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57 Cards in this Set
- Front
- Back
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Special things to know about Steinman |
Nobel Prize for finding DCs Had cancer, tried to treat himself via DC therapy |
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Key learning issues for DCs |
Know their Migratory behavior Activating potential and Priming capacity |
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Major Challenges in DC research |
EXTREMELY RARE overlapping markers between subsets some subsets have different origins |
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what are the 2 common precursors for DCs |
common myeloid progenitor cells common lymphoid progenitor cells |
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what do you add to Monocyte and DC progenitor (MDP) to get monocytes?
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M-CSF and CCL2 |
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what do you add to Monocyte and DC progenitor (MDP) to get Dendritic Cells |
Flt3L |
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classes of dendritic cells (1st tier) |
Conventional and non- conventional DCs |
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Classes of conventional DCs |
Migratory and lymphoid DCs |
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Classes of non conventional DCs |
plasmacytoid DCs (end) monocyte derived DCs |
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In what organs are DCs found |
lung, liver, skin, kidney, intestine |
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What are the 4 DC subsets |
CD103+ CD11c hi CD11b+ CD11c hi CD11b+ pDC CD11c dim moDC CD11+ CD11b+ |
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things to know about the subsets |
the first 2 are general in their TLR activation (contain many TLR) the latter 2 are more restricted |
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general knowledge |
DCs in the skin are set up in a web/net fashion |
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know slide |
14 |
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what is DC maturation a result of |
engagement of activation receptors on DCs (FcR,TLR, cytokine R), which involves the upregulation of MHC and co-stimulatory molecules and theacquisition of specific functions (e.g. cytokine production) that enable DC to activate T cells efficiently Endocytosis alone does not induce DC activation and can be used to target Ag to DC for the inductionof T-cell anergy in vivo |
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Factors that influence differentiation in DCs |
GM-CSF, TNFa/b, Il4, SCF, FLT-3L |
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Factors that influence maturation in DCs |
GM-CSF, TNF-a, FLT-3L/LPS |
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How do DCs recognize invading pathogens? |
Via lipids proteins and sugars |
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general info |
DC subsets expressnon-overlapping TLRs
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what do myeloid DCs express |
Il-12 TNF Il6 |
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what do plasmacytoid DC populations secrete |
type 1 interferons |
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what do CD8a+ DCs secrete |
IL-12 |
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what do CD11b+ DCs secrete |
Il10 |
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what stimulates TLR4 and what types of pathways are stimulated |
LPS MyD88 dependent and independent mechanisms |
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what is involved and results from MyD88 independent signaling from TLR4 stimulation with LPS |
IkB and NF-kB Costimulatory molecule induction and T cell stimulation |
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what is involved and results from MyD88 dependent signaling from TLR4 stimulation with LPS |
MyD88, IRAK, TRAF6, IkB and NFkB Cytokine induciton |
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what stimulates TLR9 and what kinds of pathways are there downstream |
CpG DNA only MyD88 dependent pathways |
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what will TLR9 stimulation with CpG stimulate in the cell |
Costimulatory molecule induction and T cell stimulation
Cytokine induction |
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what is the migration pathways of a pDC/IPC into a lymph node (contrast to a mDC) |
pDC/IPC migrate into a lymph node throughblood and high endothelial venules (HEV).(somewhat similar to B cells)
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what is the migration pathways of a mDC into a lymph node
(contrast to a pDC) |
mDC migrate into a lymph node through afferentlymphatics. |
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what is similar between pDCs and mDC in terms of their migration pathways and localization |
Both pDC/IPC and mDC are localized in the Tcell-rich areas.
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what pathogens do monocytes recognize and what cytokines do they secrete |
Bacteria and ssRNA viruses via TLR 4 and 8 IL 1, 6, and 10 |
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what pathogens do mDCs recognize and what cytokines do they secrete |
ds/ssRNA viruses via TLR 3 and 8 IL12 (10x more), 1, 6, 10 , TNF-a |
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what pathogens do pDCs recognize and what cytokines do they secrete |
DNA virus, CPG, and ssRNA viruses via TLR 9 and 7 IFNa/b/w (70x more), TNF-a, IL6 |
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what do C type Lectin receptors recognize (CLRs) |
viruses, bactria, paracites, helmiths |
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what does ITAM signaling via CLRs promote |
phagocytosis, cross presentation, inflammasome activation, inflammatory mediator production, innate and adaptive immunity, antimicrobial responses |
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what is the role of DC-Sign and its receptor in DC biology |
DC-SIGN recognizes self ICAM2 and ICAM3
DC-SIGN functions similarly to selectins Cell-adhesion receptors transmigration via endothelial cells activation of resting T cells (slide 25) |
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what are the functions that DC-SIGN controls in DCs to elicit immune responses |
DC migration, t cell priming, antigen capture and presentation slide 26 |
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what is the distinct central feature of the pathogens that have evolved distinctmechanisms to subvert DC functions by misusing DC-SIGN |
they cause chronic infections, and thatmanipulation of the Th1/Th2 balance by these pathogens isessential for their persistence
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how do Ebola and HIV misuse DC-Sign |
they use it to bind to DCs and when they present they infect the Tcells due to close proximity |
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major evasion functions from DCs by pathogens |
DCs provide a safe haven for some pathogens
DCs are inefficient in killing intracellular pathogens Infected DCs are poor APCs |
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some examples of DC evasion |
DCs host latent cytomegalovirus.DCs sustain the production of HIV-1, SIV, and measles.DCs assist spreading of HIV and SIV to T cells.
M. tuberculosis grow faster in DCs than in macrophages.DCs in Leishmania-infected hosts do not migrate properly |
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what are immature DCs known for doing |
antigen uptake and processing indicated more in tolerance |
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what are mature DC cells known for doing |
antigen presentation, costimulation, T cell activation indicated more in immunity |
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what will you find in mature DCs |
they induce specificmaturation markers like CD83 andcostimulatory molecules like CD80 or CD86(or CD40, not shown), whereas ICOSL israther down regulated or unaltered. Alsoantigen presentation is enhanced, displayedby higher levels of MHC II molecules show a typical morphology with strongcellular extensions |
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general DC info |
In coculture with alloreactive T cells,immature DC induce only comparable weakT cell proliferation, whereas mature DC arepotent activators of T cells |
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what's unique about immature DCs |
express low amounts ofCD28 ligands (CD80/CD86) andthereby provide strong ICOS signals.This leads to stabilization of IL-10R onthe surface of stimulated naïve T cells.Subsequently, the immunomodulatorycytokine IL-10 produced by DCmediates its function resulting in thedifferentiation into anergic Treg |
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what do we know about CD28 signaling in mature DCs |
provide strongCD28 signals that overcome thetolerogenic ICOS function resulting instabilization of IL-2 mRNA andsynthesis and thereafter, thedifferentiation into inflammatory Teffector cells
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in the immature DC what kind of signal dominates and what does this mean |
ICOSL stabilization of IL10R expression and T cell anerger and/or iTreg |
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in the mature DC what kind of signal dominates and what does this mean |
CD80/CD86 IL10R down regulation creation of t effector cells immunity |
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Why are DCs potent APCs for translating“pathogen information” to naïve T cells? |
DCs produce DC-CK1 – attractingCD45RA+ naïve T cells MHC-peptide complexes are 10-100xhigher on DCs than on other APCs 1 DC is sufficient to turn on 100-3000T cells DCs produce IL-2 transiently at earlytime points after pathogen encounter |
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tolerogenic general note 1 |
In the presence of IL-4 and GM-CSF isolated monocytesdifferentiate into immature DC within 5–7 days. Terminaldifferentiation into fully mature DC is induced upon stimulationwith inflammatory factors (IL-1, IL-6, and TNF) together withPGE2. This is a common protocol for generation ofimmunogenic DC
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tolerogenic general note 2 |
Maturation of DCcarried out in presence of IL-10 provokes differentiation intotolerogenic IL-10DC. |
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how does IL-10 affects maturation and inducestolerogenic DC |
(A) Presence of IL-10 during the maturation process ofimmature DC impairs the upregulation of costimulatorymolecules like CD80 and CD86 resulting in thetolerogenic phenotype of IL-10DC. (B) Tolerogenic IL-10DC display a reduced T cellstimulatory capacity compared to immunogenic DC(left) and induce T cell anergy, displayed by reduced Tcell proliferation after polyclonal restimulation |
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what are the immmune checkpoints |
CTLA-4 and PD-1/PD-L1 |
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what is the the ability of DC to induce different types of cell-mediated immune responses dependent on? |
lineage maturation status activation signals |
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what are the Regulatory T cell subsets induced by tolerogenic DCs |
Repetitive stimulation of T cells with iDCs leads to anergy or Treg induction.IL-10-modulated DCs induce Tr-1 cells or CD4+ and CD8+ suppressor T cells.Vitamin D3 and corticosteroids favor the induction of CD4+CD25+Foxp3+ Tregs.
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