Lecture 4 - Dendritic cells Flashcards
Dendritic cells: what are they, what do they detect, how do they do their detection, what do they do, and where can they be found?
Professional antigen-presenting cells (APCs) linking innate and adaptive immune responses
Danger signals - non-self antigens and/or inflammatory cytokines
Expresses PRRs
Take up antigen, process it, and display it for recognition by and activation of naive T cells
Can be found throughout the body but tend to be found in locations in lymph nodes where b and t cells reside (so they can act as APCs)
Differences between immature and mature dendritic cells?
Immature:
* High endocytosis, phagocytosis, or macropinocytosis
* Lower MHC II
* Low costimulatory molecules
* Low adhesion molecules
Mature:
* Low endocytosis/phagocytosis
* High MHC II
* High costimulatory molecules
* High adhesion molecules
Lymph nodes: what are the differences in location between macrophages and DCs
Dendritic cells want to interact with T- and B-cells so they can act as APCs for them
Macrophages reside anywhere in the lymph nodes to control the spread of pathogens and also act as APCs
Dendritic cell variations: are there multiple subsets in just humans, what are they differentiated on, why do they exist, what are specific examples, and what do they do?
Multiple subsets in humans and mice
Differentiated based on:
* Location
* Expression of specific surface molecules:
Allow specialised functional abilities
Lymphoid tissue-resident DCs - may gather antigens from cells moving in
pDCs - potent antiviral cells, producing type I interferons and promoting NK/CD8+ activity
pDCs: what are they, what do they do, are they good APCs, and where do they originate from?
Plasmacytoid DCs - potent antiviral cells - producers of type I interferons which promote NK and CD8+ T cell cytotoxicity and secretion of IFNγ
Less effective APC than conventional DCs
May originate from a different progenitor than other DCs (lymphoid as opposed to myeloid)
Antigen uptake by dendritic cells: what are the three potential ways?
1) Receptor-mediated endocytosis - cell surface transmembrane receptors which internalize into small clathrin-coated pits (<0.1μm)
2) Macropinocytosis - non-clathrin associated, linked to membrane ruffling, where large volume is taken up into large vesicles (~20μm)
3) Phagocytosis - engulf and digest antigens via phagolysosome pathway
Receptor-mediated endocytosis: how does it work and what examples of families detect substances that need to be endocytosed?
Cell surface transmembrane receptors which internalize into small (0.1µm) clathrin coated pits
- C-type lectin family, recognize glycosylated antigens - DEC205 (CD205), mannose receptor, DC-SIGN (binds HIV/ICAM-3)
- CD36 (recognizes apoptotic cells)
Macropinocytosis: what is it and how often does it occur?
Non-clathrin associated (linked to membrane ruffling) intake of material - a large volume is taken up and forms large vesicles (~20µm) which effect to concentrate external macro-molecules by shrinking
Constitutive
Phagocytosis: what is it, does the process benefit from antibodies, and what may occur with Fc opsonisation?
The internalisation of material, forming a phagosome which goes on to form a lysophagosome after fusion with lysosome(s) which can then kill any microbes
Yes antibodies can allow for opsonisations of macromolecules
FcRs present on DCs are receptive for IgE and IgG - Fc clustering may result in generation of larger phagosomes which may fuse with lysosomes
DCs: what happens upon the recognition of danger signals?
- DCs rapidly mature in an initial short-lived (30-45 mins) “burst” of antigen-capturing mechanisms followed by down-modulation
- Migration away from the site of antigen encounter to T-cell areas occurs
Podosomes: what are they and what do they do?
F-actin-rich structures found on the ventral surface of DCs
Thought to be involved in cell migration
How do DCs re-organize their class II?
Conflicting theories:
* Class II held intracellularly by a failure to process due to cystatin C, an endogenous proteinase inhibitor which inhibits Cathepsin S (chaperone protein) - upon maturation, cystatin C activity decreases, and class II/peptide complexes are formed and transported to the cell surface
- Class II is rapidly internalised and upon, maturation this rate is reduced by a global reduction in endocytosis
Dendritic cells: how do they know to move into lymph nodes?
Once activated, the expression of chemokine receptors (ie CCR7⁺) increases and favours the movement towards chemokine-rich areas like the lymph nodes (high amounts of CCL21)
Th cells: what are the types, what do they produce, and what are their targets?
- TH1 - IFN-γ - bacteria, viruses, protozoa
- TH2 - IL-4/13 - Helminths/allergens
- TH17 - IL-17 - Antifungal/extracellular bacteria
- Tregs - IL-10/TGFB/RA - “self” cells
Dendritic cells: as well as activating t-cells, what other interactions with t-cells can they have?
Can also produce a tolerance response, forming a semi-mature state when interacting with cells that trigger them but aren’t targets to destroy with the whole immune system (apoptotic cells, gut flora, etc)
This semi-mature state still travels to the lymph nodes and associates with t-cells, but doesn’t cause activation and instead promotes a tolerogenic response
