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101 Cards in this Set

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What happesn if naive T-cells are activated by IL-12 (probly from a DC) after APC?
differentiate into Th1 IFN-γ producing phenotype
What is Th1 important for?
Cell mediated immunity
(protecion vs intracellular antigens)
Intracell bact: Mycobacterium
Important of autoimmune disease or delayed-type hypersensitivity
What do naive T cells become if expoed to IL-4 (from basophils)?
Differetiate into Th2 cells
What do Th2 cells secrete?
IL-4,5,13
What do Th2 protect against?
Extracellular pathogens
-parasites
-some bacteria
Why are Th2 so good s extracell path?
Th2 have the intrinsic capacity to sustain optimal B cell activation, Ab production and isotype switching of the Ag specific Ig
What inflammatory conditions are Th2 cells important in?
Allergic response
Asthma
Why are cellular and humoral activity mutually exclusive?
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)
Which extracelullar signalling motifs are reqired for transduction of IL-12 and IFN-γ?
Stat1 and Stat4
Which extracelullar signalling motifs are reqired for transduction of IL-4 inducing Th2 cells?
Stat3
How is the Th17 cell lineage created?
Needs to be in the presence of:
-TGF-β1 (Transforming growth factor beta1)
-IL-6
What does Th17 protect against?
Extracellular pathogens
->Fungi
->Bacteria
What kind of autoimmne diseases does Th17 trigger?
Autoimmune diseases (MS)
Gut ass't diseases
Which cytokines, in addition to TGF-β1 and IL-6 are required to sustain Th17 after its differentiation?
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
What kind of responses are Th cells responsible for?
Inflammatory responses
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?
The transcription factor FoxP3 can be induced
What type of T cell does Fox3P induce?
Regulatory T cell: immunosuppressive and anti-inflammatory cells
What do T-reg cells secrete?
TGF-β
cytokine IL-10
Do all T cells in the body that are immunosuppressive express Fox3P?
Not necessarily
But they can still secrete the very same cytokines that arae used by regulatory T cells (TGF-β and IL-10)
Are the molecular signatures to ID T-regand Tr1 and Th3 the same?
No, the molec signatures needed for their development are distinct, despite the fact that they produce the same cytokines and are all regulatory cells
What is the transcription factor T-bet induced by? Which T cell requires T-bet for its development?
Induced by IL-12 and IFN-gamma
Needed for Th1 dev'l
What induces GATA-3?
What does GATA-3 help develop?
Induced by IL-4
Needed for Th2 dev'l
Can Th2 trigger CMI?
No, only humoral immunity
What do regulatory cells?
Important in controlling any of the immune responses specific to the suppression of a variety of self and non-self Ag responses
What are Tr1/Th3 cells important for?
Gut immunology and mucosal ass't lymphoid tssues (MALT) when we need to tolerate foreign Ag
What are some examples of foreign Ag against which responses must be tolerated?
Bacteria in the gut
Food
Which T cells are used for CMI?
Th1 and CD8+
Which MHC preent to CD8+ and Th1?
CD8+: MHC I
Th1: MHC II
What is the point of CMI?
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
What happens in humoral immunity?
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
How can Th1 cells be required in HI?
Sometimes the release of IFN-γ by Th1 is required to establish some Ab production
What determines the nature of a response?
The dominance of one cell type
What is the main role of Th1 cells?
Activate APCs
->use a variety of cytokines: IFN-γ. TNF
What are Th2 cells mostly for?
B-cell activation. B cell survval, Ig production and isotype switching (in fomr of cytokines IL4/5/13)
What happens if you infect an animal with Citrobacter rodentium (pathogenic form of E. coli)?
Prominetn Th17 rewsponse
.: IL-17 is a primary neutrophil recruiter
->allows for inflammation before the pathogen dominates the host
Diversity of effector cells.
Th1 exclusively
IFN-γ prominent cytokine here
Ass't with co-production of IL-2 and TNF-β
Activation of APCs
Diversity of effector cells.
Th2 exclusively
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)
Diversity of effector cells.
Combination of Th1 and Th2
Cytokines shared with both lineages: IL-3, TNF-α and GM-CSF (granulocyte-macrophage colony stimulating factor)
What can GM-CSF do?
specifially induce the production of a variety of granulocytes, myeloid cells and dendritic cells to support the necessary response
Diversity of effector cells.
T-reg cells.
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)
Diversity effector function.
Th17 cells
-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
How can Th2 supress Th1?
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)
What does IFN-γ do to Th2?
Acts directly pm Th2 to inhibit their proliferation, as well as the activity of TF GATA3
How can regulatory cells suppress immune responses by Th1 and Th2?
It makes TGF-β
Why are Th1 important for CMI?
Can potentially activate infected macrophages/APCs through the activity of CD40L and the secretion of IFN-γ
What does IFN do to macrophages?
-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
What would happen if the activity of TNF-α was blocked?
Block the autocrine mechanism
What does the activation of TNF-α do?
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
What happens when a macrophage is activated?
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
What can Th1 synthesize?
CD40L: sensitizes the APC
Direct secretion de novo of IFN-γ
Why are Th2 ineffective at activating macrophages?
Secrete Il-10 or Il-4 that deactivates macrophages
->Th2 can help an infecting microbe to survive in the cell body
Why can activated infected macrophages be damaging to tissus and extracellular pathogens?
They secrete O2 radicals, nitric oxide, proteases, antimicrobial peptides that can damage things
What are granulomas?
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
What are granulomas a sign f?
Immune attack
How can Th1 cells support CMI?
-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
What can CCL2 do?
Chemokine important in the accumulation of the immune cells at the site of infection (made by Th1 to support CMI)
What does the capacity of Th2 to support Ag-specific Ig depend on?
Capacity to get specific physical cellular interactions with the B cells to enable the B cell to make necessary Ig to neutralize the virus
What conditions the B cells to produce Ig?
IL-4 (produced by Th2)
What is absolutley req'd for B cells to make Ig?
CD40/CD40L path to sustain a response
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?
LFA-1
What happens when Cd8 encounters an unifected cell?
CD8 bond with adhesion molec LFA-1
If cell uninfected, then the CD8 will be released and go to another cell type
What happens when CD8 detects an infected cell?
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
What is this mechanism by CD8?
Ag-specific induction of apoptosis in target cells by CTL
What does this killing process depend on?
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
What are these mediators?
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
What are the steps of apoptosis?
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
What is needed for optimal Ag-specific CD8?
Efficient Th1
What nduces secretion of IL-12 by DC?
Viruses and some bacteria
What does this IL-12 act on?
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
What do extracelluar pathogens do?
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
Can the smae APC induce either Th1 or Th2?
Yes, depending on the condition
(same for Th17/T-reg)
What does CD4 cell express when no infection?
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)
What happens when there is an infection?
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
What can induce bystander CD8 T cells to make IFN-γ?
IL-12 and IL-18
What happens in cytokine mediated bystander resistance to infection?
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)
What triggers apoptosis in T cells?
TNF α/β
(also FAS ligand)
Expressed on the surface of effector T cell
What do T cells apotose?
Kill target cel that express the receptors Fas or TNFR-1
What else express Fas?
Activated lymphocytes (in addition to expressing the FAS ligand)
Why are Fas and TNFR-1 important at initiating death?
Have DEATH domain in their cytoplasmic region/tails
->Induces apoptosis (programmed cell death) in activated lymphocytes
What happens if Fas or Fas-L (both are expressed on recently/highly activated cells)are mutated?
->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
What 2 families can regulatory Tcells comfrom?
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)
Which regulatory cells are key to balance between tolerance and immunity?
CD4+ FoxP3 T-reg
What do these cells constitutively express?
IL-2 receptor alpha chain
(cuz they have a higher affinity for self Ag than do conventional cells)
What % of cells do these T ells make up?
1-10% of CD4+ T cells
Are professionally anergic (don't respond)
Why don't these cells proliferae on their own? What is required to actvate them?
Don't make their own IL-2
Need IL-2 to be activated
what is an important marker and switch factor for these cells?
FoxP3
What happens if FoxP3 is removed or mutated?
No developmetn of these cells
=>death
-scruvy in mice
-IPEX in humans (x-linked disease, young boys susceptible to it)
What are features of these CD4+ FocP3+ T-reg cells?
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
What are the 3 stages of infection by a parasite?
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
What happens if you're reifected with the same pathogen?
Completely resistant to it
What are the mechanisms that support the IL-10 producving FoxP3?
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
What are the mechanisms that support IFN-γ producing T-effector cells?
Inc resistance to primary infection
Inc Th1 respons
Pathogen clearane
High susceptibility to secondary infections
What happens when adaptive immunity is maximal?
Bug burden goes back down to the point of pathogen clearance
What happens in ppl whose lymphocyte dev'l has been abrogated?
Initial phase of infection is the same as in normal ppl
->at point where adaptive should take place, the infection is completely uncontrollable
What is the innate req'd for?
Signalling through TLRs (require ptn MyD88)
I
What happens if we remove MyD88?
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
Describe effector memory T cells
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
Describe central memory T cells
Express CCR7 (receptor for SLC/CCL21)
Take longer to differentiate then effector T cells
Traffic to LN
What is req'd for entry of T-cells to LN?
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)
What are memory cells for?
Dev'p of effecor and memory cells important for control of infection -> vaccination
What is req'd for the best CD8 response?
Optimal CD4: support sufficient CD8 differentiation/activation