T-cell Immunity Flashcards
What must occur for a T cell to be activated?
The adaptive immune system is initiated when naive T cells recognize peptide-MHC complex on the sruface of APCs;
Upon TCR signaling, T cells are “activated” leading to effector T cells
Do effector T cells act on target cells, pathogens, or both?
Effector T cells act on target cells, not the pathogens themselves
What is the surface marker for Naive T cells vs Memory T cells?
Naive: CD45RA
Memory: CD45RO
Differentiate effector memory T cells from central memory T cells
Effector: rapidly mature into effector cells upon reactivation and enter inflamed tissues
Central memory: take longer than effector T cells in producing cytokines; they remain in the lymphoid tissue and circulate as naive T cells
What is the relative life-span of memory T cells?
Long-lived
What are three signals required for productive activation of T cells upon meeting its antigen?
1) Activation: TCR binds to antigen:MHC complex
2) Survival: B7: CD28 co-stimulation
3) Differentiation: Cytokine production by APCs drive naive T cell to differentiate and proliferate
CD40/CD40L is also present
How do activated T cells respond to IL-2 signaling?
Activated T cells express high affinity IL2Ralpha (CD25) and proliferate in response to IL2 in an autocrine fashion.
What is the main function of CD8+ cytotoxic T cells?
Kill virus-infected cells.
CTLs target viruses and some intracellular bacteria
What is the primary function of CD4+ Th1 cells?
Activation of infected macrophages. Provides help to B cells for antibody production.
Th1 cells target microbes that persist in macrophages and extracellular bacteria
What is the main role of CD4+ Th2 cells?
Provide help to B cells for antibody production, especially switching to IgE
Effective against helminth parasites
What is the main role of CD4+ Th17 cells?
Enhance neutrophil response, and promotes barrier integrity (skin and intestines)
Targets fungus
What is the main role of Thf cells?
B-cell help: isotype switching + antibody production
What is the main role of Treg cells?
Suppression of T-cell responses
Which cytokines drive the differentiation of naive T cells into Th1 cells? What transcription factor is responsible for the differentiation?
IFN gamma
IL12
Transcription factor: Tbet
What cytokines are produced by Th1 cells?
IFN gamma, IL2, LTalpha
What cytokine drives the differentiation of naive T cells into Th2 cells? What transcription factor promotes this differentiation?
IL4
Transcription Factor: GATA3
Which cytokines are produced by Th2 cells?
IL4, IL5, IL13
Which cytokines drive the differentiation of naive T cells into Th17 cells? What transcription factor promotes this differentiation?
TGFbeta, IL6, IL21, IL23
Transcription Factor: RORgammaT
Which cytokines are produced by Th17 cells?
IL17, IL21, IL22
Which cytokines drive the differentiation of naive T cells to Thf cells? What transcription factor promotes this differentiation?
IL6
Transcription Factor: BCL6
Which cytokines are produced by Thf cells?
IL6, IL10, IL21
Which transcription factor promotes the differentiation of naive T cells to Treg cells?
FOXP3
Which cytokines are produced by Treg cells?
TGFbeta and IL10
Type I immune response (regulated by Th1 cells) are effective against what pathogens?
Intracellular pathogens
Type II immune responses (regulated by Th2 cells) are effective against which type of pathogens?
Extracellular pathognes
iTreg cells are important for what process?
Immune tolerance/ regulation of immune response to self-antigens
Th17 cells are important for providing immunity to what?
The gut
Thf (T follicular helper cells) are important for what process related to B cells?
Thf cells aid in the formation of germinal centers and differentiation of B cells into memory B cells and plasma cells
What type of immune response is implicated in autoimmune diseases (e.g diabetes)
Th1 - type 1 response
What type of immune response is implicated in the immunopathology of allergies, asthma and dermatitis?
Th2 - type 2 response
what is the general definition of an interleukin?
IL’s are heterodimers produced by leukocytes for the purposes of communication between leukocytes
Where in the cell are TLRs found?
TLRs are present on both the cell surface membrane and the membrane of intracellular vesicles
Which MHC is upregulated in mature DCs?
MHC II
Which co-stimulatory molecules are upregulated in mature DCs?
CD80, CD86, CD40
Discuss the translocation of DCs following activation.
Mature DCs migrate to lymphoid tissues following the CCR7 chemokine so that it can present antigen to T cells
Which cytokines are upregulated in mature DCs?
IL12 and IL18
T cells not activated by DCs in the lymph node exit via what?
The cortical sinus
What happens to T cells that do encounter their antigen in the lymph node?
They proliferate and differentiate into effector T cells and then exit the lymph node
Which T cells are involved in cell mediated inflammation?
Th1 cells
WHich T cells are involved in delayed-type hypersensitivity?
Th1 cells
Which factor, secreted by activated APCs maintains and stabilizes the Th1 response?
IL18
What is the main characteristic of IFN gamma?
IFN gamma is a potent pro-inflammatory cytokine
IFN gamma is the signature cytokine of what type of T cell response?
Th1
What two other cells produce IFN gamma and participate in the Th1 response to intracellular pathogens?
NK cells and CD8+ cells
How does IFN gamma affect macrophages?
IFN gamma activates macrophages to increase antigen processing, upregulate MHC I and MHC II expression, increase microbicidal activity and chemokine secretion
IFNgamma is a potent suppressor of what two T cell responses?
Th2 and Th17
What is the characteristic job of IL-2?
IL-2 is a T cell growth factor, particularly for regulatory T-cells (for most T cells)
Which T-cell receptor binds IL2?
HIgh affinity IL-2R (the alpha/beta/gamma)
Mutations in the gamma chain of IFNgamma leads to what immune deficiency?
Mutations in the gamma chain leads to SCID
Although LT alpha is a signature cytokine of Th1 cells, what other cells can produce LT alpha?
CD8, NK, B cells and macrophages
Lymphotoxin alpha, LT alpha, is implicated in the progression of what two diseases?
Rheumatoid arthritis and multiple sclerosis
What 4 cytokines make up the classic tetrad of macrophage produced pro-inflammatory cytokines?
IL1, IL6, IL8 and TNF alpha
What two cytokines are responsible for the production of a fever during a pro-inflammatory cytokine response?
IL1 and IL6
What is IL1Ra?
IL1 receptor antagonist
IL1 drives the differentiation of naive T cells to what?
IL1 promotes differentiation into Th17, along with TGF beta, IL6, IL21 and IL23
How does IL-6 affect B cells?
IL6 has strong growth and differentiation effects on B cells in the presence of other “B” cell cytokines
How does IL6 affect bone?
IL6 activates osteoclasts, and therefore has an effect on bone mineral metabolism
Which cytokine acts as the most potent stimulus for mobilizing and recruiting neutrophils to the site of infection?
IL8
By what cells/when is IL8 secreted?
IL8 is produced mainly by macrophages and neutrophils during intense inflammation by endothelial cells
What is another name for hypersensitivity reaction type IV?
Delayed-type hypersensitivity
Hypersensitivity type IV is mediated by what cells?
Th1 and CD8+ cytotoxic T cells
IL3/GM-CSF released during a type 1 immune response stimulate what?
IL-3/GM-CSF stimulate monocyte production by bone marrow stem cells
Which cytokine induces the expression of vascular adhesion molecules during a type 1 immune response?
IFN-gamma
TNFalpha is a pro-inflammatory cytokine with pleiotropic functons. Name some.
Potent macrophage activator
Potent activator of endothelial homing and adhesion molecules
Potent upregulator of MHC and other cytokines
Potent inducer of apoptosis and angiogenesis
Systemic effects range from flu-like symptoms to death
Soluble antigen, bacteria and multicellular parasites generate what type of immune response?
Th2 (type II)
Why would a macrophage produce IL4 instead of IL12 and generate a Th2 response (instead of a Th1 response)?
Depends on the TLR that binds the antigen. Certain TLRs lead to the production of IL4 rather than IL12
What role do Th2 cells play in the maintenance of B cell activation?
Th2 cells produce cytokines like IL4, IL5 and IL6 which act on b cells and maintain B cell activation
What MUST occur for the generation of a Th2 response?
Induction and maintenance of high GATA3 expression
How are high levels of GATA3 induced and maintained?
1) Initial interaction between TCR and peptide/MHC II , together with co-stimulatory molecules (CD20-CD80/86, CD40L-CD40) induces low initial levels of GATA3
2) IL2Ralpha (high affinity) and IL2 expression is induced –> high GATA3 levels
There is a positive feedback of GATA3 inducing IL4 expression, which further induces expression of GATA3
What is the primary role of the Th2 cell response?
Enhance B cell function and ultimately antibody production
How does IL4 affect the development of Th1?
IL4 inhibits the development of Th1, EVEN WITH
How does IL4 affect class switching in B cells?
IL4 induces Ig class switching from IgG1 to IgE, thus plays a role in allergies.
Is Th2 pro-inflammatory or anti-inflammatory?
Th2 is anti-inflammatory.
What is the major role of IL5?
IgA and eosinophil recruitment
What cell types make IL-10?
Major source; Th2
Other sources: Treg and Thf
What is IL10’s major role?
IL10 is the major driver of B cell differentiation and isotype switching
How does IL10 affect the pro-inflammatory cytokines?
IL10 inhibits Th1 differentiation and DC function- therefore inhibits production of IL1, IL12 and TNF alpha (through the inhibition of NFkappaB)
Which T helper cell is implicated in organ specific autoimmune diseases?
Th17
Implicated in MS, type 1 diabetes, inflammatory bowel disease, airway inflammation disease
What are the two predominant forms of IL17?
IL17a and IL 17f
IL17a is the most important form
IL17 induces the expression of which two pro-inflammatory cytokines?
IL6 and IL8
What is the role of IL22?
IL22 functions in protective immunity of the gut by restricting commensal bacteria to their niches- they induce expression of antimicrobial peptides
What is the role of Thf cells?
Thf cells facilitate a humoral immune response by assisting in B-lymphocytes with their production of pathogen-neutralizing antibodies
Where are Thf cells found?
B-cell zone of the secondary lymphoid organs (follicle, with or without a germinal center)
Recruitment of cells of the B cell zone of secondary lymphoid organs is mediated by what chemokine?
CXCR5
What is the main job of CD4+ regulatory T cells?
Control autoreactive T cells/ maintenance of self-tolerance
Differentiate iTregs from nTregs
Natural T regs, nTreg: develop in the thymus from the DP thymoctes
iTregs: developed in the peripheral lymphoid tissues
Which cytokines induce the differentiation of naive T cells into Treg cells?
TGF beta and IL2
What is IPEX?
A common FOXP3 mutation.
IPEX leads to failure of down
What is the mechanism by which Tregs suppress an immune response?
IL10 secretion,. IL10 is a key anti-inflammatory cytokine
IL10 suppresses expression of MHC class II, co-stimulatory molecules CD80/86, reduces the release of proinflammatory cytokines by mast cells
CD8+ cytotoxic T cells are essential for controlling what type of infections?
Bacterial and most importantly, viral
In very general terms, how to activated CTL respond to an infection?
Acitvated CTL travel to the infected tissue and kill target infected cells
Describe the three phases of a CTL response
1) Effector phase: 1-2 days after the acute infection
2) Contracting phase: when the source of infection is eliminated, most CTL die by apoptosis and only 5-10% survive
3) Memory phase: the survived cells established the memory pool. Can last for up to 75 years in humans
Where in the lymph node does activation of CTLs occur?
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 the early infection.
This is opposed to CD4 T cell maturation which occurs in the paracortex.
Optimal activation of CD8 cells requires parallel activation of what other type of cell?
NK cells, CD4 helper cells and/or the presence of memory cells
NK cells secrete what major pro-inflammatory cytokine that helps to activate CD8 cells?
IFN gamma
What is needed to sustain a CD8 response?
IL21, IL2 and IFN gamma
CTLs bind to cells wth low affinity through LFA-1/iCAM interactions (non-specific adhesion molecules) in absence of antigen. What changes occur when the T-cell binds to its specific antigen?
Antigen-specific recognition stabilizes the pairing and focused release of effector molecules. The CTL is then able to induce apoptosis of the infected cell, and it can move on to kill subsequently infected cells.
What is the death-receptor pathway?
FAS-FASL mediated apoptosis: CD8 CTLs express FASL which engages with FAS on target cells
This causes activation of caspase 8 –> caspase cascade and eventually DNA fragmetation
In addition to apoptosis, what is another way CTLs kill infected cells?
Release of cytotoxic granules or lysosomes
How does perforin destroy targets?
Oligomerization forms pores in target cells
How does granzyme B destroy targets?
apoptosis, both caspase-dependent and independent
How does granulysin destroy targets?
targets pathogen-infected cells and induces cytolysis of bacteria, fungi and parasites including M. tuberculosis, L. monocytogenes and Leshmania
Discuss the specificity of CTL killing through release of cytotoxic granules
Very specific- cytotoxic granules are released at the site of cell contact and will preferentially kill the target cell
Discuss the dependence of TCR gamma/delta cells on MHC
TCR gamma/delta cells are independent of Class I and Class II MHC
In contrast to alpha/beta TCRs what antigens do gamma/delta bind to?
Phospholipids, phosphoantigens,
They do not bind to peptides.
Antigens are presented to TCR gamma/delta cells by what?
CD1a, b, and c
Differentiate TCR delta 1 from TCR delta 2
delta 1: protects mucosa tissue and is associated with epithelial cell functions
delta 2: found in circulation- majority is generated in fetal liver and then expanded as an adult
How are TCRdelta 1 and 2 affected by HIV?
1 increases
2 decreases
How is TCRdelta 1 affected by parasitic infections?
increased
