Cellular Basis of the Immune Response T and B Cell Activation Flashcards
Where do superantigens bind?
Both to the Vbeta region of the TCR and to the alpha region of the MHC
What are the phases of the Primary Humoral Response?
- Lag Phase - time required for B cell division, differentiation; release of IgM followed by release of both IgM and IgG; memory B cell subset formed (4-5 days before antibody detection in serum; varies with nature of antigen – soluble antigen takes 7 days).
- Logarithmic Phase – antibody production increases logarithmically reaches peak levels (day 7-10) (day 14 for soluble protein antigen)
- Plateau Phase – equal synthesis and decline of antibody
- Decline Phase – more rapid degradation and decline of antibody
memory B cells stop dividing and enter G0 phase of the cell cycle
What are the gene products of T cell Activation?
- Immediate Genes - expressed within 30 min of
antigen recognition
- encode transcription factors,
c-fos, c-Jun, c-Myc, NF-AT and NF-κB
- Early Genes - expressed within 1-2 hrs
encode IL-2, IL-2R(receptor),
IL-3, IL-6, IFNγ
- Late Genes - expressed >2 days after
antigen recognition
encode adhesion molecules
What are the three signals required for T cell activation?
Signal 1: Interaction of MHC: Peptide with TCR: CD3 Complex
Signal 2: Interactions between CD28 on T cell and B7 on APC
Signal 3: Cytokines
What effectors are produced by cytotoxic T cells?
Soluble effectors
- Cytotoxins (perforins and granzymes)
- IFNy
- TNF- b
Membrane bound
- Fas ligand
What happens after signals 1,2,and 3 occur?
The resting cell enters the cell cycle and begins to profilerate and differentiate into effector and memory cells.
What effectors are produced by Th2 cells?
Soluble
- IL-3, IL-4,IL-5,IL-6. IL-10, IL-13, GM-CSF (low)
Membrane bound effectors
- CD40 Ligand
Only ___________% of the many B cells that are produced will enter the recirculating pool of B cells.
10
Cytokines act on their target cells by _____________
binding to specific membrane receptors
Naïve cells are activated exclusively by___________
Memory cells can be activated by ______________
dendritic cells
all 3 APCs; made possible by the large amounts of adhesion molecules
____________increases in response to activation signals
___________adhesion protein (homing to secondary sites)
___________chemokine (homing to secondary sites)
CD44
CD62L
CCR7
Bacterial superantigens have been implicated in ___________ and ___________.
food poisoning, toxic shock syndrome
What are the phases of the Secondary Humoral Response?
- Lag Phase – much shorter
- Logarithmic Phase – greater and longer lasting
_________ plays an important role in T cell homeostasis
CTLA-4
In addition to the stimulatory coreceptor, ___________delivers a negative signal that inhibits continuous B cell activation
CD22
Antibody cell signaling
- Binding antigen results in phosphorylation of tyrosines within the ITAMs (immunoglobulin Tyrosine-based activation motifs) of the Ig-α and Ig-β chains
- This creates docking sites for other molecules such as Syk
- Activated Syk phosphorylates the adaptor protein BLNK , creating docking sites for PLCγ2 and Btk
- Activated Btk phosphorylates and activates PLCγ2
- PLCγ2 cleaves PIP2 into DAG and IP3
- DAG and Ca2+ activate PKC which activates NF-кB which regulates gene expression, differentiation, activation and causes functional changes in the cell
Proinflammatory cytokines
TNF
IL-1
IL-6
Chemokine
What is the characteristic of cells in effector memory?
Some travel to tertiary sites of original infection
What effectors are produced by Th1 cells?
Soluble effectors
- IL-2, IL-3, TNF-B, IFNy, GM-CSF
Membrane bound effectors
- TNF B
Which cytokine receptors are used by the HIV virus?
CCR5 and CXCR4
What are the three signals of Thymus-dependent B cell response?
Signal 1 – multivalent antigen cross links Ig molecules
Signal 2- CD40L on T cell binds CD40 on B cell
Signal 3 – T cell cytokines bind and induce B cell proliferation
Antiinflammatory Cytokines
IL-10
IL-1a
TGF-b
Eosinophil/ Mast Cell Activating Cytokines
IL-3
IL-4
IL-5
IL-13
In what ways are natural killer cells similar to cytotoxic cells? In ways are they different?
Natural killer cells release perforins and granulozymes in the same manner as Tc cells
Natural killer cells lack CD3:TCR complex and is not MHC restricted
Can responses be thymus-independent in the secondary response?
No
Overstimulation of superantigens can lead to the overproduction of which cytokines?
IL1 and TNF
What are the characteristics of the antigens that are present with Thymus indepedent B cell Response?
TI-1 antigen- Gram negative bacterial cell wall lipopolysaccharide (LPS) interacts via Ig receptor and TLRs; mitogenic
TI-2 antigen- Highly repetitive molecules, like bacterial capsular polysaccharide, flagelin
Natural T regulatory cells originate in the __________. Is regulation antigen-specific?
Thymus; Yes because of the need for the TCR
Role of Induced T Regs
preventing the immune system from attacking the body’s cells and tissues.
Inhibit the development of autoimmune diseases by maintaining self tolerance
Inflammatory Bowel Disease
Allergic Encephalitis
Autoimmune Diabetes (Type I)
Arthritis
What is the function of Signal 2? What effect does this have? What happens if this signal doesn’t happen?
Signal 2 increases the half life of the IL-2 mRNA and stabilizes it
This allows for increased IL-2 production (100-fold)
Secretion of IL-2 induces proliferation and differentiation into memory cells and effector cells
In the absence of costimulatory signal 2, T cell receptor engagement results in T cell inactivity or Clonal Anergy.
Antiviral cytokines
IFNa, IFNb
Induced Tregs are _________ induced and ___________ mediated.
Inflammation; IL-10 and TGFBeta
Which proteins are a part of the B Cell Co Receptor Complex?
CD19
CR2
TAPA-1
Because of their immuno-modulatory role, cytokines and/or their receptors have been investigated for potential therapeutic use in :
Inflammation
Cancer
Allergy
Infectious Disease
Organ Transplantation
What are the roles of the alpha, beta, and gamma chains of IL-2?
Alpha: only expressed in activated T cells
βγ-chains can induce signal transduction
The trio chain is needed for high affinity binding
Characterstics of Cytokines
Pleiotropy
Redundancy
Synergy
Anatagonism
What are the effector T cells? Which cytokines does each secrete? What are their functions?
short-lived cells with special functions:
CD4 helper T cells :
- CD4TH1 - IL-2, IFNγ, TNFβ
- responsible for cell-mediated functions
- Delayed hypersensitivity and Cytotoxic T cell activity
- CD4TH2 - IL-4, IL-5, IL-6, IL-10
- responsible for B cell activation
- CD4 CD25 T regulatory cell (Treg)
- regulates T cell responses
- CD4 Th17
- (inflammatory cell; involved in fungal and extracellular bacterial infections; also associated with chronic autoimmune disorders)
- CD8 cytotoxic T cell
Cytokine- Induced Signal Transduction
- Cytokine binds to the receptor on cell membrane
- Dimerization of the receptor
- Phosphorylation of JAK
- Phosphorylation and dimerization of STATS
- Translocation of STAT to the nucleus where transcription of target genes occurs.
What are ways that cytokines can play roles in theraputic use?
Place an antibody against the cytokine receptor
Create an analog that binds in the place of the cytokine, thus preventing it from binding
Attach a toxin. Allow the cytokine to bind and the toxin will destroy the target cell
Macrophage activating cytokines
IFNy
Hematopoietin (Class I) – dimers or trimers with conserved ____________in their extracellular domains and a conserved ____________sequence.
cysteines; Trp-Ser-X-Trp-Ser
B Cell Activating Cytokines
IL-4
IL-5
IL-6
IL-21
Ig- α tail is _______ aa in length
Ig- β tail is ________ aa
61
48
B7 has 2 isoforms, __________and_________; they are constitutively expressed on ___________and induced on activated ____________ and ________
B7-1; B7-2; dendritic cells; macrophages; B cells
What are the systemic reactions to superantigens?
Fever, widespread blood clotting, and eventually shock
Is IL-2 a dimer or trimer?
Trimer
In naive cells CD44 is ____________, CD62L is __________ and CCR7 is _____________.
In effector cells CD44 is ____________, CD62L is __________ and CCR7 is _____________.
In effector memory cells CD44 is ____________, CD62L is __________ and CCR7 is _____________.
In central memory cells CD44 is ____________, CD62L is __________ and CCR7 is _____________.
Low, positive, positive
Positive, low, negative
Postitive, variable, negative
Positive, positive, positive
What roles do CD28 and CTLA-4 play in relation to B7?
CD28 and CTLA-4 compete to bind to B7. C28 is expressed on both resting and active T cells. CTLA-4 is virtually undetectable on resting T cells but is expressed on active T cells. CTLA-4 has a higher binding affinity. C28 yields a positive signal and CTLA-4 yields a negative signal.
T- Cell activating Cytokines
IL-2
IL-4
IL-12
IFNy
T cell dependent B cell response (Sequence of Events)
Sequence of events:
- Ag binding to BCR provides “Signal 1” to B cell.
- Ag internalized; processed; antigenic peptides displayed on MHC for T cell recognition.
- helper T cell recognizes ag:MHC complex via the TCR, which provides “Signal 1” to T cell.
- B7 on B cell binding to CD28 on T cell provides “Signal 2” to T cell.
- T cell activation leads to up-regulation of CD40L which bind to CD40 providing “Signal 2” to B cell.
- Cytokine production by activated T cell also helps to activate B cell.
- B cell proliferates and differentiates into antibody secreting B cell (plasma cell).
Tregs act antagonistically with the ___________cells
Th17
What three forms can the IL-2 receptor exist in?
Monomeric (just alpha chain, no signaling)
Intermediate (beta and gamma chains, signaling)
High affinity (all three chains)
What is the characteristic of cells in central memory?
Cells stay in secondary sites for long periods of time
T cell - B cell collaboration
•Required for antibody response to complex antigens such as proteins, lipids
•
Requires direct, physical B-T interaction
•
Involves multiple cell surface receptors on T and B cells
•
Both B and T cell must recognize antigen (but not necessarily the same epitope).
•
Both B and T cells need signal 1 (through antigen receptor) and signal 2 (co-stimulation)
What is CVID?
a disorder that impairs the immune system. People with CVID are highly susceptible to infection from foreign invaders such as bacteria, or more rarely, viruses and often develop recurrent infections, particularly in the lungs, sinuses, and ears.
Low Ig levels, especially IgM, IgA, and IgG
All isotypes of the _______Ig have short cytoplasmic tails. What’s the significance of this?
Monoclonal
Tails are all too short to interact with tyrosine kinase to generate a signal
Ig-α/Ig-β heterodimer acts as the signaling complex, while the mIg acts as the ligand binding molecule
Chemokine Family – have _________ transmembrane helices Includes receptors for ______, ______, and ________. Also the ______ and ________ receptors which are used by the HIV virus are included.
7; IL-8, MIP-1, and Rantes; CCR5 and CXCR4
Which cytokine makes IgE? IgA?
IL-4; IL-5
3.Tumor Necrosis Factor Family four extracellular domains; include receptors for________,__________,_________, and _________
TNFα, TNFβ, CD40 and Fas
