Antigen presenting cells. Antigen presenting cells - (1) dendritic cells (2) macrophages (3) B cells. Morphology of Dendritic Cells. Paradigm: Immunity is the result of co-evolution of microorganisms and the immune system. Gram-. Gram+. Fungi. Parasites. Virus. INFECTIOUS NON SELF.
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(1) dendritic cells
(3) B cells
Morphology of Dendritic Cells
Paradigm: Immunity is the result of co-evolution of
microorganisms and the immune system
INFECTIOUS NON SELF
Dendritic cells (DC):
the sentinels of the immune system
DC orchestrate both innate and adaptive immunity
CD8a- and CD8a+
DCs progenitors are generated in the bone marrow.
They give rise to circulating DCs precursors.
Circulating DCs precursors enter nonlymphoid tissues as immature DCs. DC are scattered
throughout all non lymphoid tissues where they reside in a resting, (so-called immature) state.
In the absence of ongoing inflammatory and immune responses, they constantly migrate at
low rate to draining lymph nodes.
In inflammatory conditions, immature DC migrate
to draining lymph nodes where after maturation
(mature DC), they prime the rare circulating
naïve antigen-specific lymphocytes.
There are no lineage-specific surface markers that are expressed on all DC.
Moreover, DC are a heterogenous cell population.
However, it has been clearly demonstrated that at least 3 distinct types of DC can be
myeloid DC CD11b+CD11c+,
myeloid DC CD11b+ CD11c+/-, CD4+,
lymphoid DC CD11b- CD8a+
The existence of different subsets of DC has lead to possibility that they can perform
Dendritic Cell Subpopulations
Plasmacytoid Dendritic Cells
Process of Dendritic Cell
Migration to Lymph Nodes
Growth factor-dependent DC
Phagocytosis by DC
The innate repertoire: the specificity of DC recognition
is mediated by an extended family of receptors binding
a variety of ligands
TLR 5: flagellinR
TLR 2: LTA/ Gram+
TLR 4: LPS/ Gram-
TLR 9: CpG
PAMP‘s : Pathogen-Associated Molecular Patterns
conserved structures produced only by microorganisms but not by the host
bacterial glycolipids &
triacylated bacterial lipopeptides
zymosan, peptidoglycan &
diacylated bacterial lipopeptides
E. coli LPS,
RSV F protein
Toll-like receptor signaling pathways
of key molecules for the
Initiation of adaptive
LPS, LTA, CpG, PGN
T cell activation
MHC and costimulatory molecules upregulation
Immature Dcs express a variety of chemokine receptors (CCR1, CCR5, CXCR1 and CCR6)
that participate in their recruitment to inflammed tissue and/or to allow their residency into
Exemple: Imm. Dcs express CCR6 the receptor for MIP-3a that is constitutively express
in liver and lungs.
Upon maturation, there is a downregulation of receptors for chemokines produced at the
site of inflammation and upregulation of CCR7. SLC is a ligand for CCR7 and is expressed
at high levels by HEVs in LNs and by stromal cells in T cell areas of many secondary
lymphoid organs. ELC (other ligand of CCR7) made in T cell areas of lymphoid tissue.
SLC (6Ckine) and ELC (MIP-3b) act
together to direct DC migration to T cell areas
Of lymphoid tissue and to promote encounter
with T cells.
Banchereau J. et al. Immunobiology of dendritic cells
Ann. Rev. Immunol. 18:767-811, 2000.
MIP-1a, RANTES, MCP-3, MIP-5
MIP-1a, MIP-1b, RANTES
MIP-3b, SLC (6Ckine)
Expression of Chemokine Receptors
on Dendritic Cells
Abbreviations: DC, dendritic cell; MIP, macrophage inflammatory protein; RANTES, regulated on activation, normal T cell expressed and secreted; MCP, monocyte chemoattractant protein; TARC, thymus and activation-regulated chemokine; MDC, monophage derived chemokine; SDF, stromal derived factor; IL, interleukin; SLC, secondary lymphoid-tissue chemokine.
Functional downregulation of chemokine receptor expression
during DC maturation
LPS 0.5 h
RNAse protection assay
[Ca2+] : nM
CLPS 2 h
LPS 3 h
FURA-2 loaded D1 cells stimulated with MIP-1
Developmental Stages of
Developmental stages of dendritic cells (DCs) in vivo. The generation of DC precursors in the bone marrow, the recruitment of immature DCs in peripheral tissues, and the migration of DCs into the lymphoid organs are illustrated. The maturation of DCs into potent antigen-presenting cells in case of infection or inflammation and their migration have been amply documented (right), but there is also evidence that in the "steady state“ – that is, in the absence of a "danger signal“ – these immature DCs may migrate into the lymphoid organs while remaining at the immature stage (left). The phenotype of the DC migrating in baseline conditions is still unclear. The movement of maturing DCs and the "constitutive" migration of immature DCs have been shown to depend on chemokine gradients.
MHC and costimulatory molecules upregulation
Overview of Dendritic Cell
MHC and costimulatory molecule upregulation
Molecules Involved in
T Cell – DC Interactions
Dendritic Cells in Association
with T Cells in vivo.
Innate immunity regulates the expression of key molecules for the
initiation of the adaptive immune response
B71/2CD40MHC II MHC l
MHC class I
MHC class II
Peptides bind to MHC molecules through structurally related anchor residues
Peptides that bind MHC class II molecules are variable in lenght
The expression of MHC molecules differs between tissues
MHC class I loading
HLA class I synthesis
M. Rescigno PNAS 1998
Cross-Presentation of Antigen by
Peptides derived from phagocytosed antigens can be presented to CD8+ T cells on MHC class I. Phenomenon called
Soon after or during formation, phagosomes fuse with the ER. After antigen export to the cytosol and degradation by the proteasome, peptides are translocated by TAP into the lumen of the same phagosomes, before loading on phagosomal MHC class I molecule. Therefore, cross-presentation in dendritic cells occurs in a specialized, self-sufficient, ER-phagosome mix compartment.
Dendritic Cells Deliver Exogenous
Antigens to the Class I MHC Pathway
The Class II MHC Antigen
Processing and Presentation Pathway
Function of HLA-DM
(H-2M in Mice)
HLA-DM is Physically Located
In the MIIC Vesicle
M. Rescigno PNAS 1998
Phenotypic Changes Associated
with Antigen Presentation
Immature DC are less efficient in MLR
when compared to mature DC
cpm x 10-3
APC (x 10-3)
Allogeneic CD4 T cell proliferation
Allogeneic CD8 T cell proliferation
Comparison of Antigen Presentation
Abilities of DCs and Macrophages
Functional Features of Dendritic Cells
Small numbers of DCs pulsed with low doses of antigen stimulate strong T-cell responses.
Naive and quiescent T cells can be activated with antigens on DCs.
CD4+ T helpers and CD8+ T killers are primed in vivo.
DC are involved in the tolerization of peripheral T cells