Flashcards in T-Cell Immunity II Deck (26):
Describe the characteristics of Th2 response.
Included any infection or antigenic stimulus that causes dominant production of what type of interleuken?
What type of pathogens might elicit this response?
When will this occur?
Describe inducer cytokine, transcription factor and signature cytokines.
Any infection or antigenic stimulus that causes dominant production of IL4 by the
activated T cells:
- Soluble antigen
- Multi-cellular parasites
This will occur when:
- TLR signaling does not result in the production of IL12
- There are TLRs that induce DCs to produce IL4 instead of IL12
- Naive T cells engage in antigen recognition presented by B cells
For the Th2 response:
Describe inducer cytokine, transcription factor and signature cytokines.
Inducer cytokine: IL4
Transcription factor: GATA3
Signature cytokines: IL4, IL5, IL10, IL13
How do B and T cells activate each other?
BCRs on B cells bind antigens, which are then processed and presented by MHC II
molecules. Interaction between B cells and T cells results in activation of both parties
through expression of co-stimulatory molecules (CD40L on T cells) and cytokines. Activated Th2 cells produce cytokines like IL4, IL5 and IL6 which act on B cells and
maintain B cell activation.
Figure p 14
-Antigen-specific B cell binds antigen
-Specific antigen efficiently internalized by receptor-mediated endocytosis
-High density of specific antigen fragments presented
-Antigen recognition induces expression of effector molecules by the T cell, whic activates the B cell
-B-cell activation by antigen and helper T cells
What are initial exogenous IL4 sources?
What are Th2 signature cytokines?
The key for Th2 response is to induce high expression of GATA3 and maintains its
expression at high level. Describe the stages of this process.
This occurs in several stages: The initial interaction between TCR and peptide/MHC II, together with co-stimulatory molecules (CD28- CD80/86, CD40L- CD40) induces the initial expression of a low level of GATA3.
This interaction also induces
expression of the high affinity IL2R-alpha subunit and IL2. IL2 signal further induces expression of GATA3.
The increase in expression of GATA3 then induces expression of IL4 by the T cells which augments GATA3 expression.
IL4 can also come from other cells beside T cells like mast cells, basophils, eosinophils and
TCRgamma/delta T cells.
How does Th2 response affect B cells?
Enhance B cell function and ultimately antibody production:
- Make pathogens more attractive to Macs and Polys
- Bind toxins
- Target mutant/viral infected cells for killing
See figure p 16
-Antigen recognition induces expression of effector molecules by the T cell, which activates the B cell
-B cell proliferation
-Differentiation to resting memory cells and antibody-secreting plasma cells
Summarize the functions of the Th2 cytokine IL4
- IL4 initiates and is an absolute requirement for a Th2 response
- IL4 is the growth factor for Th2 cells; it is also produced by Th2 cells
- On B cells, IL4 promotes B cell growth and induces B cells to differentiate into antibody-producing plasma cells. May play a role in pathogenic autoantibodies
- IL4 also induces Ig class switching from IgG1 to IgE, thus plays a role in allergies
- On T cells, IL4 inhibits the development of Th1, even with high concentration of IFNgamma
- IL4 also inhibits Th1-mediated macrophage activation, thus functions as antiinflammatory
Describe the functions of other Th2 cytokines: IL5, IL 10, IL13.
- IL5 plays a critical role in eosinophil maturation and recruiting of mature eosinophils
- IL10 is the major drivers of B cell differentiation and isotype switching-major source
is Th2 cells; other cells that make IL10 are iTreg and Thf
- IL10 also inhibits Th1 differentiation and dendritic cell function: inhibits production of
pro-inflammatory cytokines IL1, IL12, TNFalpha
- Both IL5 and IL13 are capable of driving allergic type inflammatory response and
promoting pathology of Th2-mediated immune diseases such as asthma
Which cells make IL10?
Th2, iTreg, Thf
What are the inducers, transcription factor, and signature cytokines for the Th17 response?
Inducers: TGFbeta, IL1, IL6, IL21, IL23
Transcription factor: ROR-gamma-t
Signature cytokines: IL17, IL21, IL22
Describe Th17 cell functions:
What kinds of pathogens do they target?
What types of diseases?
What is the most prominent interleuken they produce?
Extracellular bacteria, fungi, eukaryotic pathogens
Organ specific autoimmune diseases: MS, type I diabetes, inflammatory bowel
disease (IBD), airway inflammatory disease
- The Th17 cell produces multiple types of IL-17 (6 different a-f); the prominent are
What do IL17, IL21 and IL22 do?
- Recruitment of and activation of neutrophils and monocytes
- Induce expression of pro-inflammatory cytokines IL6, IL8
- IL21: enhances B cell function; contributes to antibody mediated pathology such as
hyper IgE syndrome. These patients face recurrent staphylococcus and fungal
- IL22: functions in protective immunity of the gut by restricting commensal bacteria to their niches, induce expression of antimicrobial peptides
What are the inducer, transcription factor, and signature cytokines of Thf T cells?
Transcription factor: BCL6
Signature cytokines: IL6, IL10, IL21
Describe T follicular Helper T Cells (Thf).
What type of immune response to they facilitate and how?
Where are they found?
Where are fully mature Thf found?
What transcription factors are critical for the development of Thf cells?
- Thf cells facilitate humoral immune responses by assisting B-lymphocytes with the production of pathogen-neutralizing antibodies
- Found in the B cell zone of the secondary lymphoid organ i.e. lymph nodes
- Recruitment into the B cell zone is mediated by the chemokine receptor CXCR5.
This induces further migration in to germinal center of the follicle
- Fully mature Tfh are found in germinal center upon interacting with B cells
- The transcription BCL6, IL6 and IL21 are critical for the development of Thf cells
Describe CD4 regulatory T cells.
What are the two types?
Describe their development?
What is the function of FOXP3?
What will a FOXP3 mutation lead to?
There are two types:
The natural Treg or nTreg : developed in the thymus from the DP thymocytes.
Induced Treg or iTreg is developed in peripheral lymphoid tissues
TGF-beta and IL2
- Production of IL2 is mediated by TCR signaling
- Both act to promote FOXP3 expression
- Continuous expression of FOXP3 is required for suppression of iTreg
- FOXP3 mutation: IPEX
What are the inducer, transcription factor and signature cytokines for CD4 regulatory T cells?
Inducer: TGF-beta, IL2
Transcription factor: FOXP3
Signature cytokines: TGF-beta, IL10
What are Treg functions?
What do they play a major role in?
What do they regulate?
What are the two mechanisms of suppression?
- Play a critical role in maintenance self-tolerance
- Regulate immune responses
- Mechanism of suppression: Cell-cell contact
- Inhibitory receptors i.e. CTLA4 (cytotoxic T-lymphoid cell associated protein
4), PD-1 (Programmed cell death protein 1)
- Mechanism of suppression: IL10
- Act on APCs: reduce expression of MHC II, co-stimulatory molecules
CD80/86, suppress their activation and functions
- Reduces the release of proinflammatory cytokines by mast cells
- Important in inflammatory bowel diseases, colitis
Describe CD8 cytotoxic T cells (CTLs)
What are they essential in?
Where to activated CTL go?
Describe the 3 phases of the CTL response.
- Essential in controlling bacterial and particularly viral infection: Infectious
mononucleosis caused by EBV
- Activated CTL travel to the infected tissue and kill target infected cells
- There are three phases of the CTL response:
- Effector phase: 1-2 days after the acute infection
- Contracting phase: when the source of infection is eliminated, most CTL die
by apoptosis and only 5-10% survive
- Memory phase: the survived cells established the memory pool. Can last for up to 75 years in humans
Where does activation of CD8 cytotoxic T Lymphocytes (CTLs) take place?
Where does initial activation of naive CD8 occur? Describe it.
Activation of CD8 Cytotoxic T Lymphocytes (CTLs) take place in the lymph node, but in a distinct area as compared to CD4 T cells
Initial activation of naive CD8 occurs in the peripheral region near the marginal sinus where both naive CD8 and DC migrate into from the deeper T cell zone of the paracortical region.
The marginal sinus is antigen-rich region in early infection.
Describe the effector phase: activation of CD8 T cells.
APC stimulates effector CD4 T cell, to induce CD40L and IL2
Stimulation of APC through CD40 increases B7 and 4-IBBL, which co-stimulates naive CD8 T cell
Describe CD8 Antigen Specific Cytotoxicity.
What did it evolve to do?
Describe its recognition. What does it produce?
What does optimal activation of CD8 cells require?
What does initial detection of virus by NK cells induce?
- The CD8 cell evolved to specifically recognize and kill foreign, mutated and viral
- The recognition is via display of endogenously produced peptide in a MHC-I
determinant on DCs – also produce IL12
- Optimal activation of CD8 cells requires parallel activation NK cells, antigen specific CD4 helper cells and/or the presence of memory cells (later). Preferably all three…….
- Initial detection of virus by NK cells induces IFNgamma which acts on dendritic cells i.e. up regulation of CD40
- Antigen activated CD4 cells activate DCs, continue to produce IL21, IL2 and IFNgamma and sustain a continuing CD8 response
Describe the initial interaction of CTL to target cell.
See figure p 23.
First, adhesion molecules, followed by TCR recognition of peptide MHC I.
The initial interaction of CD8 cell with target is made by nonspecific adhesion molecules
No antigen-specific interaction; cells separate
Antigen-specific recognition: stable pairing and focused release of effector molecules
Death of target and release of CD8 T cell
-CTL recgonizes and binds virus-infected cell
-CTL programs target for death, inducing DNA fragmentation
-CTL migrates to new target
-Target cell dies by apoptosis
Describe the three CTL mechanism of killing.
- Contact-mediated cytolytic effect
- FAS-FASL mediated apoptosis: CD8 CTL express FASL which engages with FAS
(CD95) on target cells:
Activation of caspase 8: mitochondria damage, activation of other caspase
and eventually DNA fragmentation
- Cytotoxic granules or lysosomes:
Perforin: oligomerization forms pore in target cells
Granzyme B: apoptosis, both caspase-dependent and independent
Granulysin: targets pathogen-infected cells and induces cytolysis of bacteria,
fungi and parasites including intracellular pathogens M. tuberculosis, L.
monocytogenes, Leshmania major
Describe TCRgamma/delta T cells.
What is their role?
Describe their unique characteristics as compared to adaptive TCR-alpha/beta T cells.
What is restricted repertoire?
How are antigens presented?
- Restricted repertoire: 3 Vdelta, 7 Vgamma
- Antigens are not presented by MHCI or II, but by CD1a, b, and c
- Antigens are not peptides:
Phopholipids: endogenous, bacterial sources i.e. Mycobacterium
-Phosphoantigens: phosphorylated intermediated of bacteria, protozoa and
stressed cells induced by infection, inflammation and cancer
- TCR delta1: Mucosa tissue, associated with epithelial cell functions
- TCR delta2: Circulation. While also generated in the thymus, the majority is generated in fetal liver and then expanded in adult