Term
| What cell type is the only type that does not express class-I tissue type molecules (MHC-I) |
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Definition
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Term
| Explain what it means for T-cells to react to "non-self" molecules on you "own" cells. |
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Definition
MHC-1 molecules sample the intracellular environment for foreign antigens. If they find any (viruses or some bacteria), they migrate to the cell surface and present them to T-cells, which can then kill the infected cells.
These MHC-I proteins are displaying foreign antigens on self-cells to kill them before infections spread. |
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Term
| Explain how immature T-cells arrive at the Thymus and then undergo positive and negative selection. |
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Definition
SHORT
1) Bone marrow progenitors migrate to the thymus, proliferate and are "double positive," (they still lack a TCR)
2) TCR gene rearrangement occurs and TCR-alpha/beta dimers migrate to cell surface (or gamma/delta)
3) TCR+ cells scan thymic epithelium for MHC-I (become CD8+) and MHC-2 (become CD4+), and those that recognize MHC survive (positive selection). CORTEX
4) TCR+, CD8+ and CD4+ T-cells reach medulla and those that bind MHC I and II tightly undergo apoptosis (negative selection). Those that survive are MHC-restricted
5) Those cells that survive are MHC restricted, self tolerant and diversly-responsive cells that go to secondary lymphoid tissues
LONG EXPLANATION
1) Progenitors are generated in bone marrow and then migrate to the thymus to mature (thymus enlarges until puberty and the involuted by age 30).
2) When they arrive at the thymus, T-cells express few markers and they do not express any TCRs ("thymocytes")
They begin to proliferate and to express CD4 and CD8 ("double positive")
3) TCR gene rearrangement occurs to produce TCR-alpha and TCR-beta chains, and then send TCR-ab dimer to cell surface (A given T-cell expresses thousands of IDENTICAL TCRs). Very few thymocytes will share TCRs
4) TCR+ cells proliferate and "scan" the thymic epithelium in the cortex, which express high amounts of MHC class-I and class-II molecules.
5) T-cells that can bind MHC molecules receive a positive signal; survive, proliferate and traffic to the medulla (otherwise, they die of neglect).
6) Thymocytes that bind Class-1 MHC will lose CD4 and become CD8+, while those that bind Class-2 MHC will lose CD8 and become CD4+
7) All cells that reach the medulla can bind "self-peptides," but with different affinities. Those that bind more tightly are potentially "self-reactive," and are eliminated by apoptosis (negative selection). Those that bind with low affinity are kept (now called "MHC restricted" because they only bind to peptide antigens in the context of the MHC molecule presented by their host) |
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Term
| What does it mean for a mature T-cell to be "MHC-restricted" |
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Definition
| They only bind to peptide antigens in the context of the MHC molecules presented by their host (these cells are in the medulla and are TCR+, single positive cells that bind weakly to MHC molecules). |
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Term
| Where do T-cells undergo positive and negative selection, respectively? |
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Definition
1) Positive Selection occurs in the thymic cortex epithelium (TCRs have to find a MHC molecule/ those that don't die of neglect)
2) Negative Selection occurs in the thymic medulla (TCR+ cells that bind WEAKLY to MHC survive/others undergo apoptosis). |
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Term
| What is "TCR triggering" in the context of T-cell maturation in the Thymus? |
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Definition
| When thymocytes exhibit low binding affinity towards MHC-self peptide complexes, but that exhibit a "better fit" for foreign peptides. |
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Term
| Where do you find most CD4+ T-cells? |
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Definition
These are helper T-cells and they are found primarilly in the lymph nodes.
That being said, these cells have cytolytic capabilities and can leave the lLNs to kill virus-infected cells (like CD8+).
They can also become Tregs and inhibit CD8+ and NK cells. |
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Term
| What happens when phagocytes like macrophages and DCs get "full," or when they sense danger? |
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Definition
SHORT- switch adhesion molecules and chemokines in order to get to the draining LNs, and then increase MHC and B7 expression to present and activate T-cells. Some DCs die and are taken up by others.
1) Become less phagocytic and switch their adhesion (MIP1alpha and beta for MIP3beta) molecule and chemokine receptor expression (CCR7 for CCR1 and 5) in order to migrate via the lymphatics to draining lymph nodes.
2) Increase MHC expression (both I and II) for better Ag presentation, as well as B7 co-stimulatory molecules to ensure T-cell activation.
3) Some DCs die and then are taken up by other DCs (maximize antigen presentation!) |
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Term
| How do T-cells become "primed" and then leave the LNs to enter sites of assault? |
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Definition
1) T-cells that see antigens down-regulate CD62L expression (L-selectin) and CCR7
2) Increase expression of LFA-1, VLA-4, ect. and express chemokine-receptors such a RANTES and CXCR3.
3) Chemokine-Receptor binding on luminal side of post-cappillary venues in assaulted areas allows for adhesion and extravasation. |
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Term
| How do CD4+ T-cells help macrophages better "kill" intracellular microbes? |
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Definition
1) T-cells recognize specific antigens presented on macrophage's MHC class II molecules ("I need help!")
2) T-cells release IFN-y, which binds and activates macrophages
3) CD40L on T-cells binds to CD40 on macrophages, enhancing their activation.
4) Macrophages increase MHC expression and co-stiulatory molecules such as B7, which react with CD4+ cell receptors (TCR and CD28, respectively
5) Macrophages release cytokines and chemokines to stimulate inflammation and activation of more macrophages and lymphocytes |
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Term
| What cytokines and chemokines are released by activated macrophages and what do they each do? |
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Definition
1) IL-1 (caspase-1 and NFkB dependent)
activates vascular endothelium, lymphocytes and local tissue destruction, leading to FEVER and IL-6 PRODUCTION (operates through JAK/STAT)
2) IL-8
attracts leukocytes, increases access of effector cells, activates B2-integrin binding as well as PMN's (with TNF-a)
3) TNF-a
activates vascular endothelium, increases permeability leading to increased entry of IgG, complement and cells, and increased fluid drainage to lymph nodes (leads to FEVER, MOBILIZATION OF METABOLITES AND SHOCK)
4) IL-6
activated by IL-1 and leads to lymphocyte activation and increased Ab production, causing FEVER and ACUTE-PHASE PROTEIN RESPONSE.
5) IL-12
activates NK cells and induces differentiation of CD4 T cells into TH1 cells. |
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Term
| Explain the role of Regulatory T cells (Tregs). |
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Definition
-"break" on the immune system (can't live with em' if you have cancer, but can't get rid of them cause' you get autoimmune)
- Arise from CD4+ T-cells and T-cells being stimulated by IL-2 w/o co-stimulation from CD28
- Produce IL-10 and TGF-b, which inhibit priming and proliferation of T cells in LNs and the effector functions of helper and killer T cells as well as NK cells
- Protect tumor by interfering with development and function of anti-tumor helper and killer T cells and with NK cells
- W/O Tregs, you get autoimmune diseases |
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Term
| What are the 3 primary roles of CD4 T cells in lymph nodes. |
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Definition
These helper cells
1) Direct immune response in Th1 or Th2 direction
2) Help B-cells become active and to produce the right Ab
3) Help CD8+ become activate and then become cytotoxic T lymphocytes (CTL's) |
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Term
| What do CD4+ T-cells do in the periphery? |
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Definition
| Help macrophages to increase their ability to engulf and kill microbes |
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Term
| How are CD4+ T-cells activated? |
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Definition
| TCR binds MHC class II+peptide AND receive co-stimulation via B7-CD28 interactions. |
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Term
| What is the main function of activated CD8+ T cells ("Cytotoxic" T cells). Secondary action? |
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Definition
1) Kill cells housing intracellular microbes such as virus and certain bacteria and parasites (example- Neisseria gonorrhoeae)
2) Produce IFN-y to activate macrophages and inhibit virus development |
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Term
| How do CTLs (i.e. CD8+ T-cells) kil virus-infected cells? |
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Definition
1) Need to find antigen presented in MHC class I on target cells (CD28-B7 co-stimulation NOT NECESSARY as it was with CD4+ cells)
2) Release Perforin (polymerizes in target cell membrane and pokes holes) and Granzymes (caspase-mediated apoptosis when Perforin fails) from vesicles into area of contact (synapse)
3) Only a few minutes of contact are necessary (cell departs before the target actually dies!)
3) |
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Term
| True or False; 1 CTL can kill 1 target cell |
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Definition
False!
1 CTL (i.e. CD8+ T-cell) can kill many infected targets!) |
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Term
True or False
CD4+ and CD8+ T-cells require CD28-B7 co-stimulation for antigen recognition and activation. |
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Definition
False!
Only CD4+ cells (the helpers) need this. The CD8+ (the killers) cells just need the MHC-I. |
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Term
| How do CD8+ T-cells activate macrophages? |
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Definition
SHORT
CTLs and Th cells release IFN-y and TNF-a to activate macrophages. Macrophages try and kill microbes with ROS, proteases and NO. If this fails, they secrete IL-12 to stimulate more T-cells (and so on).
1) Released IFN-y and TNF-a from CTLs (as well as CD4+ Th1 cells) activate macrophages
2) Macrophages increased ROS, NO and Protease production (when phagosome fuses with lysosome, most microbes are destroyed).
3) If microbe persists in macrophage, or "escape" to cytosol, macrophage makes IL-12 to stimulate T-cells and NK cells to release more IFN-y, which further activates the macrophages (LOOP)
** GRANULOMAS MAY FORM ** |
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Term
| How can microbes "defend themselves" from macrophages and NK cells? |
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Definition
1) Mycobacteria inhibit phagosome/lysosome fusion
2) Viruses interere with antigen presentation by:
-inhibition of TAP-mediated transport of peptides into
ER (Herpes Simplex)- remember TAP "taps" proteins into the ER in the MHC-1 pathway
- Removal of MHC-I from ER (CMV)- prevents antigen presentation to CTLs
- Inhibition of proteasomal activity (EBV)
** EBV also stimulates infected cells to produce IL-10, which is a suppressive cytokine **
** Pox virus makes infected cells produce soluble cytokine receptors, which inactivate cytokines such as IFN-y (inhibit macrophage activation) and IL-1 (inhibit fever and IL-6 activation, impairing acute-phase protein response) ** |
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Term
| How does the Pox virus avoid T-cell-mediated destruction? |
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Definition
Pox virus makes infected cells produce soluble cytokine receptors, which inactivate cytokines such as
1) IFN-y (inhibit macrophage activation)
2) IL-1 (inhibit fever and IL-6 activation, impairing acute-phase protein response |
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Term
| How does the Ebstein Barr Virus avoid T-cell-mediated destruction? |
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Definition
1) Inhibits proteosomal activity
2) Stimulates infected cells to produce IL-10, a suppressive cytokine |
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Term
Where do you find gamma-delta T cells and NKT cells?
What are their defining characteristics? |
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Definition
1) Mucosal membranes ("intra-epithelial lymphocytes")
yd T-cells found in gut mucosa between epithelial cells (intraepithelial lymphocytes, or "IELs")
NKT cells express CD161 (NK1.1), CD15 and CD56, AND co-express TCRS (usually alpha/beta)
2) Relatively invariant TCRs which recognize lipid antigens presented by MHC-like CD1d molecules.
yd T-cells are first-line defense to gut microbes. They can develop memory phenotypes (adaptive), but often just act as pattern recognition receptors (innate)
NKT cells are also partially innate and adaptive. They release cytokines (IL-2, IFN-y, TNF-a and IL-4) to promote or suppress different immune responses. |
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Term
| What types of diseases are associated with lack/dysfunction of NKT cells? |
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Definition
Autoimmune conditions!
Examples include diabetes, atherosclerosis, asthma and cancer. |
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Term
| What are the most important characteristics of NK cells? |
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Definition
SHORT-
1) Immediate Viral Defense
2) Digest Ag for APCs to present to T-cells
3) By with perforin and granzymes
4) Initiate apoptosis
5) ADCC (CD16)
6) 2-receptor model
7) No clonal expansion
LONG
1) Immediate responsiveness (first-line again viruses).
2) "hold down the fort" until CTLs arrive, supplying early cellular debris for APCs to present to T-cells in the adaptive response.
3) Kill by induction of perforin and/or granzymes (just like CTLs)
4) Can stimulate apoptosis.
5) Can interact with Fc of Ab through CD16, and kill Ab-recognized cells (Antibody-dependent cellular cytotoxicity)
6) Balance of activating and inhibitory signal receptors expressed by NKs determines whether they will kill (MICA and MICB recognized by NKG2D means "kill" and MHC molecules determine "don't kill").
7) No clonal expansion, but the better the NK at killing, the more it hangs around |
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Term
| How can NK cells induce apoptosis in target cells? |
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Definition
| Express TNF, TRAIL and lymphotoxin on surface membrane, which can stimulate death receptors on target and stimulate apoptosis |
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Term
| How can NK cells induce antibody-dependent cellular cytotoxicity? |
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Definition
| Can interact with Fc of Ab through CD16, and kill Ab-recognized cells. |
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Term
| True or False: NK Cells can undergo clonal expansion |
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Definition
FALSE!
No clonal expansion, but the better the NK is at killing, the more it hangs around |
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Term
| Can can NK cells act as regulatory "helper" cells? |
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Definition
SHORT
NK cells sense danger (TLR) and stimulate DCs with IFN-y and CD40L. DCs produce IL-12, which stimulates NKs. This signaling biases CD40+ cells to go the Th1 route (i.e. macrophage-mediated)
1) Only a few NKs found in LN, and those that are express lots of CD56 (a little less cytotoxic)
2) Constantly cross-talking with pAPCs (DCs) during immune response. Thus, if NK senses danger (perhaps through TLR), they produce IFN-y and express CD40L, stimulating DCs to produce IL-12, which stimulates NK cells to keep producing IFN-y (and so on....)
3) The presence of IFN-y and IL-12 signaling in LNs during DC-CD4+ cross-talk biases CD4+ cells toward Th1 type immune response |
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Term
| What are examples of "intracellular microbes" that must be cleared by T-cells? |
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Definition
Viruses
Bacteria (Tb and Syphilis) |
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Term
| Where do the 1st and 2nd checkpoints take place in T-cell development |
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Definition
1st-(+) selection In thymic cortex, where TCRa/b scan epithelium to see if they can bind MHC-1 or MHC-2 molecules
2nd- (-) selection in thymic medulla, only TCRa/b that bind MHC relatively weekly are al0owed to stay alive (don't want to recognize self antigens too tightly!) |
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Term
| Why does transplant rejection occur? |
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Definition
| Sometimes, foreign MHC complexes are recognized as "self" AND "foreign" and are eliminated. Those that are recognized only as "self" are tolerated. |
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Term
| What is Peripheral Tolerance? |
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Definition
| Protects against auto-reactive T-cells that have been released into the periphery from the thymus (i.e. were not selected against in the medulla, but still interact too strongly with "self") |
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Term
| How do naive, mature T-cells become activated? |
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Definition
1) They leave the thymus and circulate in the blood until extravasating into a lymphoid tissue.
2) If they encounter a pAPC in the tissue that is presenting a recognizable antigen presented on a MHC (signal 1) AND receive costimulation from B7 on their CD28 receptors (signal 2), they become functionally active.
3) Activated CD4+ T cells in LN produce IL-2 (T-cell growth factor), leading to clonal expansion and IL-2R expression on CD8+ and CD4+ T-cells.
Aside- Adhesive ICAM on APC also binds CD11a to anchor interaction. |
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Term
| What is the structure of an "Immunological Synapse" between an APC and a T-cell in a lymph node? |
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Definition
1) MHC-1 or MHC-II presenting antigen (APC) to T-cell
2) B7 (APC) binding to CD28 (T-cell)
3) ICAM (APC) adhesion to CD11a (T-cell) |
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Term
1) Which adhesion and chemokine receptors keep phagocytic cells in tissues.
2) Which adhesion and chemokine receptors cause phagocytic cells to migrate to LN? |
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Definition
1) MIP1-a and b (adhesion) and CCR1 and 5 (chemokine)
2) MIP3-beta (adhesion) and CCR7 (chemokine) |
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Term
| Which adhesion and chemokine molecules are involved in T-cell (primed) migrating from LN to sites of assault? |
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Definition
1) In LN, T-cells express CCR7 and CD62 (L-selectin)
2) To get to tissues, they express LFA-1, VLA-4 (adhesion), RANTES and CXCR3 (chemokine receptors) |
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Term
| What determines whether T-helper cells follow the Th1 or Th2 response? |
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Definition
The type of immune stimulation
1) Th1 is driven by IL-12 production ("cellular" immune response) and leads to the production of IFN-y to activate macrophages (anti-microbial) and induce Complement-binding and Opsinizing Abs.
2) Th2 response is driven by IL-4 (the "humoral" immune response) and involves Ab-producing B-cells, IL-4 (IgE production for Mast-cell activation) and IL-5 (Eosinophil activation). |
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Term
Which 3 transcription factors are most important in T-cell signal transduction?
How does Cyclosporin relate to these and to transplant rejection? |
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Definition
NFAT, NFkB and AP1
Cyclosporin inhibits Calcinuerin, which prevents these t-facors from being transcribed (immune suppression) |
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Term
| What is the important of CTLA-4 in T-cell signaling? |
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Definition
| It is a negative regulator of T-cells found in Tregs, that binds to B7 and shuts down CD8+ T-cells (often leading to apoptosis) |
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Term
| What is the CD8+ "kiss of death"? |
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Definition
Wants CTLs are primed in the lymph nodes, they need only see their specific antigen presented in MHC class 1 molecules to get lytic machinery activated (no co-stimulation required)
A few minutes of contact is sufficient! |
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Term
| What is the 2-receptor model of NK cell activation? |
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Definition
Kill-Activating- NK cells look for "stressed" of "infected" ligands (MICA and MICB by NKG2D)
Kill-inhibiting- NK cells look for MHC-1 (if it is present, they are inhibited). |
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