Dendritic cells Flashcards
What is the primary function of dendritic cells?
Capture and presentation of protein antigens to naive T cells
What are the 2 major functions of APCs?
Capture and process antigens for presentation to T cells
Produce signals required for proliferation and differentiation of lymphocytes
Why are DCs unique?
They are the only cells with the ability to present antigens to naive T cells and induce primary immune responses
What are DCs generated from?
HSCs in the bone marrow
How do DCs differentiate?
Under the control of a complex network of soluble growth factors produced by BM stroma and direct cell-cell contact with BM stromal cells
e.g. GM-CSF, IL-3, FLT3L
What do DCs give rise to?
Circulating precursors that remain in tissues where they reside as immature cells
Where are immature DCs found?
Widely distributed in all tissues - particularly those which interface the environment
Located throughout epithelium of skin, respiratory tract and GI tract
Where are immature DCs recruited to?
Sites of inflammation in peripheral tissue by chemokines (CCL20, CCL5, CCL3)
What chemokine receptors do immature DCs express?
CCR1
CCR2
CCR5
CCR6
CXCR1
What are immature DCs efficient at?
Antigen capture
What does antigenic material include?
Apoptotic bodies
Bacterial material
Material from virally infected cells
Hsp/antigen complexes
Immunoglobulin cross-linked material
Extracellular fluid
Material from healthy cells
What is receptor mediated endocytosis?
Antigen will bind to specific receptors on DC surface and become internalised in clathrin-coated vesicles or clathrin-uncoated vesicles
C-type lectin receptors e.g. mannose receptor, CEX-205
Fc-gamma receptor types I (CD64) and II (CD32)
CD91 alpha2-macroglobulin receptor (hsp)
What is phagocytosis of particulate material?
Apoptotic and necrotic cell fragments
Bacteria inc. mycobacteria
Intracellular parasite such as Leishmania major
Viruses
Latex beads
What is macropinocytosis?
Internalisation of antigens into macropinosomes - actin dependent process that requires stimulation for growth factors e.g. colony stimulating factor (CSF-1, epidermal growth factor (EGF) or platelet derived growth factor (PDGF)
Antigens processed and loaded onto MHC molecules of DCs
Aquaporins may be responsible for constitutive macropinocytosis
How do immature DCs become mature?
Must receive maturation stimulus to trigger transition from immature antigen capturing cells to mature antigen presenting cells
What are the maturation stimuli?
Pathogenic molecules due to infection - LPS, bacterial DNA, dsRNA
Balance between pro and anti-inflammatory signal in local environment
T cell derived signals - CD40L
What happens upon maturation of DCs?
Down regulation of receptors for inflammatory chemokines - loss of endocytic and phagocytic receptors
Down regulation of antigen capture
Change in morphology
Upreg of receptors for homing to lymphoid tissue - CCR7
Upreg of antigen presentation
Upreg of co-stimulatory molecules - CD40, CD58, CD80, CD86
What changes in morphology occur upon maturation?
Loss of adhesive structures
Cytoskeleton remodelling
Acquisition of high cellular motility
What regulates migration of DCs to lymphoid tissues?
Chemokine-chemokine receptor interactions
What do DCs become responsive to upon maturation?
CCL19/MIP-3beta
CCL21/6Ckine
Where is CCL19 expressed?
Afferent lymph ducts
Where is CCL21 expressed?
High endothelial venules of lymph nodes
T cell areas of spleen and lymph nodes
What do CCL19 and CCL21 do?
Guide DCs from tissue to T cell areas of lymph nodes
What interactions occur in the lymph node?
Mature DCs migrate to T cell zones
Stimulation of quiescent, naive and mature T and B cells
Selection of rare CD4+ and CD8+ T cells and B cell clones
Induction of immune reaction by primary cytotoxic T cells and helper T cells
What are the DC-T cell interactions?
DC-SIGN
Dectin-1
CD80 & CD86
CD40-CD40L
Describe DC-SIGN
DC-specific intracellular adhesion molecule (ICAM)-3 grabbing non-integrin
DC specific ligand for ICAM-3 expressed on naive T cells
Promotes transient clustering between a DC and a T cell, allowing a DC to screen numerous T cells for a matching TCR
Describe Dectin-1
DC specific type II C-type lectin
It binds to T cells to promote proliferation
Describe CD80 and CD86 interactions
Co-stim molecules expressed on mature DCs
Regulate T cell activity
Describe CD40-CD40L interactions
T cells can activate DCs via CD40L
How do DCs direct B cell activation?
DC secretes cytokines to stimulate proliferation of B cells and Ig production
CD40-CD40L interaction at DC
Where does DC interaction with NK cells occur?
Site of infection
How are NK cells activate by DCs?
Pathogen activated DCs can activate NK cells through cell-cell contact and soluble signals
e.g. IFM-alpha, IFN-beta, IL-2, IL-12, IL-15, IL-18
Leads to NK cell secretion of IFM-gamma and cytolytic activity
Non-MHC dependent
What can IFN-gamma and TNF release from NK cells do?
Cause maturation of DCs
What peptides are presented by DCs?
Endogenous and exogenous
Can present antigen in context of either MHC I or II
Where is endogenous material presented?
MHC I
Where is exogenous material presented?
MHC I and II
What is cross-presentation?
Loading of both endogenous and exogenous antigens on MHC I
How does exogenous material become loaded onto class I?
Mechanism not yet fully understood
Hypothesis is that route of antigen internalisation is critical for loading onto MHC I
Receptor mediated endocytosis and phagocytosis results in presentation on MHC I
Dependence on TAP, suggesting cytosolic to ER transport involved
What are the problems with cross-presentation?
Cross-presenting DCs are valid targets for cytotoxic T cells as they express viral peptides and MHC-I on cell surface
What protects DC from lysis?
SPI-6
What induces SPI-6 in DC?
Th1 cells
What is an alternative way of cross-presenting?
Cross-dressing
Transfer of MHC-I molecules from tumour cell to DC
What do DCs differ in?
The signals they respond to
The regulatory signals they transmit
They precursor cells they derive from
Their location
Stage of maturation
What groups did early studies divide DCs into?
DC1 and DC2 based on their ability to induce either Th1 or Th2 responses
