Advanced Molecular Immunology And Cell Biology (AM_470656)
Institución
Vrije Universiteit Amsterdam (VU)
Detailed summary of 5/8 modules, based on the lecture slides and recordings.
The following modules are included:
- Dendritic cells and migration, host innate immune receptors
- (Auto)antibodies in infection and inflammation
- Immune responses to glycolipids and polysaccharides
- Immune defici...
Advanced Molecular Immunology And Cell Biology (AM_470656)
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Advanced Molecular Immunology and Cell Biology
M Biomedical Sciences 2021-2022
Lecture 1: DCs in tailored adaptive immunity and their role in PRRs
Pattern recognition receptors (PRR) and DCs are involved in shaping the adaptive immunity:
I. DCs are needed to activate adaptive immune responses.
II. PRR expressed by DCs enable sensing of infection and induction of tailored immunity.
III. DC-specific PRR can be targeted for therapy (vaccination).
Part I: DCs are important for adaptive immune responses
Our immune system attacks infectious pathogens that may cause disease. Pathogens include
viruses, bacteria, helminths, yeast, and protozoa. Each of them has specific ways of activating our
innate immunity. Innate immune cells include granulocytes, macrophages, NK cells and DCs.
DCs induce adaptive immunity. DCs from the tissue migrate to the LNs via the lymphatic system.
In the LNs, DCs will activate the cellular responses (T cells) and humoral responses (antibody-
secretion).
3 main phases of immune activation initiated upon infection with a pathogen:
1. Innate immunity (quick, 0-4 h): epithelial barrier fails to contain pathogen → infection
→ pathogen is recognised by our innate immune system (complement system) → plasma
enzymes bind to pathogen and help destroy it. Macrophages and other innate immune cells
are also activated. In case of bacterial infection, there will be neutrophils. NK cells are
usually recruited when there are viral infections. When this fails, there will be an early
induced innate response.
2. Early induced innate response (4-96 h)
3. Adaptive immune response (>96 h)
→ Complement system: C3 can be cleaved into C3b and C3a (toxins that cause inflammation).
This part of the complement system ensures that inflammation at the site of infection is enhanced.
C3a (anaphylatoxins):
- Increase of vascular permeability
- Recruitment of neutrophils and degranulation of mast cells and basophils.
C3b: enhanced phagocytosis by macrophages and MAC.
Phagocytes: innate immune cells that take up pathogens by encapsulating and destroying them.
DCs and macrophages are phagocytes that reside in our tissue at steady state, ready to encounter
any possible pathogens present in the environment. Their role in immunity differs: DCs can
activate naive T cells (and thus the adaptive immune response), whereas macrophages are mainly
important for the induction of inflammation (secretion of pro-inflammatory cytokines and
recruitment of other phagocytes). Macrophages stay within the tissue, whereas DCs travel to the
LNs to activate naive T cells. Macrophages are not as good as DCs at activating the adaptive
immunity.
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, - Both DCs and macrophages use specific receptors to detect infection (non-self). This is
done via associated molecular patterns: PAMPs, DAMPs and SAMPs. There are also
receptors for direct or indirect pathogen binding (via complement receptors), there are
also receptors for phagocytosis. Some of these receptors have intracellular signaling
molecules, which can trigger cytokine production (this is especially relevant for
macrophages).
DCs link the innate and adaptive immune systems. In the tissue, they are called immature DCs.
At that stage, they are fully prepared to phagocytose. If the molecule being phagocytosed is
pathogenic, their receptors will be activated → DCs will migrate and mature.
- They migrate to the LNs via the lymphatics. There, these mature DCs will activate naive
T cells. This interaction is based on the 3-signal paradigm:
1. Antigen presentation (pathogen-specific signal to a specific TCR, the following signals
are for clonal expansion).
2. Co-stimulation (important for signal activation and proliferation of naive T cells).
3. Cytokines/chemokines (needed for differentiation of different Th cell types).
CD8+ T cells proliferate if the antigen is presented on MHC class I (with the help of co-
stimulation or signal 2). Naive Th cells differentiate based on the cytokines secreted by DCs.
Th1 cells can activate macrophages and produce cytokines that help CD8+ T cells. Th2 cells are
needed for B cell activation and antibody production. Th17 cells activate neutrophils. T reg cells
are needed for immune suppression (late stages of infection). Thus: DCs determine what types
of cells/immune responses get activated. Note: only mature DCs activate naive T cells via the
3-signal paradigm. DCs mature only after their PRRs are activated due to infection → their
maturation state depends on what kind of receptors are stimulated by the pathogen → this will
determine what kind of adaptive immunity is activated.
- When DCs mature, their phagocytic capacity is reduced → when they phagocytose
enough of the pathogen, they will focus on presenting its antigen to the naive T cells
(together with the co-stimulatory molecules and cytokines). On the other hand,
macrophages keep phagocytosing.
Thus, after maturation, DCs stop phagocytosing but they enhance their antigen processing and
presentation abilities. Their MHC expression goes up, together with their costimulatory markers
and inflammatory cytokines. They improve their migration to the LN capacity.
Each DC can express different types of receptors:
1. Indirect pathogen binding (needs another factor to be present):
- Complement receptors: pathogen opsonization.
- Fc receptors: binding of antibodies.
2. Direct pathogen binding: based on the pattern recognition receptors (PRRs).
- C-type lectin receptors (CLR): DC-SIGN, langerin
- Toll-like receptors (TLRs)
2
, - RIG-1 like receptors
- NOD-like receptors
These receptors are essential for shaping the adaptive immune responses, as they can be used for
phagocytosis (leading to the 1st signal, antigen presentation → determines whether CD8+ or
CD4+ T cells will be activated). They can also be used for signaling to trigger co-stimulation
(2nd signal), which can lead to proliferation or activation/inhibition. The 3rd signal, cytokine
secretion, will also be stimulated, leading to Th cell differentiation.
Thus: the adaptive immune system activation and priming is dependent on DCs and their
receptors.
Fc receptors can activate or inhibit immune cells through the binding of immune complexes
(antibody + antigen via opsonization) → Fc tails of antibodies can activate different innate
immune cells. IgA production leads to neutrophil activation, IgE activates mast cells and
basophils, IgG binds to the Fc receptors expressed by macrophages. This leads to enhanced
phagocytosis and overall effectiveness. For adaptive immune cells, Fc receptors can modulate the
function of DCs in the tissue and LNs. They can inhibit naive B cell function, so that memory B
cells are activated instead when there is an infection.
C-type lectin receptors (CLR) are found on the DC surface and they can recognize different
pathogens. They bind to pathogens via the CRD (carbohydrate recognition domain) → they
are calcium dependent, and they recognise the specific pathogen carbohydrate structures. They
can internalise the antigen to enhance phagocytosis and present the antigen. They also help
DCs to adhere to T cells. There are also intracellular signaling motifs present → this influences
the maturation process of DCs and the handling of phagocytosed antigens → cross-presentation
and inflammation activation. This tailors the response for the pathogen (specific).
Toll-like receptors (TLR) are found in both the intra- and extracellular space (endosomes or
phagosomes). They are signaling receptors with intracellular signaling molecules → leads to
macrophage and DCs activation and to specific pro-inflammatory cytokine release by the DCs.
Different TLRs can recognize different types of pathogens via PAMPs: bacteria, fungi, protozoa,
genetic material of viruses or intracellular bacteria. Once they recognise a pathogen, they will
activate our innate immune cells via intracellular signalling mechanisms.
Key concept: DCs are essential for modulating the adaptive immunity via PRRs. Each pathogen
needs a specific response of the adaptive immune system.
→ TLRs and C-type lectin receptors are DC receptors that can directly bind pathogens to induce
intracellular signaling cascades.
3
, Part II: PRRs and tailored adaptive immunity
Depending on the pathogen and its ligands, many PRRs can be triggered, leading to tailored
immunity. Receptors expressed on the cell surface (TLRs and C-type lectin) recognize
extracellular pathogens, such as bacteria.
- Cytosolic receptors (NOD and RIG-like) in the cytoplasm recognize viral material or
bacterial products → they send out signals to the DC, so they know what kind of pathogen
there is.
- Endosomal receptors (TLRs) can recognize viruses, bacteria or other parasites that live
in the endosomes.
All PRRs have intracellular signaling motifs → activation of cells expressing the receptor and
transcription factors. They also lead to the secretion of different types of cytokines by
DCs/immune cells. There are 3 types of cytokine responses (don’t memorize):
1. Inflammatory or priming cytokines: produced via NFkB transcription. Examples: IL-
4, IL-6, IL-12, TNFa and TGFb. They are secreted by DCs depending on the type of
infection.
2. Type I Interferons (IFN): needed for when there is a viral infection and are produced by
IRF3/7 transcription. There is the production of IFNa and IFNb.
3. IL-1 family: produced when there is a cytosolic infection (by viruses, bacteria or fungi),
upon inflammasome activation → IL-1a, IL-B and IL-18.
TLRs expressed on the cell surface (recognizing extracellular pathogens) via PAMPs → once
bound to their ligands, they send out signals via MyD88 or TRIF → when these signaling
molecules are activated, they get phosphorylated and induce phosphorylation cascades
intracellularly.
Important: TLRs induce activation of NFkB (transcription factor), which gets transported
to the nucleus → production of (pro-)inflammatory cytokines. This is important for T cell
differentiation.
The production of certain types of cytokines depends on which PRR is activated on DCs.
Mature DCs provide signals 1 and 2 (antigen presentation and co-stimulation) to naive T cells.
Upon activation of TLRs, there is a 3rd signal → priming cytokines. These cytokines are
needed for the differentiation and proliferation of Th cells. These Th cells will also produce
different types of cytokines (inflammatory cytokines since they influence other immune cells
and tissues → adaptive immunity).
Important: Endosomal TLRs and RIG-like receptors are needed during viral infection → they
sense the cytoplasmic viral genetic material. This will lead to activation of their signaling
molecules (MyD88 or TRIF for TLRs and RIG-1 or MDA5 for RIG-receptors). RIG-like
receptors are TLR-independent → there could be many TLRs that simultaneously detect the
same virus → RIG-like receptors do not interact with on-going signals from TLRs.
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