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115 Cards in this Set

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at which anatomical sites do naïve T cells encounter Antigen?
1) Naïve T cells encounter Antigen, and start the primary immune response, in a secondary lymphoid tissue (for example, lymph nodes, spleen, peyer’s patches, tonsils).
at which sites specifically would a pathogen or its antigens end up, and how, if they entered the body?
through a small wound in the skin?
from the gut?
got into the blood?
1) lymph nodes.
2) GALT
3) Spleen.
lymph nodes?
1) The pathogen, and dendritic cells that have ingested the pathogen, are carried to the nearest lymph node in the afferent lymph
GALT?
1) Gut- associated lymphoid tissues such as peyers patches.
2) Pathogen s enter GALT via specialized cells (Mcells) in the gut epithelium
Spleen?
1) Pathogens circulating in the blood enter the spleen directly from the blood vessels that feed it.
how do T cells arrive at these sites?
1) T cells are delivered to all secondary lymphoid organs from the blood
Do all T cells leave thes locations after priming, and if so, how?
after activation by antigen only CD8+ T cells and TH1 cells exit the lymphoid tissue (via efferent lymph which delivers them eventuallly into the blood) in search of infected tissues.
Do all T cells leave the lymphoid tissues after priming (activation by An)?
and if so, how?
1) CD8+ cells and TH1 > YES
a) (via efferent lymph which delivers them eventually into the blood) in search of infected tissues
2) TH2 cells > NO
a) remain in the lymphoid tissue where they provide help to antigen-specific Bcells.
unlike innate immune responses which can begin within hours of the onset of an infection, adaptive immune responses involving T cells usually take several days. What accounts for this delay b/t the initiation of an infection and the engagement of an adaptive immune response?
1) Transportation
2) Relavent T cells
3) p/d
Transportation ?
1) Antigen needs to be transported to a nearby secondary lymphoid tissue, processed, and presented by An –presenting cells to naïve cytotoxic T cells or helper T cells in order to activate them.
Relevant T cells?
1) the number of T cells specific for a given pathogen will be only around 1in 10,000 to 1/100,000 (10^-4 to 10^-6) of the circulating T-cell repertoire;
a) thus it can take some time before the relevant Tcells circulating through the secondary lymphoid tissues get to the tissue that contains the An that will activate them.
proliferation and Differentiation?
1) it takes several days for an activated T cell to proliferate and differentiate into a large clone of fully functional effector T cells.
which selectins, mucin-like vascular addressins and integrins play a role in the circulation of T cells between the blood and lymphoid tissues?
1) T cells (and B cells) express L-selectin.
2) three types of mucin-like vascular addressins are involved:
a) GlyCAM-1and
b) CD34
c) MAdCAM-1,
T cells (and B cells) express L-selectin which binds?
1) to sulfated carbohydrates of mucin-like vascular addressins in HEV’s
GlyCAM-1and CD34 expressed on ?
1) expressed on lymph node HEV’s
MAdCAM-1 expressed on?
1) expressed on mucosal endothelium.
HEV’s
1) high endothelial venules
chemokines
1) made by endothelium and bound to its extracellular matrix
ICAM-1
1) An intercellular adhesion molecule
2) Expressed on the endothelium
diapedesis
1) T cell squeezes b/t the endothelium jnx.
a) Gaining entry to the lymph node
1) Chemokines (made by endothelium and bound to its extracellular matrix)
a) induce T cells to express
(i) LFA-1,
(ii) integrin ,
2) LFA-1 binds with high affinity to ICAM-1 (expressed on the endothelium)
3) Diapedesis
a) T cell gains entry into the lymph node.
Describe in chronological order how T cells migrate across lymph node HEV’s from the blood using these molecules?
identify three types of professional antigen-presenting cells?
1) dentritic cells
2) macrophages
3) B cells
How are they distributed in secondary lymphoid tissues?
1) Dentritic cells
a) Found in T-cell rich areas of secondary lymphoid tissues;
2) macrophages are
a) distributed throughout the tissue;
3) B cells are
a) localized in lymphoid follicles
what kinds of antigen do Dentritic cells present efficiently to T cells?
1) all types of antigen, but present viral antigens particularly efficiently
what kinds of antigen do macrophages present efficiently to T cells?
1) bacterial antigens well because they bear generalized receptors that can bind and internalize many different bacteria.
what kinds of antigen do Bcells present efficiently to T cells?
1) peptides of soluble protein antigens, such as protein toxins, that they have internalized via their antigen receptors
Which cell-surface glycoprotein distinguishes professional antigen-presenting cells from other cells and is involved in co-stimulation of T cells?
1) Expression of B7, a co-stimulator molecule
a) distinguishes professional-antigen presenting cells from other cells
b) is a glycoprotein
what receptors can B7 bind on the Tcell?
and what signal does it deliver in each case?
1) CD28
a) an activation signal is delivered
2) CTLA-4,
(i) an inhibitory signal is delivered
CD28?
1) The B7 receptor expressed earliest on Tcells
When B7 binds to CD28 an activation signal is delivered and?
1) T cells undergo clonal expansion and differentiation.
a) This interaction requires, of course,
(i) that the T-cell receptor and CD4 co- receptor are engaged specifically w/ a peptide:MHC class II complex.
(ii) a.k.a (Tcell receptor) + (CD4 receptor) + (peptide:MHC class II complex)
2) CTLA-4
a) binds B7 w/ ~20-fold higher affinity than does CD28
when B7 on the Antigen-presenting cell binds CTLA-4 receptor an inhibitory signal?
1) And is delivered to the T cell
a) Regulates T-cell proliferation and
b) suppress T-cell activation after an immune response
explain the consequence of antigen recognition by T cells in the absence of B7 on the antigen-presenting cell?
1) T cells will become anergic instead of activated. This is one mechanism by which T-cell tolerance may be achieved.
Anergic?
1) Cell becomes irreversibly non-responsive
explain the functional differences between immature and mature dendritic cells?
1) immature
a) very efficient at phagocytosis.
b) take up extracellular material indiscriminately.
c) specialized pathways of antigen processing
d) do not express co-stimulatory molecules.
e) migrate to nearby lymphoid tissue following antigen ingestion.
(i) Upon arrival they differentiate into mature dendritic cells.
2) Mature
a) These are non-phagocytic and
b) express the co-stimulatory molecules B7.1 and B7.2
immature dendritic cells are very efficient at phagocytosis owing to ?
1) expression of the receptor DEC 205.
immature dendritic cells take up extracellular material indiscriminately by ?
1) macropinocytosis.
Immature dendritic cells have specialized pathways of antigen processing for?
that can present these antigens on?
1) for extracellular antigens
2) both MHC class I and class II molecules.
Discuss why you think these functional changes should occur?
1) Immature dendritic cells
a) need to be phagocytic.
b) Expression of B7 in non-lymphoid tissue is not required
2) mature dentritic cells
a) no longer need to phagocytose material.
b) need to express B7 molecules, .
Immature dendritic cells need to be phagocytic?
b/c they are located in sites susceptible to infection.
Immature dendritic cells > Expression of B7 in non-lymphoid tissue is NOT required because?
his is not where Tcells circulate and sample MHC:peptide complexes.
Once outside the infected tissue, mature dentritic cells Do not?
1) no longer need to phagocytose material.
Once outside the infected tissue, mature dentritic cells Do not?
1) do need to express B7 molecules,
a) b/c w/out co-stimulation,
(i) Tcells do not receive the necessary activation signal for differentiation into effector Tcells.
Give an example of an immature and a mature dendritic cell?
1) An example of an immature dendritic cell is the Langerhans’ cell of the skin which matures into an interdigitating reticular cell in the lymph node
the three classes of effetor Tcells –
1) cytotoxic Tcells,
2) TH1 cells and
3) TH2 cells –
effector Tcells are specialized to ?
1) deal w/ different classes of pathogens and produce different sets of cytokines
for cytotoxic Tcells, describe how antigen is recognized?
and the corresponding effector function?
1) recognize An on the surface of a cell presenting antigen bound to MHC class I molecules.
2) responds by killing these target cells by inducing an apoptotic pathway.
for TH1 Tcells, describe how antigen is recognized?
and the corresponding effector function?
1) recognize An bound to MHC class II molecules
a) on the surface of an antigen-presenting cell such as a macrophage.
2) responds by activating the macrophage to
a) and destroy intra-vesicular bacteria and increase antigen bound to MHC class II molecules on the surface of B cells.
for TH2 Tcells, describe how antigen is recognized?
and the corresponding effector function?
1) responds by secreting cytokines
2) that will activate B cells to differentiate into antibody-producing plasma cells
Give an example of an antigen for cytotoxic Tcells
1) is a virus replicating in the cytosol of the target cell
Give an example of an antigen for TH1 cell
1) is a protein encoded by Mycobacterum teberculosis
Give an example of an antigen for TH2 cell
1) is diphtheria toxin produced by corynebacterium diptheriae.
Virus infected cells attacked and killed by effector cytotoxic Tcells are ?
1) often surrounded by healthy tissue which is spared from destruction
explain the mechanism that ensures that cytotoxic T cells only kill the virus- infected cells (the target cells)?
1) polarization.
2) orientation.
3) Alignment in the Tcell,
4) not killed in this process,
polarization?
1) Cytotoxic Tcells focus their killing machinery on target cells through this process
Orientation?
1) The cytoskeleton and the cytoplasmic vesicles
a) containing lytic granules
2) are oriented toward the area on the target cell
a) where MHC class I:peptide complexes are engaging T-cell receptors.
Alignment In the Tcell?
1) align towards the target cells
a) the microtubule-organizing center,
b) Golgi apparatus and
c) lytic granules, (which contain cytotoxins),
Alignment of the lytic granules?
1) The lytic granules then fuse with the cell membrane
a) releasing their contents into the small gap b/t the Tcell and the target cell,
b) resulting in deposition of cytotoxins on the surface of the target cell.
The cytotoxic T cell is not killed in this process?
1) and will continue to make cytotoxins for release onto other target cells,
2) therby killing numerous target cells in a localized area in succession.
what cytotoxins do cytotoxic Tcells produce?
1) perforin,
2) granzymes and
3) granulysin molecues
a) which induce apoptosis of the cell.
what molecules have roles in the signal transduction pathway leading from the T-cell receptor?
1) the CD3 complex
2) protein tyrosine kinaseLck
3) CD45
4) ZAP-70
5) the zeta chain
6) IP3
7) calcineurin
what is the role of the CD3 complex in the signal transduction pathway leading from the T-cell receptor?
1) the CD3 subunits y, d, and e
a) help transmit
(i) the signal from the Tcell receptor:MHC:peptide interaction (at the cell surface) into the interior of the cell
(a) through ITAM’s (present on their cytoplasmic tails.)
(i) these are phosphoylated
(ii) when the antigen receptor is activated, and in turn activate further molecules of the signaling pathway
the CD3 subunits y, d, and e ?
1) associated w/ the antigen-binding Tcell receptor
ITAM’s?
1) immunoreceptor tyrosine-based activation motifs(ITAMs) (present on their cytoplasmic tails.)
ITAMS are phosphoylated by
1) associated protein tyrosine kinases,
a) such as Fun,
b) when the antigen receptor is activated, and in turn activate further molecules of the signaling pathway
Associated protein tyrosine kinases
1) Fun
2) Lck
cytoplasmic protein tyrosine kinase
1) ZAP-70
cell surface protein phosphytase
1) CD45
what is the role of Lck in the signal transduction pathway leading from the T-cell receptor?
1) Phosphorylates ZAP-70
a) Lck associates with the tails of the CD4 and CD8 co-receptors.
(i) When these participate in binding to MHC:peptide complexes,
(a) Lck is activated and phosphorylates ZAP-70,
what is the role of CD45 in the signal transduction pathway leading from the T-cell receptor?
1) CD45 helps activate Lck and other kinases
a) by removing inhibitory phosphate groups from their tails
what is the role of ZAP-70 in the signal transduction pathway leading from the T-cell receptor?
1) When ZAP-70 is phosphorylated it binds to the phosphorylated ITAM’s of the zeta chain,
what is the role of the zeta chain in the signal transduction pathway leading from the T-cell receptor?
1) which initiaties the signal transduction cascade
a) of activating phospholipase C-y(PLC-y) and
b) guanine-exchange factors
what is the role of IP3 in the signal transduction pathway leading from the T-cell receptor?
1) causes an increase in intracellular Ca2+ levels,
a) which leads to the activation of the protein calcineurin
IP3 which is produced by
1) the action of PLC-y on membrane inostitol phospholipids,.
what is the role of calcineurin in the signal transduction pathway leading from the T-cell receptor?
1) activates the transcription factor NFAT enters the nucleus,
2) and together with the transcription factors NFkB and AP-1
a) will initiate the transcription of genes
(i) that lead to T cell p/d.
describe the morphology of a granuloma?
1) A granuloma contains
a) at its center macrophages and giant multi-nucleated cells
(i) infected w/ bacteria which are replicating intracellularly
b) Epitheloid cells surround the core.
c) Epitheloid cells are surrounded by activated CD4 Tcells.
giant multi-nucleated cells are
1) created by macrophage fusion,
a) are infected w/ bacteria which are replicating intracellularly
epithelial cells consist of
1) non-fused macrophages
which types of infection would lead to the formation of granuloma
1) chronic infections resistant to macrophage killing mechanisms
a) for example in tuberculosis, caused by Mycobacterium tuberculosis growing inside intracellular vesicles.
why is this type of pathology actually beneficial to the host?
1) If the infection were not localized in this fashion, it could disseminate systemically to other anatomical locations.
How is the infection localized
1) Granulomas surrounded by CD4 Tcells cut off the infection from the blood supply
a) and the cells in the core of the granuloma will die
(i) from oxygen deprivation and toxic products of the macrophages.
example of localized infection?
1) In tuberculosis, the dead tissue is referred to as caseation necrosis because it has a cheesy consistency
cyclosporine A
1) is an immunosuppressive drug
2) commonly used in transplant patients to prevent graft rejection by alloreactive T cells.
How does cyclosporine A work?
It acts by interfering with the signaling pathway
a) that leads from the T-cell receptor to transcription in the nucleus
(i) of the genes for the cytokine IL-2 and the a-chain of the IL-2 receptor.
`
Why does preventing the transcription of IL-2 and the a-chain of the IL-2 receptor lead to immunosuppression?
1) The a- chain is required to form the high-affinity receptor.
2) in the absence of IL-2 and its high affinity receptor,
a) T cells will not be fully activated,
b) will not differentiate and
c) will not undergo clonal expansion.
3) by preventing the production of IL-2 and its receptor,
a) prevents the
(i) clonal expansion of Tcells specific for the foreign antigens on the graft.
(ii) their differentiation into effector Tcells
(a) and thus suppresses the immune response directed against the graft.
High-affinity IL-2 receptor is composed of
1) a-, B- and y-chains
In an immune response, the binding of IL-2 to a high-affinity IL-2 receptor
1) drives the p/d of T cells that occurs after they have encountered their specific antigen.
The activated T cell will divide?
producing?
1) two to three times daily for about a week,
2) producing a clone of thousands of identical antigen-specific, effector Tcells.
Why is the a- chain is required
1) to form a complex with pre-existing y- and B-chains to make the high-affinity receptor.
The receptor formed by the y- and B-chains on their own
1) is of low affinity for IL-2.
in the absence of IL-2 and its high affinity receptor, T cells will?
1) not be fully activated,
2) will not differentiate and
3) will not undergo clonal expansion
By preventing the production of IL-2 and its receptor,
1) cyclosporine prevents the clonal expansion of Tcells (specific for the foreign antigens on the graft)
2) and their differentiation into effector T cells,
3) and thus suppresses the immune response directed against the graft.
the etiological agent responsible for leprosy
1) is Mycobacterium leprae,
2) which survives and replicates within the vesicular system of macrophages.
Explain the difference between tuberculoid leprosy and lepromatous leprosy
in the context of T-cell differentiation and effector function?
1) effective immune responses against intra-vesicular pathogens living in macrophages are mediated by TH1 cells rather than TH2 cells.
2) In tuberculoid leprosy,
a) TH1 cells.
b) The disease is chronic, progresses slowly,
(i) Causes damage to skin and peripheral nerves.
3) In lepromatous leprosy,
a) TH2 cells.
b) Humoral immunity is induced, which results in the production of antibodies
effective immune responses against intra-vesicular pathogens living in macrophages
1) are mediated by TH1 cells rather than TH2 cells.
Many factors influence the differentiation of CD4 T cells into TH1 or TH2 cells,
1) including the cytokines produced by the antigen-presenting cells and
2) leukocytes involved in the innate immune responses,
3) the antigen concentration and MHC:peptide density,
4) T-cell receptor affinity for MHC:peptide, and
5) the cytokines produced by TH1 and TH2 cells themselves.
If TH1 cells dominate an immune response,
1) then a cell-mediated immune response is favored.
If TH2 cells dominate an immune response,
1) then a humoral immune response is favored.
In tuberculoid leprosy, the predominant effector Tcells produced after infection?
1) are TH1 cells.
a) These are effective in containing the infection,, although they do not clear it completely.
In lepromatous leprosy Humoral immunity is induced, which results in the production of antibodies which are?
1) ineffective against intracellular bacteria.
what causes the damage to skin and peripheral nerves in tuberculoid leprosy
1) mainly by the inflammatory responses initiated by activated macrophages.
What causes severe tissue destruction in lepromatous leprosy
As a result of humeral immunity, M. leprae replicates unchecked,
(i) causing severe tissue destruction and eventually the death of the patient
Bcells are activated by
what needs to be shared?
what does not need to be shared?
1) CD4 TH2 cells
2) only if both cell types recognize the same antigen.
3) The same epitope, however, does not need to be shared for recognition
discuss why this characteristic is important in vaccine design?
1) Adult humans
a) can b protected by subunit vaccines made from the capsular polysaccharide-specific, Tcell independent and IgM.
2) children
a) The Bcell will then produce IgG anti-polysaccharide antibodies. This type of vaccine can be used to immunize children in order to induce protective anti-polysaccharide antigens.
Many bacteria are surrounded by
1) a polysaccharide capsule,
2) and in some cases, antibodies against the capsular polysaccharides
a) give protective immunity against the pathogen
Antibodies produced against polysaccharide antigens are generally restricted to
1) the IgM isotype
the help needed to switch isotypes to IgG is provided by?
1) by Tcells,
a) which only recognize peptide antigens
Adult humans make?
vaccine?
effective immune responses to polysaccharides alone
a) and thus can b protected by subunit vaccines
(i) made from the
(a) capsular polysaccharide-specific,
(b) Tcell independent and
(c) IgM.
Children do not make
1) effective immune responses to polysaccharides alone
2) and thus cannot be immunized with such vaccines
if the polysaccharide is conjugated to a protein,
1) peptides from the protein part of the molecule can activate specific TH2 cells.
B cells specific for polysaccharide will
1) bind and internalize the whole antigen via their antigen receptors,
2) process it ,
3) and then present peptides from the protein part on their surface.
T cells specific for these peptides will
1) interact with the B cell,
a) delivering the necessary cytokines
(i) (such as IL-4) and
(ii) the CD40-CD40-ligand signal required for isotype switching
The Bcell will then produce
1) IgG anti-polysaccharide antibodies.
What type of vaccine can be used to immunize children
1) IgG anti-polysaccharide antibodies
2) in order to induce protective anti-polysaccharide antigens.
haemophilus influenzae B polysaccharide
1) which can cause pneumonia and meningitis.
provide an example of a conjugate vaccine used to stimulate IgG antibody synthesis to haemophilus influenzae B polysaccharide
a vaccine of this type has been produced against
haemophilus influenzae B (HiBC),
2) The conjugate vaccine is composed of a capsular polysaccharide of H. influenzea
a) conjugated to tetanus or diphtheria toxoid (a protein).
3) The antibody response is polysaccharide-specific, T cell dependent, and IgG, and children are protected from meningitis.