Dendritic cells Flashcards

Question

Expression of chemokine receptors by immature vs mature DC's?

Answer 1

``` Immature DC receptors CCR1 CCR2 CCR4 CCR5 CCR6 CXCR1 CXCR4 ``` Mature DC CCR7

Answer 2

``` CCR1 - MIP-1α (CCL3), RANTES (CCL5), MCP-3, MIP-5 CCR2 - MCPs CCR4 - TARC, MDC CCR5 - MIP-1α, MIP-1β CCR6 - MIP-3α (CCL20) CXCR1 - IL-8 CXCR4 - SDF-1 ``` Mature DC CCR7 - MIP-3β (CCL19), 6Ckine (CCL21)

Answer 3

CCR7 is a surface receptor upregulated during DC maturation it is specific for driving these cells from the circulation from the tissues to the lymph nodes

Answer 4

1. inducing factors - Cytokines: e.g. GM-CSF, Il-3, FLT3L - Endothelial migration DC precursors - properties: Cytokine Release - IFN alpha, TNF, IL-1 ``` Immature DC - properties: Antigen Capture Endocytosis Phagocytosis High intracellular MHCII (MIICs) High CCR1, CCR5, CCR6 Low CCR7 Low CD54, 58, 80, 86 Low CD40 Low CD83 High CD68 No DC-LAMP Tissue distribution ``` ``` Mature DC - properties: Antigen Presentation Low endocytosis Low phagocytosis High Surface MHCII Low CCR1, CCR5, CCR6 High CCR7 High CD54, 58, 80, 86 High CD40 High CD83 Low CD68 High DC-LAMP ``` immature DC into a mature DC: Pathogens: e.g. LPS, bacterial DNA, viral dsRNA Cytokines: e.g. TNF, MCM T cells e.g. DC40L

Answer 5

germinal centres

Answer 6

Mature DCs migrate to the T cell zones in the lymph node Stimulate quiescent, naïve and memory T and B lymphocytes Selection of rare CD4+ and CD8+ T cells and B cell clones Induce an immune reaction by priming cytoxic T cells and helper T cells - Antigens presented in the context of Class II prime T helper cells - Antigens presented in the context of Class I prime Cytotoxic T cells

Answer 7

DC-SIGN (DC-specific intercellular adhesion molecule (ICAM)-3 grabbing non-integrin) DC specific ligand for ICAM-3 expressed on naïve T cells Promotes transient clustering between a DC and a T cell, this allows a DC to screen numerous T cells for a matched TCR Dectin-1 DC specific type II C-type Lectin binds T cells promoting their proliferation CD80 and CD86 Co-stimulatory molecules expressed on mature DCs Regulate T cell activity CD40 – CD40L T cells can activate DCs via CD40L

Answer 8

Follicular areas of the lymph node DC can directly signal B cells to proliferate CD40 : CD40L (T cell) interaction at the DC (menage a trois) DC secretes cytokines to cause proliferation of B cells and Ig production DC may hold onto a Tcell for a number of hours before all the appropriate signals have been transferred to activate the T cell

Answer 9

Occurs at site of infection - DCs maintain the NK cells in a state of readiness at the site of infection Pathogen activated DCs can activate NK cells through cell-cell contact and soluble signals - IFNα, IFN-β, IL-2, IL-12, IL-15 and IL-18 - Leads to NK cell secretion of IFNγ and cytolytic activity Il-12, IL-18 and IL-15 from DC promote NK proliferation and survival IFNγ and TNF release from NK cells can mature DCs Non-MHC dependent

Answer 10

Both endogenous and exogenous peptides are presented by DCs DCs can present antigen in the context of either MHC class II or MHC class I Endogenous material is presented on MHC class I molecules Exogenous material can be presented on both MHC class II (and MHC class I) molecules

Answer 11

Dendritic Cells are also able to load exogenous antigens on Class I How does exogenous material become loaded onto Class I? Mechanism not yet fully understood Hypothesis: route of antigen internalisation is critical for loading on to MHC class I Receptor mediated endocytosis and phagocytosis results in presentation on MHC class I e.g. FcR and CD91 mediated internalisation Dependence on TAP – suggesting cytosolic to ER transport involved

Answer 12

MHC class II presentation Cathepsin cleaves the invariant chain of MHCII, which in immature DCs is inhibited by cystatin C DCs can take antigens from the outside and load this onto the proteasome system to present on Class I

Answer 13

Cross-presenting DC are valid targets for CTL, express viral peptides and MHC-I on the cell surface. DC contain SPI-6 (serine protease inhibitor-6) protect against lysis. Th1 cells induce SPI-6 in DC BUT ALSO, they can die: Death of the DC may be a way of self-limiting the response. Sufficient clonal expansion Too many CTL may be damaging - Some of the DCs die when there is enough CTL activation NEEDS TO BE CONTROL

Answer 14

Although all DCs perform essentially the same function to collect, process and present antigen they are a heterogenous group cells ``` DCs differ in: the signals the respond to the regulatory signals they transmit the precursor cells they derive from their location stage of maturation ```

Answer 15

Early studies divided dendritic cells into two groups called DC1 and DC2 based on their ability to induce either Th1 or Th2 responses respectively The DC1 and DC2 division is an oversimplification 2 diff models - plasticity - specialised lineage

Answer 16

DC's tend to have a more activated phenotype in tissues than in blood (increased CD80, 86, 83 and 40 and CCR7).

Answer 17

Major population of DC in blood, tissues and lymphoid organs (~1% mononuclear cells)

Answer 18

Plasma-cell like morphology Minor population of blood DCs May have rearranged BCR/TCR Some ability to present antigen, express MHC2, CD80 and 86 High expression of TLR7 and 9 Primary role seems to be in production of Type 1 IFN in response to virus CD34+/CD11clow/CD45RA+ CD123+ (IL-3R) Recent evidence suggests that mDC and pDC MAY have a common precursor.

Answer 19

Langerhans Cells Found in the skin and skin draining lymph nodes Express high levels of langerin Dermal/interstitial DCs Found in all tissues Traffic to draining lymph nodes

Answer 20

Some T cells need to be tolerised DCs play a role in both central and peripheral tolerance Infection needs to tell ‘tolerising’ DC to become ‘immune activating’ Danger signals

Answer 21

Mediated by thymic DCs | Thymic DCs Induce the apoptotic death of potentially self-reactive T cells within the thymus

Answer 22

Mediated by DCs DCs promote tolerance by killing T cells, paralysing T cells (anergy) or by inducing the generation of antigen specific regulatory T cells All DCs have the capacity to induce tolerance or immunity, the distinction is depending on their maturation state Either immature DCs produce tolerance whereas mature DCs immunity Or Mature DCs need to be activated to produce immunity, quiescent mature DCs maintain self-tolerance “Danger signals” are required to produce immunity

Answer 23

Pattern Recognition Receptors, which recognise “Danger Signals” Toll-Like Receptors are a large family of pattern recognition receptors expressed on dendritic cells Recognise conserved molecular products derived from various classes of pathogen including bacteria, viruses, fungi and protozoa - pathogen associated molecular patterns (PAMPs) TLR triggering has pleiotrophic effects on DCs - Promoting survival, chemokine secretion, expression of chemokine receptors, migration, cytoskeletal and shape changes or endocytic re-modelling

Answer 24

Danger signals act directly on DCs to drive migration and maturity Danger signals affect the DC:T cell interaction

Answer 25

TLR signalling regulates three categories of signals DCs deliver to T cells Antigen (Signal 1) Co-stimulation (Signal 2) Cytokines (Signal 3)

Answer 26

In vitro treatment of DCs with LPS increases antigen loading onto MHC class II and surface display of MHCII:peptide complexes Poly I:C treatment of mouse DC enhances MHCI presentation and cross-presentation.

Answer 27

All TLR agonists tested to date increase expression of CD40, CD80 and CD86 in at least one DC sub-set

Answer 28

E.g. CpG and LPS stimulate DCs to produce IL-6 which makes responding T cells refractory to suppression by regulatory T cells TLR signalling can promote synthesis of IL-1, IL-2 and/or TNF-α by DCs, all of which can contribute to clonal expansion of T cells TLR ligation can induce production of IL-12p70 which directs differentiation of CD4+ and CD8+ T cells into type 1 effectors

Answer 29

TLRs found on cell surfaces TLR1, TLR2, TLR4, TLR5, TLR6 TLRs found in the membranes of the endosomes used to degrade pathogens TLR3, TLR7, TLR8, TLR9 Many of the TLRs signal in pairs e.g. TLR1/TLR2 bind bacterial lipopeptides and GPI-anchored proteins in parasites TLR-6/TL2 pairs bind lipoteichoic acid from gram-positive cell walls and zymosan from fungi TLR-4/TLR-4 pairs bind lipopolysaccharide from gram-negative cell walls pairs

Answer 30

Th1 Key cytokine in polarising immune response is IL-12p70 produced by dendritic cells IL-12p70 produced in response to DCs detecting intracellular infection e.g. signalling through endosomally located TLR3 in response to dsRNA in apoptotic cell body IFN-α produced by pDCs also polarises for Th1 Th2 IL-4 directs CD4 T cells to promote B cell proliferation In response to DC detecting an extracellular infection e.g. signalling through cell surface bound TLR5 in response to flagellin

Answer 31

May affect the DC ability to act as an APC Evade the CTL response BUT cross-presentation of virus taken up by uninfected DCs will induce the CD8 response