Exam 2 Flashcards
(91 cards)
1
Q
molecular structure of class II MHC
A
- found on antigen presenting cell
- possess Ig domains
- are heterodimeric (alpha and beta chain)
- Both chains pass through the plasma membrane
- A peptide-binding cleft is formed by the pairing of alpha1 and beta1 domains.
2
Q
class I MHC
A
- Ig domains
- found on all nucleated cells
- larger alpha chain with three external domains
- Beta 2 microglobulin domain (like a3 domain and single transmembrane domain)
3
Q
what methods do MHC molecules use to increase their diversity of antigen presentation?
A
Class I and II molecules exhibit polymorphism in the peptide-binding region with several hundred different allelic variants expressed in humans. Up to six different class I molecules and 12 different class II molecules can be expressed per person. A given MHC molecule can bind numerous different peptides, and some peptides can bind to several different MHC molecules
4
Q
MHC class II peptide binding groove
A
- longer
- 13-18 amino acids
- conserved residues
- entire peptide is at constant elevation (no bulge) due to open MHC ends
5
Q
MHC class I peptide binding groove
A
- shorter
- 8-10 amino acids
- hydrophobic anchor residues
- peptide bulge in the middle because of the closed ends
6
Q
how do MHC alleles play a role in health, disease, and mate selection?
A
Cheetah’s and Florida black panthers have increased viral susceptibility due to limited MHC polymorphism. Native Americans devastated by the introduction of smallpox. Tasmanian devils are highly susceptible to a deadly form of cancer missing MHC I that is spread by biting.
MHC alleles occur at a much higher frequency in people suffering from certain diseases than in the general population including autoimmune diseases, viral, and allergies. There is some evidence that MHC affects mate choice - odor for MHC-dissimilarity enhances attraction for mate choice. It is possible we have evolved to be more attracted to MHC diverse individuals.
7
Q
what cells are MHC class II
A
found on antigen presenting cells
8
Q
cells with MHC class I proteins
A
Ig domains, found on all nucleated cells
9
Q
Describe the Nobel prize winning experiment demonstrating self-MHC restriction of CD8 T cells.
A
Rolf Zinkernagel and Peter Doherty used mice to study how T -lymphocytes could protect animals against infection from a virus. Infected mice developed killer T-lymphocytes were reactive against that virus but were not able to kill virus-infected cells from another strain of mice. Thus, they demonstrated the requirement for the cellular immune system to recognize simultaneously both ‘foreign’ molecules (e.g. virus) and presented by self-molecules (MHC).
10
Q
immunoproteosome
A
temporarily expressed in infected cells or activated professional APCs
- cleaves proteins into fragments that are optimized for MHC I presentation resulting in improved peptide presentation
- turns over quicker than the constitutive proteosome, likely to help prevent autoimmunity.
11
Q
constitutive proteasome
A
Cytoplasmic intracellular proteins (MHC I presented peptides) are processed by the endogenous pathway and are generated by protease complexes
12
Q
TAP in antigen processing and presentation for MHC class I molecules
A
essential for transporting peptides from the cytosol to the rough endoplasmic reticulum (RER).
13
Q
HLA-DM molecules in antigen processing and presentation
A
exchanges CLIP (a small portion of the invariant chain) out of the groove for a peptide fragment
14
Q
endogenous antigen processing and presentation
A
Peptides from cytoplasmic intracellular proteins are generated by proteasomes or immunoproteasomes. Peptides are transported from the cytosol to the rough endoplasmic reticulum (RER). TAP molecules in the RER membrane move the fragments. Peptides are loaded onto the MHC class I molecules in the RER.
15
Q
exogenous antigen processing and presentation
A
Extracellular antigen peptides are generated from internalized antigens in endocytic vesicles. Endosomes are fused with lysosome and degraded. Simultaneously, MHC class II molecules are produced and exported from the ER in vesicles. It takes 1- 3 hours for antigen to be processed and presented on the cell surface.
16
Q
What is cross presentation and why is it important?
A
Cross-presentation is the ability of certain APCs (predominantly DCs) to take up, process and present extracellular antigens with MHC class I molecules to naïve cytotoxic T cells. Cross-presentation permits the presentation of exogenous antigens, which are normally presented by MHC II, on the surface of uninfected dendritic cells by MHC I. This is important since some viruses or tumors do not normally infect APCs and could avoid immune detection. This may require dendritic cell interactions with helper cells first (Dendritic cell licensing).
17
Q
Describe the stages and location of T cell development.
A
- bone marrow = very early thymocyte development
- thymus = four double negative (no CD4 or CD8) and then double positive
- peripheral bloodstream = after positive selection they become single positives
18
Q
What is the importance of Notch1 ligand to bone marrow cell development?
A
When cells arrive at the thymus, they aren’t technically T cells. They can also become NK cells,
dendritic cells, B cells, and even myeloid cells. A receptor on cells known as Notch1 commits them to
the T lineage. Notch1 binding can commit cells to T lineage even without the thymus being present.
If Notch1 is knocked out lymphoid precursors become B cells instead of T cells!
19
Q
different molecules involved in development of T cells
A
C-kit (CD117)—receptor for stem cell growth factor. CD44—an adhesion molecule.
CD25—the α chain of the IL-2 receptor.
20
Q
double negative 1 developmental stage
A
migrate to the thymus
21
Q
double negative 2 developmental stage
A
T cell lineage commitment and beta chain rearrangement
22
Q
double negative 3 developmental stage
A
Expression of pre-TCR and beta chain selection
23
Q
double negative 4 developmental stage
A
proliferation, allelic exclusion of beta chain, alpha chain
rearrangement, and progress to DP
24
Q
How are alpha beta T cells and gamma delta T cells similar and different?
A
Thymocytes can express either TCRαβ or TCRγδ receptors. TCRαβ outcomes are 3x more likely than
TCRγδ, however, TCRγδ are more common in fetal development. gamma delta T cells provide rapid “innate-like”
defense near the mucosal tissues and skin, bolstering the initial response to microbes. gamma deltaT cells have
less diverse TCR repertoire than αβ T cells and recognize unconventional antigens such as lipids
presented by unconventional MHC molecules.
25
positive selection
bind self-MHC molecules. Positive selection selects thymocytes bearing
receptors capable of binding self-MHC molecules, resulting in MHC restriction.
26
negative selection
don’t bind too well to self-MHC molecules
- selects against
high-affinity receptors for self-MHC/peptide complexes, resulting in self-tolerance.
27
How do we delete thymocytes reactive to tissue-specific antigens?
Medullary epithelial cells express a unique transcription factor called “AIRE” that allows them to
express, process, and present proteins that are ordinarily only found in specific organs.
28
Describe the affinity model of thymocyte selection.
TCR affinity for self-MHC/peptide complexes determines the fate of a thymocyte. Affinity being too
low results in failure to be positively selected (death by neglect). Intermediate affinity results in
positive selection and survival unless the affinity is too high which results in negative selection.
29
What is the altered peptide model of thymocyte selection described in the chapter?
The altered peptide model is an alternative to the affinity model. The altered peptide model proposes
that cortical epithelial cells that induce positive selection make peptides that are unique and distinct
from those made by thymic cells that induce negative selection. Thus, those that are negatively
selected by unique peptide-MHC complexes will not automatically be negatively selected when
browsing peptides presented by negatively selecting cells.
30
Describe the three models that describe how lineage commitment occurs.
The instructive model
The stochastic model
the kinetic signaling molecule
31
instructive model
states that TCR-CD4 and TCR-CD8 co-engagement generate unique signals
that directly initiate distinct developmental programs.
32
stochastic model
proposes that a positively selected thymocyte randomly downregulates CD4
or CD8. Those that have the “correct” co-receptor to engage the right peptide MHC will get a signal
that is strong enough for them to survive.
33
kinetic signaling model
has the strongest experimental backing to date. It proposes that
thymocytes commit to the CD4 lineage if they receive a continuous signal in response to TCR-
coreceptor engagement and they commit to the CD8 lineage if that TCR signal is interrupted.
34
Summarize the four methods that Tregs are believed to use to suppress immune cells.
Regulatory T cells (TREG) are a CD4+ subset that helps to quench adaptive immunity.
TREG cells are believed to function by: 1) Depleting the local area of stimulating cytokines.
2) Producing inhibiting cytokines. 3) Inhibiting APC activity and 4) Directly killing T cells.
35
locations of B cell development
B-cell development begins in the bone marrow and is completed in the periphery in 1-2 weeks.
Hematopoietic stem cells progress to common lymphoid progenitors that can become either T or B
cells. Progenitor cells destined to become T cells migrate to the thymus and the majority of those that
remain in the bone marrow become B cells. Only negative selection is required for B cell development
since there is no need for MHC restriction.
36
stages of B cell development
Key stages in B cell development include pro-B, pre-B,
immature B cell, and plasma cell. During the early and late stages of Pro-B the heavy chain is
rearraigned and during the Pre-B stage the light chain is rearraigned. In the spleen, two two B cell
subsets (T1 and T2) differ in gene expression as they progress through the spleen for further
maturation. T1 cells develop into T2 cells in 3-4 days. T2, but not T1, transition to immature B cells
and can enter the B cell follicles and recirculate.
37
How were the stages of B cell development determined?
B cell development stages are defined by the location of the cells, the presence of cell-surface markers,
expression of specific transcription regulators, and rearrangement status of immunoglobulin genes.
38
What is the role of stromal cells in B cell development?
Stromal cells in the bone marrow (BM) provide support and growth factors to developing cells and
help these cells grow and develop. They do this in two ways: 1) retaining the developing cell
populations in specific BM niches so they get appropriate molecular signals for differentiation and 2)
diverse stromal cells generate different cytokines so precursor B cells are guided by these chemokines
and temporarily exposed to different chemokines that initiate transcription factors.
39
What organ do most B cells go to after they become “immature” B cells and what stages of
development do they undergo in that organ?
Immature B cells traffic from the bone marrow to the spleen and then undergo the T1 and T2 stages
and finish positive and negative selection on their way to becoming mature B2 cells.
40
What developmental stage are B cells at when the first and second checkpoints occur?
1st checkpoint – Late pro B cell stage (just before pre B cell stage).
2nd checkpoint – Late pre B cell stage (just before immature B cell stage).
41
Autoreactive B cells in the bone marrow often undergo clonal deletion, but some initiate the
process of light chain receptor editing. What is light chain receptor editing?
Light chain receptor editing occurs during B cell maturation when B cells are tested for interactions
with self-antigen. If the maturing B cells strongly interact with self-antigens, they undergo apoptosis.
Some avoid apoptosis by modifying the sequence of light chain V and J genes (undergoing another round of light chain recombination) so that the modified receptor has a different specificity and may not recognize self-antigens anymore.
42
Describe what clonal anergy means.
When B cells have contact with soluble self-antigen, they can be rendered anergic and are non-
responsive to further stimulation. Is a means of removing or making autoreactive B cells anergic or
these self-reactive cells may be more likely to become regulatory B cells and inhibit autoimmunity.
43
How are B1 cells different than B2 follicular cells?
B1 cells appear before B2 cells in development and secret high levels of IgM to protect fetus and adult.
B1 cells display much more limited V region diversity than B2 cells and more often directed towards
microbial carbohydrate antigens. B1 cells populate a different anatomical niche (occupy pleural and
peritoneal cavities) than the late rising B2 cells. B1 cells develop from a separate lineage of
progenitor cells in the liver and can self-renew whereas B2 cells need to be constantly replenished
from new cells coming from the bone marrow.
44
What makes Marginal Zone B cells different than B2 follicular cells?
Marginal Zone (MZ) B cells respond to both carbohydrate and protein antigens and some appear to
be able to do this without T cell help. MZ B cells have high levels of membrane IgM and the
complement receptor CD21 on their cell surface. MZ B cells have adhesive molecules that allow them
to interact with cells in the marginal zone and are long lived and may self-renew. MZ B cells derive
from the same T2 cell as B2 B cells and require a strong activation signal and, surprisingly,
interactions with Notch2 ligand
45
List the main similarities and differences between B and T cell development?
Both cell lineages have their beginnings in the fetus and the neonate. In the neonate T cells and B1
B cells are dispatched into their own peripheral niches and function as self-renewing populations
until death of the host. In the adult B and T cells both start in the bone marrow and share early phases
of development. T cells leave the bone marrow and migrate to the thymus to complete their
development, leaving the B cells behind. B and T cells must both pass through stages of positive
selection (receiving survival signals). T cell positive selection is well characterized whereas with B
cells it is not. B cells do not require the ability to recognize MHC like T cells do. Both cells must also
survive the process of negative selection in which self-reactive cells are deleted.
46
Describe the two-signal hypothesis of T cell activation and why is a third signal also important?
According to the two-signal hypothesis, activation of a naïve antigen-specific T cell requires stimulation of the T cell receptor (TCR) by pMHC (signal 1) and stimulation of costimulatory receptors (e.g., CD28) by costimulatory molecules such as CD80/CD86 (signal 2).
Three signals are required for full activation and differentiation of a naïve T cell. Signal 1 (antigen- specific TCR engagement) and signal 2 (co-stimulatory ligands) induce full T cell activation. Fully activated T cells secrete cytokines (Signal 3), which direct T-cell differentiation into distinct effector cell types. Depending on which cytokines are present as the T cell is becoming activated, different T cell differentiation outcomes occur.
47
What is the immunological synapse and how is it organized?
Successful T cell–APC interactions organize signaling molecules into a “bullseye” immunological synapse. TCR/MHC-peptide complexes and coreceptors centralize and form the central supramolecular activating complex (cSMAC). Adhesion molecules/bound ligands peripherally localize and form the peripheral supramolecular activating complex (pSMAC).
48
costimulatory receptors on the surface of T cells
CD28 (activation of naive T cells, ligands CD80 or CD86) , ICOS (maintenance of activity of differentiated T cells, part of B-T cell interactions, ilgand ICOS-L)
49
coinhibitory receptors on the surface of T cells
CTLA-4 (ligands CD80 or CD86, negative regulation of the immune response like maintaining T cell tolerance) PD-1 (ligands PD-L1 and PD-L2, has negative regulation of the immune response, and regulation of Treg differentiation), and BTLA (ligand HVEM, and is in charge of negative regulation of the immune response and regulation of Treg differentiation)
50
What are checkpoint inhibitors and how do they work?
Checkpoint inhibitors are therapies developed to block the binding of negative co-stimulatory molecules (CTLA-4 and PD-1), resulting in dramatic increases in T cell activation. Has had great immunotherapy success when combined with adoptive transfer of tumor specific T cells. These therapies work by preventing the negative co-stimulatory signal from being sent (they inhibit the “brakes” of the immune system).
51
Describe how clonal anergy in T cells is initiated and list a reason why it might occur.
Clonal anergy or T cell “exhaustion” results instead of clonal expansion if costimulatory signal is absent. Activation by TCR engagement (signal 1) without a costimulatory signal (signal 2) results in a non-responsive cell (clonal anergy). This helps provide tolerance in periphery.
52
What are superantigens, how do they function to activate T cells, and what is the result?
Superantigens are a special class of T-cell activators. Viral/bacterial proteins that bind to specific Vβ regions of TCRs and α chain of class II MHC molecules. Superantigens effectively “short-circuit” this co-stimulatory need by increasing the binding of T cells to APCs. Up to 5% of T cells can be activated by a superantigen. Produces dramatic cytokine secretion by large proportion of inappropriately activated polyclonal T cells. Often results from food poisoning and initiates huge amounts of cytokine production, systemic toxicity, and can cause death.
53
How do type 1 and type 2 immune response differ in function and what they respond to?
Type 1 responses are to viruses and many bacteria and involve activation of effector subsets that coordinate cytotoxic responses (Th1 and Th17).
Type 2 responses are to worms, protozoa, and allergens and involve the activation of effector subsets that coordinate IgE and eosinophilic responses (Th2 and Th9).
54
List the seven T helper subtypes described in the chapter and know their master gene regulators, effector cytokines, and functions.
TH1, TH2, TH9, TH17, TH22, Treg, TFH
55
TH1
gene regulator T-Bet, effector cytokines IFN-gamma(y), TNF, enhances APC activity, Tc activation, protects against intracellular pathogens involved in delayed type of hypersensitivity, autoimmunity
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TH2
gene regulator GATA-3, effector cytokines IL4,5,13, protects against extracellular pathogens such as IgE response and involved in allergy
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TH9
gene regulator PU.1, effector cytokine IL9, protects against extracellular pathogens involved in mucosal autoimmunity
58
TH17
ROR gamma t, effector cytokine IL17A, 17F, 22, protects against fungal and extracellular bacterial infections, contributes to inflammation, autoimmunity
59
TH22
gene regulator AHR, effector cytokine IL22 , protects against extracellular pathogens
60
Treg
gene regulator FoxP3, effector cytokine IL10, TGF beta, inhibits auntitumor responses
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TFH
gene regulator BCI6, effector cytokines IL4, IL21, and B cells help in follicles and germinal centers
62
List the 4 mouse and 3 human T cell memory markers discussed in the chapter
Mouse: CCR7, CD62L, CD44, CD69 Human: CD45RO, CD45RA, and Fas
63
Describe the clonal selection hypothesis and why it is important in immunology.
The clonal selection hypothesis suggested for the first time that the receptor on the lymphocyte surface and antibody products secreted by the cell had identical binding properties. The clonal selection hypothesis basics: Each B cell bears a single type of Ig receptor. On stimulation, each cell will generate a clone of cells bearing the same Ag receptor as the original. Burnett predicted the vast array of antibody specificities known to exist today when he stated, “The theory requires at some stage in early embryonic development a genetic process for which there is no available precedent.” The clonal selection hypothesis turned out to be the foundation of molecular immunology, especially in adaptive immunity.
64
What type of B cells are normally part of T cell-dependent responses and what type of B cells are normally part of T cell-independent responses?
T cell-dependent response = Follicular B2 cells T cell-independent response = B1 and MZ cells
65
What are the three main fates of a B cell following T-dependent antigen stimulation?
1) Entry into germinal center and undergo somatic hypermutation and class switch 2) Become low affinity IgM-bearing memory cells from primary response
3) Enter the primary focus and become antibody producing plasma cells
66
How do low and high molecular weight antigens enter the lymph node differently for antigen presentation?
Low molecular weight antigen can enter lymph node via leaky network of fibroblastic reticular cell conduits that are sampled by follicular B cells. High molecular weight antigens are taken up by Fc or complement receptors on subcapsular sinus macrophages (or by similar receptors on B cells), dendritic cells, and circulating macrophages and are passed on to B cells in the follicle.
67
Describe what is occurring on the cell surface of the B cell during the early steps of B cells activation after recognition of cell bound antigen.
Upon B cell recognition of antigen, the B cell membrane briefly spreads over the surface of the APC and then the B cell receptors cluster and form an immunological synapse between the B cell and the antigen. The inner ring of BCRs form the cSMAC which is surrounded by a ring of adhesion molecules called the pSMAC that is encircled by a distant ring of actin called the dSMAC.
68
Describe what is occurring on the inside of the B cell during the early steps of B cells activation and the formation of the “signalsome”.
Engagement of antigen by the BCR initiates phosphorylation of ITAM tyrosines on the Iga and Igb by kinases. This results in a cascade of signaling molecules clustering to form the signalsome. The signalsome can initiate several different activation pathways depending on the strength and duration of the BCR-antigen signal.
69
What is a “primary focus” and what transcription factors are critical for plasma cell differentiation and function?
Activated B cells can form a “primary focus” on the borders of the T cell zones or enter the follicles and form germinal center. Plasma cells form within the primary focus and secrete large quantities of nonmutated IgM and IgG antibodies that provide early protective humoral immunity. Transcription factor BLIMP-1 promotes a plasma cell fate whereas BCL-6 promotes a germinal center fate.
70
What occurs in the light and dark zones of the germinal center?
In the dark zone B cells rapidly divide and undergo somatic hypermutation. In the light zone, B cells compete to interact with TFH and follicular dendritic cells which results in directed evolution and selection of B cells bearing mutated receptors with the highest affinity for antigen.
71
Compare and contrast the changes that AID makes in somatic hypermutation and class switch recombination.
Somatic hypermutation is initiated by a cysteine deamination reaction catalyzed by the AID enzyme in the germinal centers only after T-dependent antigen simulation. DNA repair mechanisms cause alteration in variable region sequences. Class switch recombination results in AID induced replacement of an antibody heavy chain constant region and this is regulated by the cytokine environment and can occur in the germinal center or elsewhere (with or without T cell help).
72
What are the three cell surface receptors discussed in the textbook that provide negative regulation of B cell activation?
Negative signaling through CD22 shuts down unnecessary BCR signaling via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) via the SHP-1 tyrosine phosphatase.
FcγRIIb receptor (CD32) possesses ITIMs like those in CD22. Circulating IgG can bind this receptor and initiate inhibition.
CD5 is a cell surface protein found on B-1 cells that when removed results in hyperresponsive B cells, suggesting it is a negative regulator of B cell activation.
73
function B-10 cells
(Regulatory B cells) act as negative regulators by secreting IL-10 upon antigen stimulation and may act to reduce inflammatory responses.
74
What are the four main memory T cell subsets and what are the characteristics of each?
1) Tscm cells – T stem cell memory cells are self-renewing cells that are found in secondary lymphoid tissue and can develop into all other memory cell subsets.
2) TCM cells—central memory T cells reside in secondary lymphoid tissues. Live longer/divide more times than TEM cells and produce lots of IL2. Rapidly reactivated by second Ag exposure.
3) TEM cells—effector memory T cells. Circulate in the peripheral tissues. Contribute better to first- line defenses and produce effector cytokines. Exhibit effector functions upon Ag exposure.
4) Trm cells – T resident memory cells. Permanent residents of tissues that have experience infection and immediately respond upon reinfection.
75
What six mechanisms are used by antibodies to mediate the destruction of pathogens?
Neutralization, agglutination, opsonization, complement activation, antibody dependent cell- medicated cytotoxicity (ADCC), and degranulation.
76
List the five antibody isotypes described in the chapter and their effector function.
IgG, IgD, IgE, IgA, IgM
77
IgG
Most common antibody in the serum. Include several subclasses, each with distinct effector capabilities. Effective at binding Fc receptors and enhancing phagocytosis by macrophages, complement fixation, and mediating ADCC by NK cells. Commonly used in tailored immunotherapies.
78
IgD
Little IgD is secreted, it functions to activate basophils in the respiratory tract in response to respiratory bacteria and viruses.
79
IgE
Known most for their role in allergy and asthma. Plays a role in protection against parasitic helminths and protozoa. Made in very small quantities but induce potent effects. Degranulation of eosinophils/basophils.
80
IgA
Major isotype found in secretions (mucus in gut, milk from mammary glands, tears, and saliva). Effective at neutralizing toxins and pathogen and agglutination and removal via mucus. Does not fix complement, so does not drive inflammation. Huge amounts of IgA produced and able to cross epithelial barriers.
81
IgM
First Ab produced in a primary response (lower affinity but high avidity; pentavalent). Good at complement fixation leading to MAC formation and target lysis. Form dense Ab-pathogen complexes engulfed by macrophage. Made by conventional B cells but mainly by B1 cells (natural antibodies protect against common pathogens).
82
FC receptor crosslinking initiates a signal that may enhance or inhibit effector function, what is the mechanism for this difference at a signaling level?
The differing outcome depends on whether receptor is associated with ITAM/ITIM.
83
What are 3 main types of uses for therapeutic antibodies described in the textbook.
Cancer therapeutics Cytokine modulators Infectious diseases
84
What are the three signals that CTLs need to be able to recognize and kill infected or tumor cells via TCR activation?
1) Antigen specific interactions (TCR-MHC I) with a “licensed” APC that can now cross present. 2) A costimulatory signal (CD28-CD80/86) from “licensed” APC.
3) A signal from IL2 (usually produced by CD4 T cell) that binds high affinity IL2R (CD25)
85
What is MHC tetramer technology and why is important for tracking T cells?
An MHC tetramer has four identical MHC molecules bound to four peptides and linked to a fluorescent molecule. Will only bind to T cells with TCRs specific for that particular complex. Cells that bind become fluorescently labeled, allowing tracking of rare antigen specific T cells with flow cytometry.
86
What are the two mechanisms that CTLs can use to kill cells?
CTLs can kill target cells by 1) Directional release of granule contents (perforin and granzymes) and 2) Fas-FasL interactions that induce a cell death signaling cascade.
87
What are the steps in CTL- mediated pore formation in target cell membrane?
A calcium rise due to TCR-MHC interactions initiates granule fusion with the membrane and release of perforin between two cells. The perforin monomers undergo a calcium induced conformational change and insert into the membrane of the target cell. In the presence of calcium, the monomers polymerize within the membrane and form cylindrical pores. Granzyme B enters the cell via endocytosis processes and initiates a cascade of reactions that eventually results in the fragmentation of the target cell DNA into 200bp oligomers. Fragmentation starts within 5 minutes of CTL contact. CTLs have high levels of serpins (a protease inhibitor) believed to protect them from granzyme B activity
88
How are natural killer cells restricted to attacking altered self?
A key step in understanding NK cell function is the “missing self” model which states that NK cells distinguish self from non-self by recognizing the presence of normal self proteins on a cell. Later discovered that the critical self-protein was MHC class I.
89
What is NK licensing?
Normal cells present a ligand for the activating (killing) receptor on NK cells AND a ligand for the inhibitory receptor (class I MHC serves as this second ligand). When a cells MHC I is down regulated, it becomes a prime target for elimination by NK cells.
NK cells don’t automatically possess killing potential. They’re “licensed to kill” by a prior interaction with a healthy cell through MHC class I interactions. This gives the “license” only to those NK cells that can exhibit restraint when encountering a healthy, normal cell.
90
Compare and contrast how CTLs and NK cells recognize and kill infected cells or tumors.
NK cells induce apoptosis of tumor cells and virus-infected cells by similar mechanisms as CTLs (perforin/granzymes and FasL-Fas interactions), but are regulated by distinct receptors.
91
How do NK and NKT cells both have properties of innate immune cells and adaptive immune cells?
NK cells kill in a similar manner as CTLs, but have receptors similar to innate cells. NK cells respond rapidly to infection like innate cells, but more recent work has provided evidence that they appear to be able to generate memory cells.
NKT cells bridge innate/adaptive immune systems. The TCR on an NKT cell is invariant within the germline DNA. The TCR does not recognize MHC bound peptides, but rather a glycolipid presented by the non-polymorphic CD1d molecule. Can act as both helper T cells (cytokine production) and as cytotoxic cells (killing target cells; predominately via FasL-Fas interactions). NKT cells appear to be important for certain bacterial and viral infections as well as tumor immunity. Possess NK surface proteins rather than T-cell varieties.
