T Cell Immunity I & II Flashcards
What are Naive T cells?
Mature, recirculating T cells that have not yet encountered their Ag
What do effector T cells act on?
Target cells, not the pathogen itself
What cell surface markers can differentiate between naive and T memory cells?
Naive: CD45RA
T Memory: CD45RO
What 3 signals are required for T cell activation?
TCR recognizes peptide in the context of MHC
Engaging of co-stimulatory molecules
CD28 with CD80/86
CD40L with CD40
Induction of cytokine production and secretion which will help direct the fate of the T cell
What do activated T cells express, and to what do they respond?
high affinity IL2Rgamma(CD25) and respond to IL2
What drives the Th1 fate, what is the master transcription regulator, what cytokines do they produce, and against what do they act?
IFNgamma, IL12
Tbet
IFNgamma, IL2, LTalpha
Intracellular pathogens
What drives the Th2 fate, what is the master transcription regulator, what cytokines do they produce, and against what do they act?
IL4
GATA3
IL4, IL5, IL10, IL13
Extracellular pathogens
What drives the Th17 fate, what is the master transcription regulator, what cytokines do they produce, and what is their role?
TGFbeta (IL1), IL6, IL21, IL23
RORgamma-t
IL17, IL21, IL22
gut immunity - pathogen clearance at mucosal barriers
What drives the Thf fate, what is the master transcription regulator, what cytokines do they produce, and what is their role?
IL6
BCL6
IL6, IL10, IL21
Induce B cells to form germinal centers, stimulates the differentiation of B cells into plasma cells and memory B cells
What drives the iTreg fate, what is the master transcription regulator, what cytokines do they produce, and what is their role?
TGFbeta, IL2
FOXP3
TGFbeta, IL10
immune tolerance
What are Toll Like Receptors (TLRs) and what do they bind??
receptors on macrophages and dendritic cells that when bound can initiate cytokine production
bind soluble bacterial products and viral DNA/RNA
Pathogen Associated Molecular Patterns (PAMPS)
Danger Associated Molecular Patterns (DAMPS)
Microbial Associated Molecular Patterns(MAMPS)
What steps take place when an immature DC becomes a mature DC?
no longer can phagocytose
upregulates MHCII
upregulates CD80, CD86, CD40
migrates to lymphoid tissue
upregulates IL12 and IL18
Discuss a T cell passing through a lymph node
Enters via HEV
T cells not activated by Ag presented by a DC will exit via the cortical sinuses
T cells activated by Ag presented by a DC Will proliferate and lose the ability to exit the lymph node
Once activated T cells proliferate to effector T cells they will exit the lymph node
What responses are Th1 cells involved in, and against what are they directed?
involved in cell mediated inflammation and delayed-type hypersensitivity reactions
immunity against intracellular pathogens
What is IFNgamma, what cells produce it, and what does it do?
potent proinflammatory cytokine
signature cytokine of the Th1 response, also produced by NK and activated CD8 cells
IFNgamma activates macrophages
potent suppressor of the Th2 and Th17 responses
What is IL2, what cells produce it, and what does it do?
T cell growth factor for most T cells
critical growth cytokine produced by activated Th1 and CD8 cells, can act in a paracrine or autocrine mode
Growth factor for T cells, particularly Treg
defect can cause serious immunodeficiency
What is LTalpha, what cells produce it, and what does it do?
member of the TNFalpha family
produced by Th1, CD8, NK, B, and macrophages
Lymphoid organ development, maintenance of lymphoid microenvironment
implicated in rheumatoid arthritis and MS
In response to Th1 activation, what is the downstream response?
Macrophages will produce pro-inflammatory cytokines IL1, IL6, IL8, and TNFalpha
Discuss the features and function of IL1
IL1 is a proinflammatory cytokine that facilitates host response to stress
produced by a variety of cells, especially epithelial cells
promotes neutrophil growth and emigration from the bone marrow
Acts with IL6 on the CNS to promote fever and depression
has neuroendocrine effects on the adrenal gland
stimulates APCs to increase Ag presentation
Antagonist is IL1Ra
induces Th17 along with TGFbeta, IL6, IL21, IL23
Discuss the features and function of IL6
IL6 is a proinflammatory cytokine with similar effects as IL1, including fever and induction of acute phase protein (CRP)
promotes responsiveness to IL2, and accelerates Ag activation
required for Th17 development and possibly Thf development
strong differentiation effect of B cells in presence of other B cytokines
activates osteoclasts
Discuss the features and function of IL8
IL8 is a cytokine with chemotactic activity
most potent stimulus for mobilization and recruitment of neutrophils to infected tissue
produced mainly by neutrophils and macrophages, and by endothelial cells during intense inflammation reactions
What is Hypersensitivity Reaction Type IV: Delayed-Type Hypersensitivity
mediated by Ag specific Th1 and CD8 T cells
clinical situation where macrophage is part of pathological situation
can be applied to the reaction to mosquito bites
Discuss IL3/GM-CSF
released by activated Th1 cells, stimulates monocyte differentiate from HSC in the bone marrow. These will be attracted to the inflammed tissue where the Th1 cells are present
Discuss the features and functions of TNF-alpha
TNFalpha is a potent macrophage activator, is released by Th1 cells
potent activator of endothelial homing and adhesion molecules
upregulates MHC and other cytokines
induces apoptosis (local tissue damage) and angiogenesis
systemic effects include flu like symptoms and death
anti-TNF Ab can be used clinically to control it
What infection or antigenic stimulus will cause dominant production of IL4 by the activated T cell?
Soluble Ag
bacteria
multi-cellular parasites
When will IL4 production occur?
TLR signaling does not result in IL12 production
There are TLRs that stimulate the T cell to produce IL4 instead of IL12
Naive T cells engage in Ag recognition presented by B cells
How does B cell and Th2 cell interaction result in the activation of both cells?
B cells take up antigen and present it via MHCII. Expression of co-stimulatory signals (CD40 on B cell, CD40L on T cell) and cytokines results in the activation of both cells.
Activated T cells produce cytokines such as IL4, IL5, IL6 which act on B cells to sustain B cell activation
What are exogenous sources of IL4?
Mast cells
Basophils
Eosinophils
TCRdeltagamma
What is necessary for a Th2 response, and how does it occur?
High levels of GATA3
TCR:peptide/MHCII and CD40:CD40L and CD28:CD80/86 stimulates low levels of GATA3 activity and the activation of the high affinity IL2Ralpha receptor and IL2
IL2 stimulates more production of GATA3, which stimulates IL4 production, which ramps up GATA3 activity even more
What is the Th2 effect on B cells?
B cell proliferation and the release of Ab: make pathogen more attractive to macs and polys, increasing the binding of toxins, enhance the targeting of mutant/viral infected cells for killing
Describe the features and function of IL4
initiates and is required for the Th2 response - it is released by Th2 cells and is a growth factor for Th2 cells
IL4 induces B cell growth and differentiation into plasma cells
on T cells, IL4 inhibits the development of Th1, even in high concentrations of IFNgamma
inhibits Th1 mediated macrophage activation, and is thus an anti-inflammatory
What does IL5 do?
Eosinophil maturation and the recruiting of more eosinophils
What does IL10 do?
Major drivers of B cell differentiation and isotype switching
Inhibits Th1 differentiation and dendritic cell function, and thus inhibits the production of pro-inflammatory cytokines IL-1, IL-12, TNF-alpha
Th2 cells are the major releasers of IL10, iTregs and Thf also release IL10
What do IL5 and IL13 do?
drive allergic type-inflammatory responses such as asthma
discuss the features and functions of Th17 cells
implicated in organ specific autoimmune diseases
produce 6 different kinds of IL17
What does IL17 do?
Recruitment and activation of neutrophils and monocytes
induce expression of pro-inflammatory cytokines IL6 and IL8
What does IL21 do?
Enhance B cell function
Contributes to Ab mediated pathology, such as hyper IgE syndrome, where patients are at constant risk of recurrent fungal and staph infections
What does IL22 do?
protective immunity of the gut (restricts commensal bacteria to their niches)
induce expression of antimicrobial peptide
Discuss the features and function of Thf T cells
facilitate humoral response by assisting B lymphocytes with the production of pathogen neutralizing Ab
Found in the B cell zones of secondary lymphoid tissue
recruitment to B cell zone is mediated by chemokine receptor CXCR5
Where are fully mature Thf cells found?
The germinal centers interacting with B cells
What is necessary for the development of Thf cells?
IL6, IL21, and BCL6
What are the two types of CD4 T regulatory cells?
nTreg: developed in the thymus from DP thymocytes
iTreg: developed in peripheral lymphoid tissue
How does FOXP3 regulate iTreg activity?
Production of IL2 is mediated by TCR signaling, both of which activate FOXP3 expression
continuous FOXP3 expression is required for suppression (induction?) of iTregs
FOXP3 mutation: IPEX
Discuss Treg function
maintenance of self-tolerance, and regulate immune response
Mechanism of suppression: cell-cell contact! via inhibitory receptors such as CTLA4 and PD1
Mechanism of suppression: IL10 - act on APCs to reduce MHCII and CD80/86 activity, suppressing their functions
reduces the release of pro-inflammatory cytokines by mast cells
important for IBD and colitis
What is the function of CD8+ cytotoxic T cells?
essential in controlling bacterial and especially viral infections
What are the three phases of the CTL response?
Effector phase
Contracting phase
memory phase
When does the effector phase of the CTL response take place?
1-2 days after infection
What is the contracting phase of the CTL response?
When the source of infection is eliminated, most CTL die by apoptosis; ~5-10% survive
Wha tis the memory phase of the CTL response?
The CTL that survive become memory T cells, can last up to 75 years in humans
Where does CD8+ T cell activation take place?
occurs in periphery of the lymph nodes near the marginal sinus, to which both dendritic cells and CD8+ CTL migrate to from deeper T cell zones of the paracortical region
(Marginal sinus is Ag rich early in infection)
What kind of cells does CD8 CTL recognize and kill?
foreign, mutated, and virally infected cells
How does CD8 recognize the cells it will kill?
foreign peptide in context of MHCI on dendritic cells, which also produce IL12
What other cells are required for the optimal activation of CTL cells?
NK cells, Ag specific CD4+ Thelper cells (Th1), or memory cells
How do NK cells help in the activation of CTL?
detection of virus by NK cells results in the release of IFN-gamma which act on dendritic cells to up regulate CD40
How do CD4 Th1 cells help in the activation of CTL?
activate DC, continue to release IL2, IL21, IFNgamma, which helps sustain the CD8 T cell response
what is the sequence of events of a CTL and a target cell?
First adhesion molecules, then recognition of peptdie:MHCI –> the immunological synapse
What is the mechanism of CTL killing?
contact mediated cytolytic effect: FAS-FASL mediated apoptosis and cytotoxic granules or lysosomes
How does FAS-FASL mediated apoptosis work?
CD8 CTL expresses FASL which binds FAS on target cells
the activation of caspase 8 results in mitochondrial damage, other caspase activation, and eventually DNA fragmentation
How does cytotoxic granules/lysosome mediated cell killing work?
perforin: complex forms pores in target cells
Granzyme B results in apoptosis, both caspase dependent and independent
granulysin: targets pathogen-infected cells
What are the general functions of TCRgammadelta T cells?
mediators of the innate immune response
discuss the characteristics of TCRgammadelta T cells
Ag is not presented via MHC, but rather by CD1a, b, c
Ag is not peptide, but rather phospholipids (endogenous and bacterial sources) or phosphoantigens (phsophorylated intermediate of stressed cells and pathogenic bacteria/protozoa)
What are the different types of TCRgammadelta?
delta1: mucosa tissue, associated with epithelial cell functions
delta2: circulating, majority formed in fetal liver
discuss TCRgammadelta in human disease
HIV: increase in delta1 and decrease in delta2
TB: active TB has a decrease in TCRgammadelta
parasitic infections increase gamma1
