Dendritic Cells Flashcards
1
Q
What is the role of Dendritic cells?
Include their family
A
- Family of leukocytes
- Evolved to translate innate recognition into adaptive immunity
- Primary function is to capture and present protein antigens to naïve T-lymphocytes
- “Antigen presenting cells”
2
Q
List two major functions of DCs during adaptive immunity
A
– Capture and process antigens for presentation to T-lymphocytes
– Produce signals required for proliferation and differentiation of lymphocytes
3
Q
Describe the Dendritic cell life cycle
A
- Generated from hematopoietic stem cells in the
bone marrow - Differentiate under the control of a complex
network of soluble growth factors produced by
bone-marrow stroma and direct cell-cell contact
with bone marrow stromal cells
– e.g. GM-CSF, IL-3, FLT3L - Give rise to circulating precursors that home to
tissues where they reside as immature cells
*As they mature, dendritic cells express CCR7 which allows them to localize to the lymphoid tissues
*They pick up antigens in peripheral tissues, then migrate to lymph nodes, where they express high levels of adhesion, costimulatory molecules, and MHC class II molecules
*Once they have migrated, DCs stop synthesizing MHC class II molecules, but maintain high levels of MHC class II molecules containing peptides from antigens derived from the tissue where they originated
*As they mature, DCs also increase expression of key costimulatory molecules, including CD40, CD80 and CD86 (B7-1 and B7-2
4
Q
Describe Immature dendritic cells
A
- Located throughout epithelium of the skin, the respiratory tract, and the gastrointestinal tract
- Recruited to sites of inflammation in peripheral tissue
– By chemokines - MIP-3alpha (CCL20), RANTES (CCL5) and MIP-1alpha (CCL3)
– Immature DCs express chemokine receptors – CCR1, CCR2, CCR5, CCR6 and CXCR1
– DCs accumulate at the site of infection very rapidly – within an hour
5
Q
What are the different antigen materials DCs can uptake
A
– Apoptotic bodies
– Bacterial material
– Material from virally infected cells
– Hsp/antigen complexes
– Immunoglobulin cross-linked material
– Extracellular fluid
– Material from healthy cells
6
Q
List and describe the different Antigen uptake pathways
A
- Receptor mediated endocytosis
– C-type lectin receptors: mannose receptor,
DEC-205
– Fcgamma receptor types I (CD64) and types II
(CD32)
– CD91 α2-macroglobulin receptor (hsp)- Shrivastava and tumour peptide delivery - Phagocytosis of particulate material
– Apoptotic and necrotic cell fragments
– Bacteria including mycobacteria
– Intracellular parasites such as Leishmania major
– Viruses
– latex beads - Macropinocytosis
– Aquaporins – water channels involved in regulating osmotic pressure, may be responsible for constitutive macropinocytosis
7
Q
Describe maturation of DCs
A
- Dendritic cells need to receive a maturation stimulus to trigger their transition from immature antigen capturing cells to mature antigen presenting cells
- Under steady-state conditions only a small
number of tissue-resident DCs ‘spontaneously’ mature and migrate to the lymph nodes
8
Q
Describe maturation stimuli
A
- Pathogenic molecules as a consequence of
infection
– lipopolysaccharide (LPS)
– Bacterial DNA
– dsRNA - Balance between pro- and anti-inflammatory
signals in local environment
– TNF-α, IL-1, IL-6, IL-10, TGF- and prostaglandins - T cell derived signals
– CD40
9
Q
Describe the changes during DC maturation (What is up/downregulated?)
A
- Down regulation of receptors for inflammatory
chemokines - Down regulation of antigen capture
– Loss of endocytic and phagocytic receptors - Change in morphology
– Loss of adhesive structures
– Cytoskeleton remodelling
– Acquisition of high cellular motility - Up regulation of receptors for homing to lymphoid tissue
– CCR7 - Up regulation of antigen presentation
- Up regulation of co-stimulatory molecules
– CD40, CD58, CD80, CD86
10
Q
Describe Dendritic cell migration
A
- Migration of Dendritic cells to the lymphoid
tissues is regulated by chemokine - chemokine
receptor interactions - Upon maturation, surface expression of CCR7 is
up regulated - DCs become responsive to CCL19/MIP-3β and
CCL21/ 6Ckine
– CCL19 is expressed in the afferent lymph ducts
– CCL21 is expressed in high endothelial venules of
lymph nodes and in the T-cell areas of spleen and
lymph nodes - CCL19 and CCL21 guide DCs from the tissue to
the T cell areas of lymph nodes
11
Q
For all chemokine receptors expressed by dendritc cells, what are their ligads?
A
12
Q
Describe the structure of a lymph node
A
13
Q
Describe immune cells interactions in lymph nodes
A
- Mature DCs migrate to the T cell zones
- 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
14
Q
Describe DC - T Cell interactions
A
- 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
-bind to CD28 (Naive T-cells) and its homolog CTLA-4 (CD152), which is expressed after T cell activation
– Regulate T cell activity - prolongs and augments the production of IL-2 and other cytokines
- is probably important in preventing the induction of tolerance
- CD40 – CD40L
– T cells can activate DCs via CD40L
15
Q
Describe DC directed B cell activation
A
- 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
16
Q
Describe DC interactions with NK cells
A
- Occurs at site of infection
- Pathogen activated DCs can activate NK cells
through cell-cell contact and soluble signals
– IFNa, IFN-b, IL-2, IL-12, IL-15 and IL-18
– Leads to NK cell secretion of IFNg and cytolytic
activity - Il-12, IL-18 and IL-15 from DC promote NK
proliferation and survival - IFN and TNF release from NK cells can mature
DCs - Non-MHC dependent
21
Q
Describe DC1 and DC2
A
- Early studies divided dendritic cells into two groups called DC1 and DC2 based on their ability to induce either Th1 or Th2 responses
- Largely based on the premise that human pDC did not appear to produce IL-12 and preferentially drove Th2 development whereas Mo-DC produced IL-12 and droveTh1 differentiation
- In the mouse early studies suggested that mouse CD8a+ DC produced IL-12 and direct Th1 responses whereas CD8a- DC did not synthesise IL-12 and preferentially induced Th2
- BUT both mouse and human pDC can produce IL-12 a well as IFN-I and drive Th1 responses
- The DC1 and DC2 division is an oversimplification
27
Q
Give an overview of DC types
A
37
Q
TLR, Ligand, original ligand
A
38
Q
TLR locations and combinations
A
- 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
39
Q
TLR signalling pathways
A
