Flashcards in Lecture 12, T Cell Immunity II Deck (74):
What key cytokines are required to stimulate Th1 formation from CD4+ T cells?
What key cytokines are required to stimulate Th2 formation from CD4+ T cells?
What key cytokines are required to stimulate Th17 formation from CD4+ T cells?
TGF-beta, (IL-1), IL-6, IL-21, IL-23
What key cytokines are required to stimulate Thf formation from CD4+ T cells?
What key cytokines are required to stimulate iTreg formation from CD4+ T cells?
Expression of what key TS factor is required to stimulate Th1 formation from CD4+ T cells?
Expression of what key TS factor is required to stimulate Th2 formation from CD4+ T cells?
Expression of what key TS factor is required to stimulate Th17 formation from CD4+ T cells?
Expression of what key TS factor is required to stimulate Thf formation from CD4+ T cells?
Expression of what key TS factor is required to stimulate iTreg formation from CD4+ T cells?
What signature cytokines are produced by Th1 cells?
IL-2, IFN-gamma, LT-alpha
What signature cytokines are produced by Th2 cells?
IL-4, IL-5, IL-10, IL-13
What signature cytokines are produced by Th17 cells?
IL-17, IL-21, IL-22
What signature cytokines are produced by Thf cells?
IL-6, IL-10, IL-21
What signature cytokines are produced by iTreg cells?
What are e.g.'s of 3 broad ag classes that could activate Th2 cells?
- Soluble antigen
- Multi-cellular parasites
What is the typical IL that TLR's with stimulate the release of?
What is released instead, which will activate Th2 cells?
Which does B cell require to recognize Ag, MHC class I or class II?
Neither! (B cell is an APC)
When a B cell or DC encounters a naive T cell, what 3 interactions need to occur to initiate activation of the T cell?
1. CD4 (of helper T cell) binds MHC class II (of APC)
2. CD28 binds B7
3. CD40L binds CD40
During differentiation into Th2 cell, once CD4 (of helper T cell) binds MHC class II (of APC), CD28 binds B7, and CD40L binds CD40, what other 2 cytokines must be released and bind their respective receptors on the T cell for further and further upregulation of GATA3, thus completing Th2 differentiation?
(What other cytokine is NOT present?)
1. IL-2 first released by T cell, binds IL-2R (induces further GATA3 expression)
2. IL-4 released, binds IL-4R (augments GATA3 expression)
(NO IL-12 !)
What (4) types of cells release the IL-4 that further stimulates GATA3 production in developing Th2 cells (besides the Th2 cell itself)?
Mast cells, Basophils, Eosinophils, TCR
What are the effects that Th2 cells have on B cells?
What other effects do Th2 cells have, in general?
Enhances B cell growth, function, and ultimately antibody production:
- Make pathogens more attractive to MACs and Polys
- Bind toxins directly (and neutralize it)
- Target mutant/viral infected cells for killing
(May play a role in pathogenic auto-ABs)
How does IL-4, released by Th2 cells, directly affect AB structure?
Induces Ig class switching from IgG1 to IgE
- Thus plays a role in allergies
Does the IL-4 released from cells affect any other subtype of T helper cell? Positively or negatively?
IL-4 inhibits the development of Th1 (even with high concentration of IFN-gamma)
Is IL-4 pro or anti-inflammatory? Why?
Anti-inflammatory cytokine: inhibits Th1-mediated macrophage activation
Besides IL-4, IL-5 is also released from Th2 cells. What is IL-5's role?
Critical role in eosinophil maturation and recruiting of mature eosinophils
Besides IL-4 and IL-5, IL-10 is also released from Th2 cells. What is it's role?
IL-10 is the major driver of B cell differentiation and isotype switching
IL-10 also inhibits Th1 differentiation and dendritic cell function
Besides Th2 cells, what other (2) cell types make IL-10?
iTreg and Thf
Is IL-10 considered pro or anti-inflammatory? Why?
Anti-inflammatory: inhibits production of pro-inflammatory cytokines IL-1, IL-12, TNFα
(IL-10 inhibits NFkappaB, resulting in the shutdown of expression of a lot of inflammatory cytokines)
What do IL-5 and IL-13 both have in common, in terms of function? (they are both released by Th2 cells)
Both are capable of driving allergic type inflammatory response and promoting pathology of Th2-mediated immune diseases such as asthma
What are the 3 stages of Th17 development?
Differentiation, amplification, and stablization
*What is required for the Th17 differentiation stage?
(hint: 3 cytokines, 1 TS factor, 1 receptor)
TGFβ, IL1, IL6, RORγt, IL23R
*What cytokine is required for the Th17 amplification stage?
*What is required for the Th17 stabilization stage?
What dz's are associated w/Th17 dysfunction?
Organ specific autoimmune diseases:
- Type I diabetes
- Inflammatory bowel disease (IBD)
- Airway inflammatory disease
What are the main functions of IL-17, which is released by Th17 cells?
(is it anti or pro inflammatory?)
- Recruitment of and activation of neutrophils and monocytes
- Induce expression of pro-inflammatory cytokines IL-6, IL-8
IL-21 is released from Th17 cells. What is its function?
Enhances B cell function
- Contributes to antibody mediated pathology such as hyper IgE syndrome (allergic response). These patients face recurrent staphylococcus and fungal infection.
IL-22 is released from Th17 cells. What is its function?
Functions in protective immunity of the gut by restricting commensal bacteria to their niches and induces expression of antimicrobial peptides (puncture cell wall of bacteria)
What is the general function of Thf cells?
Facilitate humoral immune responses by assisting B cells with the production of ABs
Where are Thf cells found?
B cell zone of LNs
What chemokine receptor do naive T cells express that mediates their recruitment into the germinal center of the follicle of the B cell zone of the LNs?
Upon arriving at the germinal center via CXCR5, what TS factor and co-stimulator are required for naive T cells to become Thf cells?
Besides the usual T cell to APC interactions, what additional important interaction is required for a Thf cell to bind a B cell in a germinal center?
ICOS (T cell) binds ICOSL (B cell)
What are the 2 types of Tregs, and where do each develop?
- Natural Treg or nTreg : developed in the thymus from the DP thymocytes.
- Induced Treg or iTreg: developed in peripheral lymphoid tissues
What 2 cytokines act to promote FOXP3 expression in iTregs?
TGF-beta and IL-2
Recall: a FOXP3 mutation would cause what dz?
Describe some of the (2) main functions of Tregs.
- Critical role in maintenance self-tolerance
- Regulate immune responses
There are 2 mechanisms by which Tregs inhibit other T helper cells. Name them.
1. Cell-cell contact
What are the 2 main inhibitory proteins that function for Tregs to inhibit other cells thru cell-cell contact?
How does IL-10, released by Tregs (along w/TGF-beta) act to inhibit other cells?
(what 2 dz's is it relevant to?)
(IL-10 is a key anti-inflammatory cytokine)
- Acts on APCs: reduces expression of MHC II, co-stimulatory molecules CD80/86 (B7), suppress their activation and functions
- Reduces the release of proinflammatory cytokines by mast cells
- Important in inflammatory bowel diseases, colitis
What types of foreigners are CTLs programmed to kill?
What common infection are they particularly important for controlling?
Essential in controlling bacterial and particularly viral infection, as well as foreign, mutated and viral infected cells
- Infectious mononucleosis caused by EBV
What are the names of the 3 phases of the CTL response?
1. Effector phase
2. Contracting phase
3. Memory phase
How long does the effector phase of the CTL response last?
1-2 days after acute infection
What marks the beginning of the contracting phase of the CTL response?
What % of the CTL population survives?
Source of infection is eliminated
- 5-10% of the CTLs survive
How long can the surviving memory CTLs of the memory phase of the CTL response last?
Up to 75 years
In the LN, where does activation of the CTL response occur? Why?
Occurs in the peripheral region near the *marginal sinus, where both naïve CD8+ T cells and DCs migrate into from the paracortical region.
- The marginal sinus is ag-rich in early infection
After a CD4+ T helper cell binds an APC via its TCR (binding MHC) and CD28 (binding B7), what other ligand does it express? (review)
What cytokine will the CD4+ cell then release to the nearby CTL, also bound to the APC?
- CD40L (binds CD40 of APC)
- IL-2 (binds IL2R of CTL)
After a CD4+ T helper cell binds an APC via its TCR (binding MHC) and CD28 (binding B7), and the CD4+ cell expresses CD40L to the APC's CD40, production of what cytokine and surface protein are stimulated (by the CD4+ cell) on the APC, which in turn will bind the adjacent CTL?
4-IBBL (binds 4-IBB of CTL)
Parallel activation of what 3 cells is (preferentially) required for CTL activation?
1. NK cells
2. CD4+ helper T cells
3. Memory cells (later)
Initial detection of virus by NK cells induces __________(cytokine), which acts on DCs (i.e. up regulation of CD40).
After NK cells detect a virus-infected cell and release IGN-gamma to stimulate CD40 on DCs, what do T helper cells do?
CD4+ cells activate DCs, continue to produce IL-21, IL-2, and IFN-gamma, and sustain a continuing CD8+ response
What are the 2 methods by which CTLs can kill a virus-infected cell?
1. Contact mediated cytolytic effect (FAS-FASL mediated apoptosis)
2. Cytotoxic granules or lysosomes
Explain the process of FAS-FASL mediated apoptosis by CTLs.
CTL express FASL which engages with FAS (CD95) on target cells:
- Activation of caspase 8: mitochondria damage, activation of other caspases, and eventually DNA fragmentation
Name the (3) specific granules/lysosomal enzymes that are used by CTLs to kill virus-infected cells. (explain how each work, if possible)
- Perforin: oligomerization forms pore in target cells
- Granzyme B: apoptosis, both caspase-dependent and independent
- Granulysin: induces cytolysis of bacteria, fungi and parasites including intracellular pathogens M. tuberculosis, L. monocytogenes, Leshmania major
During T cell polarization and delivering of cytotoxic granules to target cells, what cellular control center is used to reorganize the CTL's cytoskeleton and cytoplasmic components so that perforin, granzyme, and granulysin can be released specifically to this single target cell?
MTOC (MT organizing center)
Of TCRγδ T cells, how many classes of delta and how many classes of gamma cells are there?
3 Vδ and 7 Vγ
Do TCRγδ T cells present Ag w/MHC class I or class II?
Neither, use CD1a, b, and c
Describe the 2 main types of Ag's that TCRγδ T cells target.
1. Phopholipids: endogenous, bacterial sources i.e. Mycobacterium
2. Phosphoantigens: phosphorylated intermediates of bacteria, protozoa and stressed cells induced by infection, inflammation and cancer
Where are TCR δ1 found?
Mucosa tissue (critical role with epithelial cell functions)
Where are TCR δ2 found? Where are they generated?
Circulation in blood. While also generated in the thymus, the majority is generated in fetal liver and then expanded in adult.
Regarding TCRδ1 and δ2, how do their numbers change during HIV infection?
Increase in frequency of TCRδ1, decrease TCRδ2
How do TCRγδ numbers change during TB infection?
What about w/healthy contacts?
- Patients with active tuberculosis decrease TCRγδ
- Healthy contacts: increase TCRγδ
How do TCRγδ numbers change during Malaria?