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298 Cards in this Set

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What is unique about BCRs that is different than TCRs?
BCRs: recognize both linear and conformational Ag determinants
membrane bound and secreted part of humoral response
TCR: recog linear Ag determinants, must be processed and presented in MHC
ONLY Membrane bound..thus cell mediated response
Structure of TCR?
heterodimers (95% alphabeta, 5%gammadelta)
Ig fold domains
hydrophobic tran membrane with pos. charged aa too attract neg charged complex
short cytoplasmic tails
constant C terminus
variable N terminus w/ CDRs
Can the cytoplasmic tails of TCR transmit signal?
no, they are too short and require additional molecules
How does the C terminus vary b/n different TCRs?
it doesn't..same in all TCR
What binds the heterodimer polypeptide chains together?
disulfide bonds
Describe the binding diveristy of TCR.
each TCR has a single binding site for Ag
Ag/MHC binding affinity lower than that of Ig for native Ag to facilitate multiple TCR interactions in order for T cell to become active
Each T cell bears single specificty (only bind 1 Ag determinant)
How many Ag determinants can a T cell bind?
only 1
T cell bears a single specificity
Which CDR of T cell is the most variable and binds peptide?
CDR3
Which CDR of T cell bind MHC?
CDR1 and CDR2
What is the mechanism(s) for generating diversity in Tcells?
TCR encoded in GENE SEGMENTS that undergo somatic recombination during T cell development to generate Ag-binding diversity
How many binding sites for Ag are there per TCR?
1 binding site per TCR
How many TCRs per T cell?
can have more than 1 like B cell
CDR1/2 bind MHC via?
shoulders
Which regions of TCR are encoded by V and J segments?
Valpha and Vgamma
* only 1 Calpha segment
* 70 Valpha and 60 Jalpha segments
Which regions of TCR are encoded by V,D and J segments?
Vbeta and Vdelta
* only 1 C segment
* 50 Vbeta, 1 Dbeta, 6-7 Jbeta
How is the constant region of TCR gene loci arranged?
constant region domain has separate gene segments for the constant, hinge, transmembrane, and cytoplasmic regions
What does TRA mean? What does TRAV mean?
TRA = alpha chain of TCR
TRAV= variable segment on alpha chain of TCR
How is TCR diversity generated?
depends on same combinatorial and jxnl mechanisms used for Ig diversity:
1. gene segments flanked w/ RSS
2. Rag-1 and 2 encoded recombinase and TdT reqd
3. Junctional flexibility
Where do the joining regions for VJ (alpha chain) and VDJ(beta chain) occur?
CDR3
**unique to TCR
Where are CDR1 and CDR2 encoded?
w/n TRVA and TRVB
How many productive gene rearrangements can occur per T cell?
only one
*NO codominance
Why is there increased diversity in joining region of TCRs?
b/c CDR3 is the region that binds Ag
What are 6 ways in which diversity is generated in TCR's?
1. RSS
2. Rag1 and 2
3. joining regions occur in CDR3
4.junctional flexibility
5.P and N nucleotide addition
6. combinatorial association of 2 chains (alpha1beta3)
Why doesn't SHM occur in TCRs?
b/c TCR's have to be able to recognize and bind MHC. They wouldn't be able to recog MHC (self) if they altered themselves after they were educated as to what "self" looks like
*no random pt. mutations after recombination complete
How do the TCRs on 1 T cell differ from each other?
they don't ..they are identical as each other
Of what percent of the total T cell pool are gammadelta T cells?
2-10% *minor component of T cell pop
Where do gammadelta T cells appear first? What happens to them there?
appear in fetal thymus
DO NOT undergo thymic selection
What are gammadelta T cells also known as?
IEL's intraepithelial lymphocytes
Where to IEL's migrate to?
emigrate as CD4- and CD8- to epithelial tissues in skin, intestines and lungs
What does it mean that IEL's are CD4-?
CD4- means that they can't recognize MHC
What line of defense are IEL's apart of?
2nd line of defense: they respond to microbes that enter large intestine for example
What is the fxn of gammadelta T cells?
immunosurveillance of transformed, damaged or stressed epithelial cells along mucosal surfaces
What do gammadelta T cells recognize?
non-peptide ligands (isoprenoids, alkylamines from microbes or stressed host cells) as well as HEAT SHOCK Proteins
Why do gammadelta T cells have limited diversity TCRs?
b/c they do no undergo thymic selection so they can't recog as diverse array
Are gammadelta T cells class restrictive?
IELs are NOT class restrictive
Where are alphabeta T cells found primarily?
found in lymphatic tissue (lymph nodes, MALT)
Do both gammadelta T cells and alphabeta T cells undergo maturation in thymus?
NO only alphabeta T cells move from BM to thymus for maturation and selection processes:get rid of self-reactants
What are alphabeta T cells divided into?
CD4+, CD8+, and NKT cells
CD4+ cells are divided into?
Th1 and Th2 cells
Th1: cell mediated
Th2: humoral
What is the fxn of CD4+ cells?
secretion of cytokines to effect the appropriate immune response or to strengthen a response
(signal other immune cells)
What is the fxn of NK T cells?
express CD3
recognize glycopeptides and glycolipids presented by CD1d rather than recog MHC
How are CD8+ cells similar to NK cells?
that act like NK cells in that they secrete granzymes and perforins
What CD marker is intimately associated with TCR?
CD3
What is the structure of CD3?
composed of six molecules and exists as three sets of dimers: gamma episolon, delta episilon and either two zetas or zeta/eta heterodimer
Does the CD3 bind Ag?
NO..part of TCR complex to transduce signals from TCR
Kinases present on cytoplasmic tails of CD3 for (transduces the external signal from the TCR to the cell cytoplasm)
How is the signal from bound Ag to TCR transduced to CD3?
when MHC/Ag binds TCR it causes a wiggle in membrane and signal is translocated to CD3 to activate T cell
What is the difference and similarity b/n CD+4 and CD+8?
both are members of Ig superfamily
CD4: monomeric
CD8: alphabeta or alphaalpha dimer
Fxn of CD4 and CD8?
T cell class restriction
CD4: MHC II
CD8: MHC I
both bind MHC and start additional signal contributing to strength of CD3 signal
What is CD28 and where is it found?
co-stim molecule found on T cell that binds CD80/86 on APCs
It is the 2nd signal in activation
What is CD28 necessary for?
necessary for IL-2 production : T cell proliferation
Plays the largest role on CD4 b/c all of them express it, only 50% of CD8 have CD28
w/o this the signal would be incomplete and T will become anergic (lack of immunity to Ag)
What does CD2 bind to?
acts as an adhesion molecule and binds to LFA-3 on APCs; interaction allows T cells to bind to many other cells
What is LFA-1?
adhesion molecule that binds ICAM-1 (ICAM-1 can be on APCs w/ LFA-1 on T cell or vice versa)
What is the fxn of CD45?
particpates in signal transduction by removing phosphates (acts as phosphatase in cytoplasmic domain)
What is CTLA-4?
molecule present on activated T cells that is similar to CD28 and binds CD80/86 on APCs acting in inhibitory manner on T cells, possibly causing apoptosis of activated cells (downregulatory)
What does CD marker CD34+ indicate?
common lymphoid precursor (CLP) from BM
How is CD44 involved in trafficking to thymus?
Binds hyaluronic acid on endothelial cells, mediates adhesion of leukocytes
What do T cells look like when they enter thymus?
When progenitor cells first enter the thymus from the bone marrow, they lack most of the surface molecules characteristic of mature T cells and their receptor genes are unrearranged. Interactions with the thymic stroma trigger an initial phase of differentiation along the T-cell lineage pathway followed by cell proliferation, and the expression of the first cell-surface molecules specific for T cells, for example CD2 and (in mice) Thy-1. At the end of this phase, which can last about a week, the thymocytes bear distinctive markers of the T-cell lineage, but they do not express any of the three cell-surface markers that define mature T cells. These are the CD3:T-cell receptor complex and the co-receptors CD4 or CD8. Because of the absence of CD4 and CD8 such cells are called 'double-negative' thymocytes
NK T cells are activated as part of the early response to many infections. How do they differ from the major lineage of a:b T cells ?
recognize CD1 instead of MHC
What is c-Kit?
the receptor for the hematopoietic cytokine, stem cell factor
What does trafficking to thymus require?
c-kit and CD44
what occurs to T cells in thymus?
Ag independent maturation
When T cell in thymus what is it called?
pro-t cell
What type of signals does pro-t receive for TCR gene rearrangement?
IL7/IL-7R and SCR/c-kit signals which direct TCR gene rearrangment
What do Pro T cells in cortex of thymus express?
express c-Kit and CD44 but not CD25
What markers do Pre-T cells in cortex of thymus display?
CD44+ and CD25+
productive b-chain gene rearrangements and express the b chain (TCRbeta or TCRgamma)
IN the cortex of thymus, what markers are added to T cell?
TCR and CD3
induction of the expression of BOTH CD4 and CD8 on ALL cells
which form of selection occurs in cortex of thymus? medulla?
positive-cortex
negative-medulla
What marker distinctions on T cell are made in medulla of thymus?
cells only express CD4 OR CD8
what does positive selection indicate?
lineage commitment and MHC recognition
What does negative selection indicate?
self reactive T cells eliminated
when a T cell expressed TCR, CD3, CD4 and CD8 on same T cell what does it undergo?
positive selection: body provides for selection of T cells with TCR's that can recog and bind self MHC
positive and negative selection is also known as?
antigen independent maturation of t cell
what cells present self Ag on both mhc i and ii to t cells in medulla?
interdigitating dendritic cells
thymic epithelial cells
what degree of association/dissociation is reqd to signal for positive selection?
moderate association
high dissociation
what degree of association/dissociation signals for inhibition of positive selection and leads to apoptosis?
high association
low dissociation (binds to tightly..could destroy our tissue)
positive selection looks for?
strength of binding
what are the outcomes of positive selection?
ensures ability of T cell to bind MHC I or II (CDR1/2 bind shoulders of self MHC)
95% t cells die during + slctn
cell lineage commitment occurs:affinity for MHC I means CD8 retained and CD4lost
Where doe CD8 and CD4 bind to MHC on stromal cells?
in conserved regions
If the T cell receives a weak Lck signal transduction what type of T cell will it become?
CD8+ when it binds to MHCI on stromal cell
If the T cell receives a strong Lck signal transduction what type of T cell will it become?
CD4+ when it binds to MHC II on stromal cell
Where does negative selection occur?
medulla of thymus
During negative selection, self peptides are presented on what type of cells to thymocytes?
SELF peptides are presented on interdigitating DC and/ore thymic epithelial cells
Where doe CD8 and CD4 bind to MHC on stromal cells?
in conserved regions
If the T cell receives a weak Lck signal transduction what type of T cell will it become?
CD8+ when it binds to MHCI on stromal cell
If the T cell receives a strong Lck signal transduction what type of T cell will it become?
CD4+ when it binds to MHC II on stromal cell
Where does negative selection occur?
medulla of thymus
During negative selection, self peptides are presented on what type of cells to thymocytes?
SELF peptides are presented on interdigitating DC and/ore thymic epithelial cells
If a TCR can bind to self-peptide MHC complexes but does so with low affinity, what type of signal will the cell receive?
weak or moderate binding elecits a survival signal that means the cell has surved
selection based on binding affinity: weak/moderate = cell survival
If a TCR has high affinity for self MHC or self peptide-self MHC complexes what type of signal will the cell receive?
strong binding elecits death during negative selection
selection based on binding affinity: high=apoptotic cell death
What are the outcomes of negative selection?
eliminates self reactive T cells
development of central tolerance
What is tolerance?
absence of specific immune response in otherwise fully immunocompetent person
T and B cells competent to elicit response but don't
What is central tolerance?
result of negative selection of self reactive T cells in thymus and of self reactive B cells in bone marrow
What is peripheral tolerance?
all mechanisms blocking self reactive T cells that have survived elimination in the thymus
2nd mech. to block self-reactive T cells that make it out of thymus and recognize Ag that is sequestered and react to it
T cells undergoing positive selection are what?
double positives expressing both CD4+ and CD8+
What are CLPs?
hematopoeitic stem cells that will give rise to T cells, B, NK and potentially some types of DCs
What are thymocytes called that lack CD3, CD4 or CD8 called?
triple negatives
CLPs that enter the thymus become what?
immature thymocytes with germ line configurations for the TCR genes and lack expression of most other cell surface markers which are present on mature T cells
Of what charge are the transmembrane regions of the CD3? What purpose does this have?
they are negatively charged so that they can interact with the positively charged transmembrane regions of the TCR chains. This draws the two together physically
what is expressed first on the CLP on its way to becoming an immature T cell?
expression of ckit to respond to growth factor SCF
What is expressed after ckit on CLP?
IL-7R to bind to IL-7 resulting in changes in chromatin structure and chemistry to make TCR accessible for rearrangement and transcription
What are the mechanisms contributing to central tolerance?
central clonal deletion (process of negative selection)
central clonal anergy (when self reactive cells escape but lack costim molecules and therefore become anergic)
What is the exception to central tolerance?
sequesterd antigens
Any self reacting T cells that are allowed to leave the thymus may be prevented from attacking self by what peripheral tolerance mechanisms?
peripheral clonal anergy
(incomplete signal transdxn b/c APC isn't induced to have CD80/86 leading to anergy)
regulatory or suppressor T cells (secretion of regulatory cytokines by regulatory, CD4, or suppressor, CD8, cells that suppress or regulate T cell activation)
Immune priveleged site (CD95L on stromal cells bding to CD95 on T cell and induce apoptosis
what are some immune priveledged sites?
eye, brain, ovary, and testis
What are alphabeta T cells called that leave after positive and negative selection?
mature, naiive T cells
have undergone Ag-independent selection
express TCR/CD3, CD4 or CD8, CD28, CD45
How does the T cell contribute to the adaptive response?
TCR provides specificity
Preformed T lymphocites ready to be exposed to Ag
Custom made responses: Th1 for intracellular, Th2 for extracellular
Clonal expansion provides memory
Faster response on 2nd exposure due to memory
What are the Ag- dependent exceptional mechanisms of T cell activation.
Superantigens stimulation
allogenic MHC
Polyclonal
Explain superantigen stimulation.
superantigens are bacterial exotoxins that bind and cross-link MHC II to keep T cell and APC in contact long enough for T to become active. It doesn't care what peptide is present (NONSPECIFIC)
Results in inappopriate immune response that activates 20% of T cells causing an abnormal increase in cytokines leading to hypovolemic shock
What is an allogenic MHC and what does it lead to?
allogenic MHC is a foreign MHC that results in activation of 1% of T cells
This is the underlying cause of graft vs. host tissue response..ability of T cells to respond to Ag by non-self MHC
What are the steps in Adaptive T cell mediated immune responses that are Ag dependent?
clonal selection
clonal expansion
terminal differentiation
What is clonal selection?
choosing T cell clone with diff specificities for specific Ag: binding of APC by Ag specific T cell
Requires 2 signals
Where does clonal selection primarily occur?
in peripheral lymph organs
Explain the signals of clonal selection.
signal 1: APC's present peptide-MHC to CD4 T cells
signal 2:APCs present co-stim molecules to the T cell leading to IL-2 production and IL2R expression (T cells expresses higher affinity IL-2R so IL2 can act back to stimulate expansion of more specific t cells
What happens during clonal expansion?
T cells are receptive to autocrine and paracrine growth factors (IL2, IL4) leading to proliferation thru autocrine and paracrine mechanisms
What is terminal differentiation?
last step in adaptive T cell mediated Ag-dependent response in which T cells respond to cytokines to become effector and/or memory T cells due to cytokine microenvironment
What contributes to the stability of binding b/n T cell and Ag-MHC complex in clonal selection?
adhesion molecules present on T and APC: LFA-ICAM bind with high affinity upon TCR engagement
If they do not bind/recog specific Ag/MHC they detach and move to next APC
Signal 1 of clonal selection involves what components?
TCR/CD3 and CD4 or CD8 bind to Ag/MHC I or II
Signal 2 of clonal selection involves what components?
CD28 on T binding to CD80/86 (B71,72) on APC causing co-stimulation
What happens after both signal 1 and 2 of clonal selection?
induction: naive mature T cells proliferate and differentiate after exposure to an immunogen and co-stim molecules by cytokine production, cell division, and cell differentiation
Specifically, what occurs during signal 1?
series of dephosphorylation/phosphorylation events that begin with CD45 phosphatase that removes negative regulatory phosphate in cytoplasmic domain of Lck, Fyn activating them to then phosphorylate ITAMs on CD3. This provides docking site for ZAP which p-lates PLC. PLC now cleaves PIP2 into IP3 and DAG. IP3 increases intracellular Ca that creates cellular response resulteing in activation of TF NF-AT and NF-betakappa
What types of custom made responses are there against intracellular microbes?
T help for cell mediated (Th1)
delayed type hypersensitivity
cytotoxic T cell response
antiboty dependent cell mediated cytotoxicity (ADCC)
What types of custom made responses are there against extracellular microbes or solbule foreign antigens?
T help for humoral immune response (Th1 Th2)
ADCC
What increases the expression of co-stim molecules on APCs?
activation of APCs by microbes, innate immune defense
What co-stim events happen during signal 2?
increased expression of B7(CD80/86) on APCs binds to CD28 on T cell resulting in small G proteins Rac and Ras recruited to the cell membrane. These activated g proteins initiate MAPKcascade with resulting activation of TF's Jun and Fos. Jun and Fos lead to new gene expression of increased affinity IL-2 R on T cell surface as well as production of IL2 for paracrine and autocrine stim. of T cells
TCR + CD3 alone =
clonal anergy w/o CD28
TCR-CD3, CD2, CD28 and LFA-1 =
clonal selection
T cell effector differentiation depends on what?
type of antigen (extracellular vs intracellular)
type of APC presenting the Ag which determines what cytokines will be produced
During what phase of Ag-dependent T cell activation does differentiation occur?
induction phase
What influences the differentiation of naive CD4 T cells into Th1 and Th2?
cytokines produced in innate response or early adaptive response
What cytokine environment determines Th1 production? Th2?
Th1: IFN-g and IL-12
Th2: little amt IFN-g NO IL12
IL-4 production
What cells secrete IFN-g and IL-12 to lead to Th1 differentiation?
macrophages and DCs
What cells secrete IL4 that leads to Th2 differentiation?
may be produced by mast cells and other T cells
What TF's are involved in Th1 development? Th2?
Th1: T-Bet and STAT4
Th2: GATA-3 and STAT6
What cell response does Th1 mediate? Th2?
Th1: cell mediated response
Th2: humoral response
What does Th1 production result in?
increased production of IFN-g which acts to down regulate Th2 arm
What does Th2 production result in?
results in procution of IL-10 which down regulates Th1 arm by inhibiting IFN-g
What effects does T-Bet have?
increase IFN-g
Increase IL-12R
decrease IL-4
What effects does GATA-3 have?
increase IL-4
decrease IFN-g by IL-10
decrease IL-12R
What is stabilized in Th1 and what is silenced?
stabilized: IFNg
silenced: IL-4
What is stabilized in Th2 and what is silenced?
stabilized: IL-4
silenced: IFN-g
Cytokines produced by Th1? Th2? both?
Th1: IFNg, IL-12, TNF
Th2: IL-4, IL-5, IL-13, IL-10
Both produce IL-3 and GM-CSF
Do both Th1 and Th2 have IFN-gR's?
only Th2 b/c it is an inhibitory R that inhibits proliferation of Th2
Do both Th1 and Th2 have R's for IL-12?
only Th1
What Ab isotypes are stimulated by Th1? Th2?
Th1: IgG2
Th2: IgE, IgG4
Do both Th1 and Th2 activate macrophages?
only Th1 activate macrophages
Do both Th1 and Th2 express CD40L?
yes!
How are Th1 and Th2 cross regulatory?
Th1 produces IFN-g that binds to inhibitory IFN-gR on Th2
Th2 produces IL-10 that inhibits production of Th1
What is the fxn of IL-7?
promotes growth of memory cells
What effect does a secondary response have on clonal expansion of lymphocytes?
memory cell pool increases and the speed of response increases on future exposures to same Ag (basis for booster shots to increase memory)
While some effector cells live to become memory, other die by apoptosis. How does this occur?
they express Fas on themselves and die by apoptosis
In cell-mediated immunity, interaction of effector T cells with APC's requires what?
CD40L on T cell to bind to CD40 on macrophage,
Tcell secretes IFN-g with then stimulates macrophages to increase phagocytic ability leading to bistandard damage production to kill (ROS, RNI)
In humoral immunity, what do activated T cells interact with and how?
T cells respond to Ag on B cells and activate the B cells by binding to CD40R on B leading to antibody secretion; neutralization and elmination of Ag
What are the 2 T cell-mediated immune rxns?
1. (INDIRECT)CD4 Th1 and CD8 cells both recognize class MHC II or MHC I associated peptide Ag's of PHAGOCYOSED microbes, and produce cytokines that stimulate inflammation and activate the phagocytes to kill the microbes
2.(DIRECT) CD8 CTL's recognize MHCI of MICROBES replicating in the cytoplasm of infected cells and cause lysis of infected cells
In a cell mediated immune rxn, CD4 Th1 produce what 2 cytokines?
IFN-g to lead to macrophage activation and killing
TNF to stimulate inflammation recruiting neutrophils and macrophages to clear site
When Ag enters the body, which Th response do you get?
also have both Th1 and Th2 responses then one predominates
What effect does IL-4 secretion by Th2 cells have on other cells?
IL-4 stimulates B cells to produce neutralizing IgG antibodies(to attack extracellular bacteria, viruses, toxins) and class switch to IgE to cause mast cell degranulation (in presence of parasites and allergies)
It also plays a role in suppressing macrophage activation
What effect does IL-5 secretiong by Th2 cells have on other cells?
IL-5 leads to eosinophil activation to kill parasites
What doe CD4 cells that differentiate into Th1 cells secrete?
IFN-g, lymphotoxin (LT) and IL-2
What effect does IFN-g from Th1 cells have on other cells?
acts on macrophages to increase phagocytosis and killing of microbes and on B cells to stimulate production of IgG2a Ab's that opsonize microbes for phagocytosis
What effect does IL-2 from Th1 cells have on other cells?
it is the predominant autocrine growth factor made by this subset of T cells, and along with IFN-g can contribute to the differentiation of CD8 cells to CTL's
What effect do Lymphotoxin (LT) and TNF from Th1 cells have on other cells?
they activate neutrophils to increase their enhanced microbial killing
What is the effect of an APC presenting to a CD8+ cell on MHC I?
CD8+ (not CTL yet) will produce IFNg to activate macrophages to kill ingested microbes through phagocytosis
This is INDIRECT killing b/c CD8 released from thymus is mature but naive ..not an effector cell yet
What is the effect of an APC presenting Ag on MHC I to CTL?
DIRECT killing of infected cells via lysis b/c the CTL is an mature effector cell now
What are the 4 effector fxns of Th1 cells?
activation of macrophage by IFNg
activation of neutrophils by TNF and LT
activation of CTL's by IFNg and IL-2
isotype switching of B cells for isotypes capable of mediating ADCC by IFN-g
How are macrophages primed by CD4+ Th1 cells?
CD4+ effector cell's CD40L binds CD40 on macrophage. T cell then secretes IFNg that binds IFNgR on macrophage activating it to now kill phagocytosed products by ROI, and NO. Macrophage now secretes cytokines TNF and IL-1 and shows increased expression of MHC molecules and costimulators
What are the phases of DTH?
induction phase
inflammatory phase
effector phase
Why is DTH called delayed?
b/c it takes 24-48 hrs for memory cells to migrate into the effected area
What happens during the induction phase of DTH?
macrophages phagocytose Ag and present it to CD4 Th1 cells. If this is the first time the body has seen the Ag, naive cells will see Ag but you will not get DTH. But, if memory T Cells are presented the Ag on 2nd exposure, the recognize peptide-MHC complex and are activated and activate macrophages by IFNg
What happens during the inflamatory phase of DTH?
luekocytes extravasate and accumulate in affected tissue
What happens during the effector phase of DTH?
activated macrophages kill the extracellular microbes or if the rxn is chronic, a granuloma will form with center of macrophages surrounded by T cells
What is the fxn of CTL's?
destroy cells infected by viruses or other intracellular parasites and tumor cells (altered self cells)They kill without causing much tissue damage by DIRECTED secretino of nonspecific efector molecules at immune synapse (aka: deliver perforins and granzymes by forming pocket-no bistandard damage like CD4+)
What 2 mechanisms can Th cells assist the activation of naive CTL's by?
1. triparte interaction b/n DC, CTL and Th
2. biparte interaction b/n Th and CTL then that activated DC with CTL
explain the triparte interaction.
The CTL, Th and DC form triparte in which DC simultaneously presents Ag to Th cell and CTL. Activation of Th results in production of IL-2 while presentation of Ag to CTL results in synthesis of IL-2R. Th produced IL-2 can then bind CTL IL-2R in a paracrine manner completing activation of CTL
explain the biparte interaction.
Th cell binds to DC activating the DC to increase its expression of the CD80/86 costim molecules. This activated DC may then be able to stimulate production of both IL-2 and the IL-2R on the CTL allowing autocrine IL-2 stimulation
In the biparte interaction, what is the key reqt. for costimulation via interaction with CD28 on the CTL cell?
up-regulated dendritic cell expression of CD80/86. An efficient way of up-regulating CD80/86 on DC's is signaling via CD40 after its ligation to CD40L expressed by activated CD4 helper cell
What are the 3 mechanims by which CTL's kill target cells?
1. perforin is exocytosed in CTL granules and polymerizes in the target cell plasma membrane to form pores that allow the entry of water and ions and may result in lysis
2. granzymes are exocytosed in CTL granules, enter target cells through perforin pores, and induce target cell APOPTOSIS from caspase activation
3.Fas L is expressed on activated CTL's, engages Fas on the surface of target cells and induces apoptosis
Explain CTL perforin/granzyme mediated cytotoxicity.
CTL binds MHCI target cells increasing expression of adhesion molecules LFA/ICAM (tight conjugate formation)causing reorganization of CTL organelles. Then cytolytic granules are released from pre-formed perforin and granyzmes in immune synapse. Perforin forms membrane pore and granzymes activate caspase cascade leading to apoptosis. CTL's detach and cycle to next target cell
Explain FasL/Fas (CD95L/95) mediated cytolysis.
FasL expresssion on CTL is induced when TCR of CTL binds MHC of APC. If CTL comes across something foreign it inducse FasR on virally infected cells to bind to it's FasL. Through signal transduction, FasR activates caspase cascade apoptosis
FasL is a member of what superfamily?
TNF/TNFR (NGF/NGFR) superfamily
How is FasL expressed on cell surface?
as trimer, binds trimeric FasR on target cell
Explain ADCC.
infected cells are coated with Ag-specific Ab's (Ab's involved include IgG1, IgG3 and IgE). An NK cell, mast cell or eosinophil then recognizes Ab bound to target cell and binds to Ab's Fc region. NK then releases granzymes and perforins. Eosinophil degranulates to kill parasites. Both result in apoptosis not phagocytosis. The FcR/Fc binding stimulates cascade w/n effector cells that delivers apoptosis machinery
How is specificity conferred in ADCC?
antibodies binding to FcR's provides specificity of binding
What are the effector fxns of IFN-g secretion by Th1 cells?
macrophage activation
cell-mediated immunity
DTH
What are the effector fxns of IL-2 by Th1 cells?
activation of CTL's and NK cells
What are the effector fxns of IL-4 and IL-5 secretion by Th2 cells in response to helminths and allergens?
IL-4 leads to class switching of B cells to produce IgE to cause mast cell degranulation.
IL-5 leads to eosinophil activation to kill via ADCC
Various protein antigens activate Th1 and Th2 to respond how?
by activating B cells and kill via humoral immunity
Where are B cells activated and how?
B cells are activated in the cortex of the thymus by BCR
Where are T cells activated and how?
T cell are activated via epitope presentation by APC in paracortex
Where does pre-ag exposure maturation of B cell take place?
BM
Where does post-Ag exposure maturation of B cell take place?
peripheral lymphoid organs
interacts with other cell types and secreted cytokines to generate an Ag'specific Ab secreting plasma cell or long lived memory B cell
What happens if a B cell never interacts with Ag?
it dies b/c it no longer receives growth signals
only 10% naive B cells bind Ag and become activated
Where are B cells activated and how?
B cells are activated in the cortex of the thymus by BCR
Where are T cells activated and how?
T cell are activated via epitope presentation by APC in paracortex
Where does pre-ag exposure maturation of B cell take place?
BM
Where does post-Ag exposure maturation of B cell take place?
peripheral lymphoid organs
interacts with other cell types and secreted cytokines to generate an Ag'specific Ab secreting plasma cell or long lived memory B cell
What happens if a B cell never interacts with Ag?
it dies b/c it no longer receives growth signals
only 10% naive B cells bind Ag and become activated
What must happen to a mature, but naive B cell before it can differentiate into an antibody-producing cell or memory cell?
B cell must be activated
What is the purpose of B cell activation?
initiate second messenger systems resulting in transcription of genes which upregulate and/or encode adhesion molecules, MHC molecules, and other proteins reqd to promote cell interaction with T cells
What happens if B cells don't interact with T cells?
they are locked into being IgM producing B cell with little memory and no T cell interaction
*this is still an activated B cell
Explain the structure of BCR.
IgM transmembrane monomer bound to B cell with Igalpha and Igbeta effectors which form S-S linked heterodimer which is non-covalently associated with mIg
How does the BCR transduce the signal?
when Ag binds to mIgm, a ripple is created in lipid raft that stimulates the Igalpha and Igbeta dimer to mediate signal transduction through interaction with cytoplasmic SRC family tyrosine kinases such as Lck, Lyn, and Fyn that initiate the activation of B cells
What is the role of Igalpha and Igbeta in trafficking?
they are important in trafficking of newly synthesized mIg from the ER to the plama membrane
explain the cytoplasmic tails of Igalpha and Igbeta
Igalpha has 61aa and Igbeta has 48aa that make up ITAMs that contain multiple Tyrosine phosphorylation sits
Is Ag binding to BCR an isolated event?
no..it involves a series of molecules. When the wiggle occurs lipid raft associates affecting internal and external cell. Crosslinking occurs of all IgMs on surface
What happens immediately following Ag crosslinking?
CD45 dephosphorylates Src kinase
p72skk (ZAP kinase) that is always in the active site then phosphorylates Src kinase
Src kinase is not active and p-lates ITAMs of Igalpha and Igbeta Directly
How does Src bind p72syk?
homology region on end of Src matches up with p72 wich then p-lates Src kinase then p-lates ITAM
Is CD45 present only on T cells?
no, it is constitutively on B and T cells
How do Src kinases bind and p-late ITAMs?
Src binds via SH2 to ITAMs
can p72syk p-late ITAMs directly?
yes
What is the fxn of adaptor protein Shc in signal transduction via the BCR?
they act as hostesses of immune response that bring molecules together to do things: it phosphorylates Grb2 and Sos that act as docking proteins for p21Ras to activate cell
Besides phosphorylating Src kinase, what other role does p72syk play in B cell signal transduction?
liberates intracellular Ca activting PLC to transcribe gene products necessary for B cell activation (MHC II, CD40 and cytokine R)
What is the B cell coreceptor?
complex of 3 cell membrane molecules: CD19, CD21, and CD81 that are NON-covalently bound
What is the purpose of CD19 on B cell?
decreases the threshold requd for activation of BCR
Explain the purpose of the B cell co-receptor.
it acts as an augmenting system: when Ag bound has been opsonized by complemen, the co-receptors turn on more p-lation enhancing system in addition to IgM signal transdxn
Where does C3d come from?
when bacteria is opsonized by C3b, CRI cleaves it to C3d
What binds to the C3d that has opsonized Ag? And what happens after it binds to C3d?
CD21, which then results in p-lation of CD19, which then binds Src kinase Lyn; this triggers signal transdxn through PLC
What is CD81 and what does it do?
part of B cell co-receptor
tetraspan transmembrane protein that stabilizes and regulates motility and signal transdxn
What are the fxnl consquences of B cell activation by BCR alone with NO T cell involvement?
activated B can clonally expand, can increase expression of B7 costimulators, increase expression of cytokine R's and migrate out of lymphoid follicles
also can secrete low levels of IgM
What does the activation of B cells by Ag in lymphoid organs initiate?
the process of B cell prolif and IgM secretion and prepares the B cell to interact with helper T cells and respnd to T cell help
What does it mean when B cells fail to respond to Ag in an person that has no thyms?
it means that activation of B cells is thymus dependent aka T cell dependent
What are some examples of thymus dependent antigens?
proteins
glycolipids
What are some examples of thymus indepent Ags?
polymeric Ag's especially polysachharides (lipopolysachharides) also glycolipids and nucleic acids
Do TD Ag's participate in isotype switching? TI Ags?
TD Ag's: yes b/c of interaction with T cells to IgG, IgE and IgA
TI Ag's: little or no if they do they switch to IgG
Affinity maturation for TI and TD Ag's?
TD: yes
TI: little or no
Are TD Ags involved in secondary response?
yes
TI Ag's evoke secondary response only with TI-2
How do TI Ags act?
directly by binding to BCR
no T cell involvement
they bind to BCR stimulate plasma cells and low affinity IgM is produced. No class switching can take place (some IgG) and NO memory
What type of Ag is part of the vaccine to Strep pnuemoniae?
TI-1 Ag producing IgM in humans (TI-1 are common as vaccine components)
Describe the kinetics of TI-1 Ag's
peak Ab levels at 2-4wks
High levels: 5-8 yrs post 1 vaccination
Do TI-1 Ag's lead to memory response?
No, no TI Ag's show a memory response b/c they don't involve T cells. Therefore they have no booster or anamnestic response: everytime you see Ag you start over with primary response
Characteristics of TI-2 Ags.
large mass, repetitive epitopic antigens such as FLAGELLA and BACTERIAL CAPSULAR POLYSACHARIDES
How can TI-2 Ags produce some memory and class switching even though technically TI's can't?
they may be presented to NON-MHC molecules on gammadelta T cells and therefore induce isotype switching in the presence of IFNg: source of IgG anti-ABO activity in some patients
What type of Ags are TD Ag's?
anything that the T cells can recognize: soluble proteins, peptides and some (glyco)lipids from whole cells, VIRUSES, and PARASITES
Do T cells recognize TD Ag's bound to BCR or MHC?
T cells only respond to TD Ags bound to MHC on B cells!! In this situation B cells act as APC's therefore T cells respond to the MHC on B's not the BCR
How do B cells process TD Ag?
ENDOcytosis via the BCR
proteolysis to 13-18 aa
presentation by MHC II
travels to cell surface
presents to CD4 T cell
Briefly describe what the 2 BT tangos are.
1st tango: induction of affinity maturation
2nd tango: induction of class switching
What does the BT tango requre?
activation of each of the participants: T and B cells
Explain the 1st BT tango
paracortical T reacts with APC becoming activated, proliferates and differentiates. T then leaves paracortical area to paracortical-cortex jxn. At the same time B binds Ag and presents it on its MHC then migrates to boundary to interact with T
Explain how DCs can present Ag to T cells in 1st B-T tango.
immature tissue resident DCs with intact and processed Ag on surface migrate as veiled cells to LN, lose phagocytic ability and become APC's the present Ag to T cells via MHC II in paracortex
How did B cells get to cortex of thymus?
they migrated as naive antigen-committed B cells from BM and entered thymus via HEV
What strenthens the BT first dance?
MHC-TCR, CD-28 with CD80/86 and CD40/CD40L interactions resulting in secretion of cytokines by T cells which activate B cells
How must the B and T interact in first tango?
intimately: cell-cell contact
must have a physical cognate interaction..replacement by cytokines is not sufficient
What is signal 1 of 1st B-T tango?
Ag cross links mIg increasing MHC expression on B to then bind to TCR
What is signal 2 of 1st B-T tango?
CD40 on B binding CD40L on T which must occur to induce production of CD80/86 on B which then binds to CD28 on T
What happens as a result of 1st BT tango?
T cell produces cytokines IL-4, IL-5 and IL-2 that upregulate R's on B and lead to B undergoing cytokine induced signal transdxn and can now proliferate and undergo SHM (CDR1 and 2 changed through pt mutations)
Where does B SHM occur?
in dark zone..after cytokine release from 1st tango it moves back to cortex
What happens when B cells finish SHM in dark zone of GC?
they move to light zone and are presented Ag directly by FDC's
What is the state of the B cell surface Ig's when they begin to undergo SHM?
they are of low affinity, they either stay with the same affinity or increase in affinity. Low affinity are apoptosed by tingible body macrophage. High affinity become sIg+ centrocytes
How does selection of high affinty centrocytes occur?
by interaction with FDC, in basal light zone, that presents Ag to B cells
Only those B cells expressing the highest affinity mIg on its surface with be bound by FDC and receive survival signals. Those that don't bind are apoptosed by tingible body macrophages
How do FDC's present Ag?
on iccosomes that are studded with Ag. NOT presented on MHC.
FDC's are non-MHC expressing Ag presenting cells
What drives clonal selection of B cells in germinal center?
FDC's: bind only highest affinity mIg B cells
What is the difference b/n centrocyts and centroblasts?
centroblasts are found in dark zone of cortex and are proliferating B cells undergoing SHM. centrocytes are non-dividing B cells in light zone bearing mutations in genes encoding V region
What happens after Ag-FDC select B cells with high affinity receptors?
these affinity selected B cells interact with T cells (2nd BT tango) in apical light zone and undergo class switching while maintaining their selected affinity. Interaction occurs via TCR-MHC II and CD40/40L
What do the Ag-FDC selected B cells express?
bcl-2: anti-apoptotic protein
After 2nd BT interaction, where do B cells go?
they leave germinal center to become memory cells in the cortex or plamsa cells (antibody secreting) in medulla
What events occur during 2nd BT tango?
isotype switching
clonal expansion
induction of memory
Where is the germinal center locted in thymus?
w/n primary follicle where B cells are
What leads to isotype class switching?
CD40/40L interaction
then the cytokines released determine what type of class switch will take place (if no cytokines released: default IgM remains)
What type of class switch will IFNg lead to? IL-4? TGFb?
IFNg: IgG1 and IgG3
IL-4: IgE
TGFb and IL-5:IgA
What happens w/n 4-7 days of primary antigen challenge?
production of plasma cells w/n primary follicles expressing IgM
What happens 7-10 days after primary response?
migration to GC for affinity maturation, class switching, and generation of Ig secreting plasma cells and memory B cells therefore increase in IgG and decrease IgM
What happens up to when plasma cells migrate to medulla?
they produce antibody for 2-4 weeks
What are the sites of Ab production?
medullary cords of the lymph nodes, red pulp of the spleen, lamina propria of the GALT, and the BM
What accts for 50% of circulting Ig?
high affinity mIg-plasma cells which have migrated and accumulated in the BM
What are plasma cells characterized by?
increased secreted Ig:mIg ratio (1000molecules Ig/cell/second)
How do Ag-Ab complexes stimulate apoptosis of B secreting cells?
the formation of Ag-Ab complex signals apoptosis of secreting cells as well as formation of memory cells. This occurs when FcRon B cell binds Ag-Ab complex that is bound to BCR. No cross linking occurs b/c mission is completed. The FcR's block activating signals b/c the cytoplasmic tail of B cell FcgammaRII contains an ITIM that binds enzymes and inhibits Ag driven B cell activation
How does the formation of ag-ab complexes signal conversion to memory cell production?
a small number of memory B cells exprssing high affinity mIg remain in LN, where upon secondary Ag exposure the dance begins again with more rapid rsponse
** as antigens are eliminated, immunologic memory is generated
What do we create memory cells from?
isotype-switched B cells, expressing IgG, IgA, and IgE: the represents the resting cell stage
What cells express high levels of adhesion molecules for recirculation and homing?
b and t memory cells
Do Naive B cells have complement receptors?
low amt.
mainly in lymph node
Where are niave B cells located? memory b cells?
naive: spleen
memory: BM, lymph node, spleen
Do both naive and memory B cels recirculate?
yes
Compare the receptor affinity of naive b cells vs. memory b cells.
naive: lower avg affinity
memory: higher avg affinity due to affinity maturation (due to SHM)
what are the isotypes seen in naive B cells? effector and memory b?
niave: IgM and IgG
memory and effector: IgG, IgA or IgE
What are the effecotr fxns of niave, effector and memory b cells?
niave: none
effector: Ab secretion
memory: none
Why do naive T cells home to paracortical region of LN?
the L-selectin on the naive T cells binds to the L-selectin Ligan on the HEV in lymph node to aid in extravasation
How do activated (effector and memory) T cells home to sites of infxn in peripheral tissues?
migration is mediated by E and P-selectin on endothelium that bind E or P selectin Ligand on activated T cells as well as LFA on T binding to ICAM on endothelium
What are the 4 phases of Ab response?
1. lag phase: no detectable Ag
2. log phase:increasing amts. of Ab
3. plateau phase: Ab titre stabilizes (peak Ab produced)
4. decline phase: Ag combines with Ab; complexes removed;memory is developed
How long after primary ag challenge is IgM detected?
4-7 days
How long after primary ag challenge does class switching occur and IgG is detected?
peaks at day 14 with a decrease in IgM
How long after primary ag challenge do Ab levels fall to baseline?
30 days after
When is the right time to inject Ag a second time?
when circulating titre levels are low, b/c if you do it when they are high the injected Ag will right away bind to the Ab that is present and the complex will be destroyed before having chance to make memory cells
What is the difference b/c primary and secondary response kinetics in humoral and cellular responses?
nothing.same situation: secondary respond leads to increased speed and affinity
Which cells are important in mediating rejection of tissue grafts?
T cells
What is the lag time following Ag administration for a secondary response?
1-3 days for response to occur
4-7 days after primary response
What is the time of peak response after primay vs. secondary responses?
primary: 7-10 days
secondary: 3-5 days
Compare the affinity of antibody after primary vs. secondary response
primary: lower avg. affinity
secondary: higher avg affinity Abs b/c of class switchings
What are the 4 effector fxns of Abs?
1. neutralization of microbes and toxins
2. opsonization and phagocytosis of microbes
3.ADCC
4.complement activation leading to lysis, phagocytosis, and inflammation
How do Ab's neutralize microbes and toxins?
normally, most toxins are not toxic until they are endocytosed therefore Ab acts to block the binding of toxin to cell surface receptors preventing infxn cells
How does opsonization occur via Ab's ?
antibodies of certain IgG subclasses bind to microbes and are then recognized by Fc Receptors on phagocytes which internalize, phagocytose and destroy the microbes
What is the affinity for Ig, cell distribution and fxn of FcgammaRI (CD64)?
high affinty for Ig
binds IgG1 and IgG3
found on macrophages, neutrophils and eosinophils
Fxn: phagocytosis; activation of phagocytes
What is the affinity for Ig, cell distribution and fxn of FcgammaRIIA (CD32)?
low affinity
found on macrophages, neutrophils, eosinophils, platelets
Fxn: phagocytosis; cell activation
What is the affinity for Ig, cell distribution and fxn of FcgammaRIIB(CD32)?
low affinity
found on B cells
Fxn: feedback inhibition of B cells
What is the affinity for Ig, cell distribution and fxn of FcgammaRIIIA(CD16)?
low affinity for Ig
found on NK cells
Fxn: ADCC
What is the affinity for Ig, cell distribution and fxn of FcepsilonRI?
high affinity
binds monomeric IgE
found on mast cells, basophils, and eosinphils
Fxn: on mast cells and basophils it is involved in cell activation, but on eosoninophils it fxns in degranulation
What is the affinity for Ig, cell distribution and fxn of FcalphaR (CD89)?
affinty for IgA
found on neutrophils, monocytes, eosinophils, macrophages, and B cells
Fxn: stimulate phagocytosis and induce degranulation
What is another name for CD64?
FcgammaRI
What is another name for CD16?
FcgammaRIIIA
What marker diagnoses NK cells?
CD16 is the R on NK only that binds IgG