Advanced molecular immunology and cell biology (AM_470656)
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Lecture 2. Dendritic cells in tailored adaptative immunity (AM_470656)
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Advanced molecular immunology and cell biology (AM_470656)
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Vrije Universiteit Amsterdam (VU)
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The Immune System
Lecture on dendritic cells, information on the role in the activation of the immune system, pattern recognition receptors and tailored immunity, and use in therapeutics and vaccines.
Lecture 9. The immune system in the brain (neuro-immunology) (AM_470656)
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Lecture 6. Immune deficiencies (AM_470656)
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Vrije Universiteit Amsterdam (VU)
Biomedical Sciences
Advanced molecular immunology and cell biology (AM_470656)
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Molecular Cell Biology and Immunology
Lecture 2. Dendritic cells in tailored adaptative immunity
INDEX
Part 1. Dendritic cells are important in activation of adaptive immune responses ..................................................................... 1
1.1. Pathogens and the immune system ........................................................................................................... 1
1.1.1. Cells of the IS ................................................................................................................................................................... 1
1.1.2. Three phases of the 1st time immune response .............................................................................................................. 1
1.2. complement system in the innate immune response .................................................................................. 2
1.3. history ...................................................................................................................................................... 2
1.4. Macrophages and dendritic cells ................................................................................................................ 2
1.5. the 3 signal paradigm ................................................................................................................................ 3
1.6. dendritic cells ............................................................................................................................................ 3
1.6.1. DC’s development ........................................................................................................................................................... 4
1.6.2. Receptors in DC ............................................................................................................................................................... 4
1.6.1. FC receptor ...................................................................................................................................................................... 5
1.6.2. C-type lectin receptors .................................................................................................................................................... 5
1.6.3. TLR ................................................................................................................................................................................... 6
PART 2. Patern recognition receptors (PRR) expressed by DC allow for sensing of infection and induction of tailored immunity 6
2.1. tailored adaptative immunity .................................................................................................................... 6
2.2. NF-κB ........................................................................................................................................................ 7
2.3. Cytokine production .................................................................................................................................. 7
2.4. Type I interferon ....................................................................................................................................... 8
2.4.1. production ....................................................................................................................................................................... 8
2.4.2. Type 1 interferon response ............................................................................................................................................. 8
2.5. nod-like receptors (NLR) ............................................................................................................................ 9
2.6. IL1 in the immune response ..................................................................................................................... 10
2.6.1. Function ......................................................................................................................................................................... 10
2.6. signal 1. Antigen presentation ................................................................................................................. 10
2.6.1. The role of TLR4 ............................................................................................................................................................. 11
2.6.2. Cross-talk of PRRs .......................................................................................................................................................... 11
PART 3. DC specific PRR can be targeted for (therapeutic) vaccination ..................................................................................... 12
3.1. Vaccine ................................................................................................................................................... 12
3.2. Anti-tumor vaccination ............................................................................................................................ 12
3.2.1. How can we choose a certain response? ...................................................................................................................... 13
3.2.2. How to make sure that response is the one being activated? ...................................................................................... 13
3.2.3. Targeting both cells ....................................................................................................................................................... 14
3.2.4. Challenges in anti-tumor vaccines ................................................................................................................................. 15
3.2.5. Vaccine formulation ...................................................................................................................................................... 15
3.2.6. Tumor immunology ....................................................................................................................................................... 15
,PART 1. DENDRITIC CELLS ARE IMPORTANT IN ACTIVATION OF ADAPTIVE IMMUNE RESPONSES
1.1. PATHOGENS AND THE IMMUNE SYSTEM
The immune system consists of multiple components together regulating health and disease.
DC are not the only in the IS, there are multiple components working to regulate the health. For one, the immune response has
to be activated when a pathogen enters. Also, the IS is important in day-to-day life. For example, when we have a wound
macrophages are important in the healing. In cancer, the IS is responsible for the malignant cells not to grow.
DC are important in the tissue specially, where there are a lot, and they scan the environment looking for pathogens. We have
different types of pathogens like viruses, bacteria and fungi. → They require different types of immune responses (CD8 in the case
of viruses, CD4 are good for extracellular bacteria). T cells know when to be active because of the DC cells, they play an important
part showing them.
1.1.1. CELLS OF THE IS
There are:
- Adaptative immune cells (B and T)
o In the first-time infection they are still naïve and they cannot get an
immune response and be activated.
- The innate response is necessary in the first-time infection (granulocytes,
macrophages, NK, dendritic cells) that are important to activate the adaptative
IS.
o Macrophages are the 1st at the infected site and start to ring the alarm
bell in case of bacteria (they make sure neutrophil are recruited) and
in the case of viruses (NK cells are recruited).
The lymphatic system is necessary for transportation of naïve T and B cells (that are also
in the blood circulation). Naïve T and B cells are in the blood and through the high endothelial venules enter the lymph node. They
go to the lymphatic organs to get trained and activated by the DCs. DCs enter the lymphatic system when they contact an antigen,
and they have to present it to the B and T cells.
1.1.2. THREE PHASES OF THE 1 S T TIME IMMUNE RESPONSE
The IR is divided in three phases in the first-time infection. There is a
difference when we get reinfected because we would have an adaptative
immune system thanks to the memory T and B cells. Like this, the 2nd
response is faster.
In the case of the 1st time infection:
- The pathogen comes in and breaches the barriers we have. As
soon as it is breached, the cells and molecules of the IS go into
play. → 1st Innate immunity gets activated within hours or
minutes.
o It is a non-specific recognition and it is very broad. The
immune cells cannot distinguish between organisms but
it can distinguish between harmful and non-harmful.
o The macrophages get activated and they start to come in
and secrete a lot ok cytokines and the complement
system gets activated.
- Cytokines and the complement system are activated. They act in
the clearance of the bacteria but not as specific as the adaptative
immune system.
o Sometimes it is enough to eliminate the pathogen.
1
, - Early induced innate response.
o It takes a bit longer than the previous.
o There is a response to PAMPs (Pathogen Associated Molecular Patterns), and it takes a bit longer.
▪ PAMPs tell which infection is ongoing (viral, bacterial, etc.).
▪ The DCs start to phagocytose but they need time to move to the lymphatic system and get to the
secondary lymphoid organs. → They are important to transport the pathogen to the secondary
lymphoid organs.
o Transport the antigen to the secondary lymphoid organs.
- When the antigen is presented, the adaptative immune response will begin. This is the later response.
o The DC take a few hours or days to be properly activated and migrate to the secondary lymphoid organs. Now,
they need time to activate the T and B cells. The expansion of the T cells also takes time.
1.2. COMPLEMENT SYSTEM IN THE INNATE IMMUNE RESPONSE
They are very important in the innate immune response.
Factor C3 can be cut into C3b and C3a.
- C3b opsonizes the pathogen and increase the
efficiency of phagocytosis.
- C3a is a smaller factor called anaphylatoxin and it
recruits leukocytes and phagocytes to make sure the
bacteria has cells surrounding them to clear it.
o It is called anaphylatoxin because besides
the leukocytes attraction, they have an
effect on endothelial cells making the
vascular wall more permeable so that other
factors like the complement can come in as
well as the monocytes and neutrophils.
It is also important that they also induce the formation of the C5 complex and later the membrane attach complex that forms
pores in the membrane of the bacteria that leads to lysis.
This is ongoing while the DC are moving to the secondary lymphoid organs in order to activate and present to the innate IS. They
enhance the effect of neutrophils and macrophages have on the pathogen.
(not very important for the exam)
1.3. HISTORY
DC were discovered by Ilya Ilyich Mechnikov and he say the innate immune cells
that had arms and thought they were neurons.
Later, they found out these cells were very equipped to phagocytose (something
neurons don’t do) and also they can encapsulate and destroy harmful bacteria.
He described that certain white cells in the blood work by “encapsulating and
destroying harmful bacteria and other microorganisms” → It was a very important discovery and he
got the novel prize in Physiology/Medicine in 1908.
1882: pointed to phagocytosis as one of the immune system’s ways of operating.
1.4. MACROPHAGES AN D DENDRITIC CELLS
The function of DC and macrophages is very different even though they can both phagocytose.
- Macrophages are in the tissue, and they have receptors to bind the pathogen.
o They are very important to start the inflammation response: vascular, becoming leaking, recruitment of other
cells.
2
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