T-Cell Immunity I Flashcards
When are T cells functionally mature?
Functional T cells are essential for defending against various pathogens.
Naïve T cells that egress the thymus, termed recent thymic emigrant (RTE), are not functionally mature and required to home to peripheral tissues and secondary lymphoid
organs for further maturation.
Define native T cells.
When is adaptive immune response initiated?
Naïve T cells: Mature, recirculating T cells that have not yet encounter their known
antigens
Adaptive immune response is initiated when naïve T cells recognize peptide-MHC complex on the surface of antigen presenting cells (APCs); upon TCR signaling, T cells are “activated”
What does successful interaction with APCs result in?
The successful interaction with APCs results in the generation of effector T cells
What do T cells act on? Pathogens or target cells?
Effector T cells then act on target cells, not the pathogens themselves
Compare Naive vs memory T cells.
How can they be identified? Give specifics.
Naive : CD45RA
Memory CD45RO
Effector memory: rapidly mature into effector cells upon reactivation and
enter inflamed tissues
Central memory: take longer than effector T cells in producing cytokines;
remain in lymphoid tissue and circulate as naïve T cells
Memory T cells are long-lived
Describe the recognition of antigenic peptide and T cell activation.
What three signals are required for successful T cell activation?
- TCR recognizes peptide in context of self MHC
- Engaging of co-stimulatory molecules: CD28 with CD80/86; CD40L with CD40
- Inducing cytokine expression and secretion; a combination of specific cytokines
dictates the generation of functionally different T cell responses and T cell fates - Activated T cells express high affinity IL2Rα (CD25) and proliferate in responding to
IL2 in an autocrine fashion.
A combination of specific transcription factors and cytokines drives functional differentiation of CD4 T cells.
For the type of effector T cell give its main functions and pathogens targeted:
- CD8 cytotoxic T cells
- CD4 Th1 cells
- CD4 Th2 cells
- CD Th17 cells
- TFH cells
- CD4 regulatory T cells (various types
See chart p 3
- CD8 cytotoxic T cells: kills virus infected cells (targest viruses some intracellular bacteria)
- CD4 Th1 cells: activate infected macrophages, provide help to B cells for antibody production (targets microbes that persist in macrophage vescicles, extracellular bacteria)
- CD4 Th2 cells: provides help to B cells for antibody production, especially switching to IgE (targest Helminth parasites)
- CD Th17 cells: enhance neutrophil response, promote barrier integrity like skin, intestine (targets fungi)
- TFH cells: B-cell help isotype switching antibody production (targets all types)
- CD4 regulatory T cells (various types): suppress T-cell responses
Draw a diagram that shows the forms a Naive CD4 can become. Include their interleukins.
p 3
becomes:
Th1, Th2, Th17, Thf, iTreg
Effector CD4pos T cells can be classified by cytokines they produce. Cytokines are communicators amongst leukocytes – the interleukins.
Describe Type I Immune response: (What type of T cells? What IL? What targets?)
- Type I immune response: T Helper 1 or Th1
- Th1: IFNγ, IL2, Lymphotoxin-α (LTα)
- Intracellular pathogens
- Various autoimmune diseases: self antigens, e.g. diabetes
Effector CD4pos T cells can be classified by cytokines they produce. Cytokines are communicators amongst leukocytes – the interleukins.
Describe Type II Immune response: (What type of T cells? What IL? What targets?)
Type II immune response: T Helper 2 or Th2
- Th2: IL4, IL5, IL13
- Extracellular pathogens
- Immunopathology of allergy, asthma, dermatitis
Effector CD4pos T cells can be classified by cytokines they produce. Cytokines are communicators amongst leukocytes – the interleukins.
Describe iTreg Cells Immune response: ( What IL? What targets?)
iTreg Cells:
- TGF beta, IL10
- Immune tolerance, regulation of immune response to self antigens
Effector CD4pos T cells can be classified by cytokines they produce. Cytokines are communicators amongst leukocytes – the interleukins.
Describe Th17 Cells Immune response: ( What IL? What targets?)
Th17 Cells
- Th17: IL17, IL21, IL22
- gut immunity (Th1)
Effector CD4pos T cells can be classified by cytokines they produce. Cytokines are communicators amongst leukocytes – the interleukins.
Describe T follicular helper Cells (Thf) Immune response.
T follicular helper cells (Thf)
- Thf: IL6, IL10, IL21; B cells to form germinal center, differentiation of B cells
into memory B cells, plasma cells (Th2)
What can initiate immune response?
Which cells respond?
Dangerous signals, either from an external source like a pathogen, or internal
source like a structurally altered protein
The cells that respond to the dangerous signals are macrophages, dendritic cells
Their unique function is to uptake pathogens, and process bacterial proteins for antigen presentation in the context of self MHC moleculules
- They can also respond to soluble bacterial products and viral RNA, DNA through the Toll-like receptors (TLRs)
Downstream signaling of TLR is orchestration of multiple cytokine gene expression
Describe toll like receptors and their ligands.
TLRs are present on both cell surface Membrane and membrane of intracellular vesicles
TLRs and their ligands
Ligands are collectively known as Pathogen Associated Molecular Patterns (PAMPs),
Danger Associated Molecular Patterns (DAMPs) or Microbial Associated Molecular
Patterns (MAMPs)
diagram/chart p 5
Describe the orchestration of T cell response to infection.
What are the critical initial players? When and how are they activated?
Antigen presenting cells like dendritic cells (DCs) and macrophages are critical initial players in inducing a T cell response. They are activated when encounter pathogens
through TLRs.
What will infections by organisms lead to?
Infections by organisms induce phagocytosis (uptake of a complex antigen) and intracellular killing.
Triggering via TLR ligands; genetic background of the host will dictate the type and intensity of TLR activation.
What will trigger a DC from immature to mature? What changes take place when this happens?
The recognition and uptake of a living pathogen or complex antigen by a DC trigger the conversion of an “immature” DC to a mature DC which then:
- No longer can phagocytose
- Upregulates its MHC-II
- Upregulates co-stimulatory molecules: CD80, CD86, CD40
- Migrates to lymphoid tissue
- Upregulates production of cytokines IL12 and IL18
Interactions between activated DCs/macrophages and T cells are initiated in the lymph nodes. Upon activated by DCs, effector T cells seek out infected cells.
Describe this process as applies to skin.
Antigen uptake by Langerhans cells in the skin.
Langerhans cells leave the skin and enter the lymphatic system.
Mature dendritic cells enter the lymph node from infected tissues and can transfer some antigens to resident dendritic cells.
B7 positive dendritic cells stimulate naive T cells.
How do T cells enter lymph node from blood?
What happens to T cells not activated by antigen presented by dendritic cells?
What happens to T cells that are activated by dendritic cells?
T cells enter lymph node cortex from the blood via high endothelial venules (HEVs)
T cells not activated by antigen presented by dendritic cells exit the lymph node via the cortical sinuses
T cells activated by antigen presented by dendritic cells start to proliferate and lose the ability to exit the lymph node.
Activated T cells differentiate to effector cells and exit the lymph node.
Describe the Th1 response:
Inducer cytokines?
Transcription factor?
Signature cytokines?
Inducer cytokines? IFNgamma, IL12
Transcription factor? Tbet
Signature cytokines? IFNgamma, IL12, LT alpha
p7
Describe the generation of the Th1 response.
Th1 T cells are quintessential cell type involved in:
Th1 T cells are quintessential cell type involved in:
- cell mediated inflammation
- delayed-type hypersensitivity reactions
They are thought to be important for immunity to intracellular pathogens
Cytokines orchestrate differentiation of naïve CD4 T cells into Th1 cells. What are the
sequential events?
- Activation of DCs/APCs by TLR ligands results in cytokine production, first IL12 and later IL18
- Interaction of activated DCs/APCs with naïve CD4 T cells: TCR with peptide MHC II, co-stimulatory molecules
- Expression of Tbet which drive expression of IFNgamma
- Up-regulation of IL12R on activated T cells which allows responding to IL12
produced by activated DCs/APCs - IL12 further induces expression of Tbet and subsequently drives the expression of signature Th1 cytokines.
- IL18 produced from activated DCs/APCs maintains and stabilizes Th1 response
p8
Describe IFNgamma.
Signature of what type of response?
What does it do?
Which responses does it suppress?
A potent pro-inflammatory cytokine
- Signature cytokine of the Th1 response
- But also by NK and activated CD8 cells
- Activate macrophages: antigen processing, MHC I and II expression, TLRs,
microbicidal activity, chemokine secretion - Potent suppressor of the Th2 and Th17 response
Describe IL2. What is it?
What cells produce it?
In what modes does it act?
What will genetic defects result in?
- Critical growth cytokine produced by activated Th1 and CD8
- Growth factor for T cells, particularly regulatory T cells
- Acts in autocrine and paracrine modes
- High affinity IL-2R (alpha-beta-gamma) expressed as a functional unit after antigen activation and
expression of the IL2Ralpha - Genetic defects – mutations in the gamma chain result in severe immune deficiency
diseases
Describe lymphotoxin-alpha.
What family is it a member of?
What cells produce it?
Implicated in immunopathology of which diseases?
- Member of the TNF superfamily
- In addition to Th1 cells, also produced by CD8, NK, B and macrophages
- Lymphoid organ development and maintenance of lymphoid microenvironment
- Function is not clear in humans
- Implicated in the immunopathology of:
Rheumatoid arthritis
Disease progression of multiple sclerosis (MS) patients
Describe Th1 response and downstream effects of the activated macrophages.
IFNgamma produced by Th1 cells activates macrophages in the infected tissue whether the
pathogens are present or not.
What are the classic tetrad of macrophage produced pro-inflammatory cytokines?
Describe their effects.
- The classic tetrad of macrophage produced pro-inflammatory cytokines are: IL1, IL6,
IL8 and TNFalpha - These cytokines have a wide range of autocrine, paracrine and systemic effects that promote inflammation
Describe IL1.
What type of cytokine is it, what does it facilitate?
What type of cells produce it?
What does it act with to cause fever or depression?
Describe its effects on CNS.
How does it interact with APCs?
Antagonist?
Describe its differentiation.
IL1: A pro-inflammatory cytokine
- Prototype primordial cytokine that facilitates host responses to stress
- Produced by a wide range of cell types: epithelial cells
- Promotes neutrophil growth and emigration from the marrow
- Acts with IL6 on CNS to cause fever, depression
- Neuroendocrine effects on adrenal gland
- Stimulates APCs to increase Ag presentation
- Antagonist is IL1Ra
- Differentiation of Th17, together with TGFbeta, IL6, IL21, IL23
Describe IL6. What type of cytokine?
What does it promote?/What other interleukins does it interact with?
What types of development is it required for?
How does it affect B clels and bone mineral metabolism?
IL6: A pro-inflammatory cytokine
- Many effects are redundant with IL1: fever, induction of acute phase protein (CRP)
- Promotes responsiveness to IL2, accelerates antigen activation
- It is required for optimal Th17 development
- May be required for Thf development
- Has strong growth and differentiation effects on B cells in the presence of other “B” cell cytokines
- Has effects on bone mineral metabolism where it activates osteoclasts
Describe IL8. What kind of activity does it have?
What is its main function?
What types of cells produce it and when?
IL8: A cytokine with chemotactic activity
- Is the most potent stimulus for mobilizing and recruiting neutrophils to the site of infection
- Produced mainly by macrophages, neutrophils and during intense inflammation by
endothelial cells
Describe Hypersensitivity Reaction Type IV: Delayed-Type Hypersensitivity.
What is it mediated by?
What test can be used?
What environmental stimulus will elicit a reaction?
- Mediated by antigen specific effector Th1 cells, CD8 cytotoxic T cells
- Commonly applied to clinical situations where macrophage activation is a central component of the disease pathology
- Tuberculin test: DH can be exploited to detect past infections
- Reaction to mosquito bites
Draw out a summary flow chart of starting with antigen is processed by tissue macrophages and stimulates Th1 cells.
Th1 gives chemokines, cytokines, and cytotoxins.
chemokines- recruit macrophages to site of antigen deposition
(cytokines) IFN-gamma- induce expression of vascular adhesion molecules. Activates macrophages, increasing release of inflammatory mediators
(cytotoxins) TNF-alpha and LT- cause local tissue destruction. increase expression of adhesion molecules on local blood vessels
(cytokines) IL-3/GM-CSF- stimulate monocyte production by bone marrow stem cells
p 11
What will production of IL3 and GM-CSF promote?
The production of IL3 and GM-CSF will promote monocyte differentiation from hematopoietic stem cells resided in the bone marrow. There will be a surge of monocytes in
the circulation which then are attracted to inflamed site where Th1 cells are present.
Antigen is injected into subcutaneous tissue and processed by local antigen presenting cells…
A Th1 effector cell recognizes antigen and releases cytokines, which act on vascular endothelium
Recruitment of phagocytes and plasma to site of antigen injection causes visible lesion
TNFalpha is a pro-inflammatory cytokine with pleiotropic functions.
Describe its activation, upregulator, inducer, properties.
Describe its systemic effects.
- Plays a central role in the immune system
- Potent Macrophage activator
- Potent activator of endothelial homing and adhesion molecules
- Potent upregulator of MHC and other cytokines
- Potent inducer of apoptosis and angiogenesis
- Has systemic effects that range from flu-like symptoms to death
- The availability of anti-TNF antibody provides a way to manipulate its effects
clinically (Infliximab, Adalimumab)
