Week 3 Lecture 5 - Dendritic Cells Flashcards
DC Subsets and Nomenclature
Derived from mononuclear phagocyte system (MPS) in bone marrow
- also, consists of monocytes and macrophages
Separated into:
- classical or myeloid DCs (cDCs) - cDC1 and cDC2)
- plasmacytoid DCs (pDCs)
- monocyte-derived DCs (moDCs)
cDCs and pDCs arise from a haematopoietic stem cell (HSC) common DC precursor (CDPs)
DC Migration and Location
Monocyte derived DCs
- derived from the blood
- involved in pathogen type responses
Plasmacytoid DCs
- derived from the blood
- type 1 IFN antiviral responses
Non-lymphoid tissue resident cDCs
- found in skin, lung, liver, brain etc.
- migrate to lymphoid tissue for antigen presentation
- present to T cells producing Th1, Th2, Th17 cells etc
- cDC1s present more cytotoxic cells which drives Th1 response
- cDC2s drives more CD4 Th2 type response
Monocyte-Derived DCs
Migratory DCs in vivo under inflammatory conditions
Potent APCs in peripheral organs during inflammation
Can also be generated in vitro with GM-CSF + IL-4
Monocytes provided with GM-CSF -> immature dendritic cell
Immature dendritic cells provided with GM-CSF, IL-4, TNF-a, IL-6 etc. -> mature DC (upregulates co-stimulatory molecules, CD83, CD80, CD86, ICOSL)
Plasmacytoid DCs
Predominantly reside in lymphoid tissues
Anti-viral responses
Express Toll-like receptor (TLR)7 and TLR9
Production of type I interferons (IFN)
- 60% of transcriptome dedicated to IFN production
- release 100-fold more IFN than any other cell
Classical or Myeloid DCs
Populate lymphoid and non-lymphoid tissues
Sense injuries, capture environmental and cell-associated antigens
Induce immunity to foreign antigens
Enforce tolerance to self-antigens
DC Migration
Ability to migrate is key to immune responses
- maintenance of immune surveillance
- tissue homeostasis
- resolution of pathogens
Dependent on CCR7
DC Morphological Changes During Migration/Maturation
Immature DCs have ruffled appearance
Antigen encounter, DCs uptake antigens
Round up in tissue for migration
Extends dendrites once in lymph node
Increase opportunities for T cell interaction
DC Functional Changes During Maturation
Upon antigen encounter:
1. Adhesion (CCR7)
- enable migration
2. Upregulation of MHC class I and II molecules
- improve presentation to T Cells
3. Co-stimulatory molecules (CD40, CD80, CD86)
- activate T Cells
4. Cytokines
- activate and polarise T cells into effector subsets
DC Maturation and Metabolism
Requires a large amount of energy throughout maturation
Oxidative phosphorylation: homeostasis
- occurs in mitochondria
Glycolysis: enables fast response, but inefficient
- occurs in cytoplasm
Migration and Maturation - Immature DC
Migrate from bone marrow
Attracted to damaged tissue site through chemokines
Antigen uptake and processing
DC Activation Through Pattern Recognition Receptors
Activate DCs -> ‘danger signal’
Recognise pathogen components e.g. PAMPs
- such as Toll-like receptors (TLRs)
Recognise endogenous alarmins e.g. DAMPs
Release inflammatory cytokines e.g. IL-12
Upregulate MHC class I and MHC class II
Upregulate co-stimulatory molecules e.g. CD80, CD86
T Cell Contact Time and Signal Strength
Resting DC
- low ag
- no costimulation
- short contacts
Active DC
- high ag
- high costimulation
- cytokines
- long contacts
Exhausted DC
- high ag
- high costimulation
- short contacts
Why are DCs best at priming T cells?
DCs continuously sample their surroundings - ingest antigens
DCs travel to lymph node and spleen - take antigens to the ‘right’ place
Mature DC 100xs more potent than other APC in stimulating resting T cells
DC express high levels of costimulatory molecules e.g. CD86
Expression of MHC-peptide complexes is 10-100 fold > on DC than other APCs
DC express high levels of IL-12 upon maturation
Why are DCs best at priming T cells?
DCs continuously sample their surroundings - ingest antigens
DCs travel to lymph node and spleen - take antigens to the ‘right’ place
Mature DC 100xs more potent than other APC in stimulating resting T cells
DC express high levels of costimulatory molecules e.g. CD86
Expression of MHC-peptide complexes is 10-100 fold > on DC than other APCs
DC express high levels of IL-12 upon maturation
Only DCs cluster naive T cells
Can interact with many T cells at one time
Only DCs cluster naïve T cells in antigen-dependent and antigen-independent fashion
