioned the CD8 cells to make IFN-γ
Bystander CD8 cell that IFN-γ acts on might not be specific for the same epitope that is presented by the DC cell
-Inflammation can spread wildly (non-specifically) as a result (this is why we want reg'l)

Front 76

What triggers apoptosis in T cells?

Back 76

TNF α/β
(also FAS ligand)
Expressed on the surface of effector T cell

Front 77

What do T cells apotose?

Back 77

Kill target cel that express the receptors Fas or TNFR-1

Front 78

What else express Fas?

Back 78

Activated lymphocytes (in addition to expressing the FAS ligand)

Front 79

Why are Fas and TNFR-1 important at initiating death?

Back 79

Have DEATH domain in their cytoplasmic region/tails
->Induces apoptosis (programmed cell death) in activated lymphocytes

Front 80

What happens if Fas or Fas-L (both are expressed on recently/highly activated cells)are mutated?

Back 80

->leads to lymphoproliferative and autoimmunedisorders
-> get an accumulation of activated cells (many of which are self-reactive)
->Intrinsic mech for control has been destroyes, homeostasis lost and you get autoimmunity

Front 81

What 2 families can regulatory Tcells comfrom?

Back 81

1-Thymus: T cell made there and then moves to periphery
->Post-thymically or peripherally induced regulatory cells: T cell becomes FoxP3 cell to control Th cell responses
2-Precursor dev'l endogenously (NOT in t periphery, but in the thymus as a thymocyte)
->these ones are instructed to become immunosuppressive in the thymus (born immnosuppressive)
->thymically-derived, naturally occuring regulatory cell (might look like post-thymic FoxP3 cell)

Front 82

Which regulatory cells are key to balance between tolerance and immunity?

Back 82

CD4+ FoxP3 T-reg

Front 83

What do these cells constitutively express?

Back 83

IL-2 receptor alpha chain
(cuz they have a higher affinity for self Ag than do conventional cells)

Front 84

What % of cells do these T ells make up?

Back 84

1-10% of CD4+ T cells
Are professionally anergic (don't respond)

Front 85

Why don't these cells proliferae on their own? What is required to actvate them?

Back 85

Don't make their own IL-2
Need IL-2 to be activated

Front 86

what is an important marker and switch factor for these cells?

Back 86

FoxP3

Front 87

What happens if FoxP3 is removed or mutated?

Back 87

No developmetn of these cells
=>death
-scruvy in mice
-IPEX in humans (x-linked disease, young boys susceptible to it)

Front 88

What are features of these CD4+ FocP3+ T-reg cells?

Back 88

Immunosuppressive in vivo and in vitro
Suppression of a wide variety of cell types (CD4-> NK)
In vitro: need contact with target
In vivo: cytokines, depending on the circumstances, can make 1+ cytokines
Can develop in th periphery from conventional cells
Hurt their fct in some way: auto immuity occurs
If proficiency/# of these cells is increased: we are immunosuppressed an susceptible to tumours and pathogens
-These cells are targets for immunotherapy

Front 89

What are the 3 stages of infection by a parasite?

Back 89

Silent phase: pathogen enters, but doesn't affect immune response (pathogen makes a home)
Acute: parasite #'s dec and stabilize. This timeframe coincids with the induction of optimal immunty (indicated by size of granuloma/lesion)
As granuloma size inc, # of parasites dec
Chronic phase: tug-of war between regulatoy and effector mech in form of dif cytokines

Front 90

What happens if you're reifected with the same pathogen?

Back 90

Completely resistant to it

Front 91

What are the mechanisms that support the IL-10 producving FoxP3?

Back 91

Inc susceptibility
Decrease Th1 responses (that are otherwise req'd for cell activation and eradication of microbes)
Pathogen persistance (chronic phase)
Complete resistance to secondary infections

Front 92

What are the mechanisms that support IFN-γ producing T-effector cells?

Back 92

Inc resistance to primary infection
Inc Th1 respons
Pathogen clearane
High susceptibility to secondary infections

Front 93

What happens when adaptive immunity is maximal?

Back 93

Bug burden goes back down to the point of pathogen clearance

Front 94

What happens in ppl whose lymphocyte dev'l has been abrogated?

Back 94

Initial phase of infection is the same as in normal ppl
->at point where adaptive should take place, the infection is completely uncontrollable

Front 95

What is the innate req'd for?

Back 95

Signalling through TLRs (require ptn MyD88)
I

Front 96

What happens if we remove MyD88?

Back 96

Cell type no longer responsive to most TLR signals
->won't have enough Il-12 and IFN-γ
Innate immne response critical for the initiation and support of subsequrnt adaptive immune responses

Front 97

Describe effector memory T cells

Back 97

Lack chemokine receptor CCR7
Secrete large amounts of IFN-γ, IL4 and IL5 or cytotoxic mediators (CD8+ effector memory cells)
Express high levels of β1 and β integrins
Traffic to tissues

Front 98

Describe central memory T cells

Back 98

Express CCR7 (receptor for SLC/CCL21)
Take longer to differentiate then effector T cells
Traffic to LN

Front 99

What is req'd for entry of T-cells to LN?

Back 99

L-selectin binding
Followed by CCR7 signalling by SLC
->this code is expressed by naive T cells and CCR7+ central memory T cells (but not by effector memory T cells)

Front 100

What are memory cells for?

Back 100

Dev'p of effecor and memory cells important for control of infection -> vaccination

Front 101

What is req'd for the best CD8 response?

Back 101

Optimal CD4: support sufficient CD8 differentiation/activation