IMI 5: Integration of Innate and Adaptive Branches of the Immune System Flashcards
1
Q
Observe the learning outcomes of this session
A
2
Q
What is another name for cellular immunity?
A
- cell-mediated immunity
- T-cell-mediated immune responses
3
Q
What type of pathogens are T-cell-mediated immune responses directed at?
A
- those that have survived the innate immune responses and need the orchestration of a stronger response
- those that replicate inside cells, away from antibodies, which circulate in the blood or are found in extracellular spaces
4
Q
Which two types of T-cells are the main players of cellular immunity?
A
- T helper cells (TH):
- express the CD4 co-receptor on their surface
- referred to as CD4+
- Cytotoxic T-cells or lymphocytes (CTL):
- express the CD8 co-receptor on their surface
- referred to as CD8+
5
Q
Define antigen
A
- An antigen is (usually) a foreign substance that binds specifically to the T cell receptor or to immunoglobulin
- As antigens stimulate an immune response they are often called immunogens.
6
Q
How do conventional T-cells recognise antigens?
A
- conventional T-cells can only recognise ntigens if they are presented to them in association with proteins known as the Major Histocompatibility Complex (MHC)
7
Q
Where are MHC proteins found?
What is the name for humans?
A
- MHC proteins are found in all higher vertebrates
- in humans, the complex is also called the Human Leukocyte Antigen (HLA) system
8
Q
What are the two classes of MHC involved in antigen presentation?
A
- MHC Class I
- MHC Class II
9
Q
Use this image to describe how different types of antigens are processed depending on their location
A
- endogenous pathway:
- antigens presented through MHC class I are normally derived from endogenous proteins,
- both normal or mutated proteins in the case of cancer cells or viral proteins
- These proteins are processed through the proteasome and loaded into MHC class I in the endoplasmic reticulum
- exogenous pathway:
- Exogenous antigens are normally processed in the phagosome, where digested peptides are loaded into MHC class II
- a subset of dendritic cells has the ability to divert exogenous antigens into the endogenous pathway and present exogenous antigens via MHC class I to cytotoxic T lymphocytes
- This step is fundamental for the activation of CTLs but the mechanism by which exogenous antigens are loaded on MHC class I has not yet been completely elucidated
10
Q
Antigens on which MHC class do cytotoxic T cells recognise?
Why?
A
- Cytotoxic T cells recognise antigens presented on MHC Class I complexes, which are present on all nucleated cells.
- The binding between the TCR and the MHC class I must be accompanied by the interaction of CD8 with the MHC Class I for proper antigen recognition.
- In fact, CD8 acts as a co-receptor of cytotoxic T cell’s TCR.
11
Q
Antigens on which MHC class do T-helper cells recognise?
A
- T-helper cells recognise antigens presented on MHC Class II complexes, which are found on professional antigen-presenting cells (APC) such as dendritic cells (DCs), macrophages and B cells
- CD4 interacts with MHC class II and acts as a co-receptor of the TCR on T helper cells in antigen recognition.
12
Q
How intertwined are the innate and adaptive branches of the immune system?
Describe the differences between appropriate and inappropriate interactions
A
- The innate and adaptive branches of the immune system are intricately intertwined
- They may be better visualised as two mutually supportive sub-systems, each providing information and assistance to the other.
- This provides a remarkable degree of flexibility and responsiveness, providing the best possible defence against an ever-changing world.
- Appropriate interactions between the innate and the adaptive immune systems lead to highly efficient recognition and clearance of pathogens or damaged cells, but inappropriate or unwanted interactions between them can result in harmful immunological responses including allergy, autoimmunity, and allograft (same species transplant) rejection.
13
Q
Which cells link the innate and adaptive immune responses?
A
- dendritic cells
14
Q
Describe the ways in which dendritic cells inform and activate the adaptive arm of the immune system
A
- Mature dendritic cells (DCs) phagocytose pathogens or fragments of it and degrade its proteins into small peptides in a process called antigen processing
- These peptides are then loaded onto MHC class II molecules, which then relocate to the DC membrane for antigen presentation. - Simultaneously, PRR signalling activates the DCs and they start upregulating cell-surface receptors that act as co-receptors for T cell activation (such as CD80, CD86 and CD40).
- DCs also upregulate chemotactic receptors, such as CCR7, that allow them to travel to secondary lymphoid organs where naïve T cells reside and where DCs act as antigen-presenting cells (APCs)
- The antigen presentation is the primary signal DCs send to T cells. - Co-receptors on DCs interact with ligands on T helper cells:
- an important example is CD80/86 binding to CD28 on T cells surface, shown in the figure below.
- This represents the secondary signal. - Finally, DCs secrete a diversified panel of cytokines that provide a tertiary signal
- These signals induce helper T cells differentiation into a specific subtype (i.e. Th1, Th2, Th17) which are specialised to mount the most appropriate response.
15
Q
Use this diagram to describe the three signals that activate a naive T-cell
A
- Although we often refer to 2 signals required to activate a naïve T cell, three can be considered
- Signal 1. The TCR/MHC-peptide interaction plus CD4 and CD8 co-receptors.
- Signal 2: Co-stimulation by additional proteins.
- Signal 3: Cytokines released from dendritic cells will result in T cells gene expression activation.
- T cells can also produce cytokines that act in an autocrine fashion for example, for promoting their proliferation.
16
Q
What are the two signals (at the very least) needed to activate T-cells?
A
- Recognition of an antigen loaded onto the MHC Class molecule by the TCR (Primary signal), called also T cells priming.
- Co-stimulatory signal (or secondary signal) provided by CD80/86 binding to CD28.
17
Q
Why does the activation of T cells need to be controlled?
A
- a response must be deployed when it is truly necessary
- once the target has been hit, the response must cease or the damage could have sustained collateral effects
18
Q
What signals do T-cells receive to ensure they are deployed only when needed?
A
- activating signals:
- e.g. those provided by co-stimulatory signals
- inhibitory signals
19
Q
Give an example of immune checkpoints for T-cells
A
- Alongside activating receptors such as CD28, T cells also express inhibitory receptors such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1)
- CTLA-4 competes with CD28 for binding the corresponding ligand CD80/86 on antigen-presenting cells.
- CTLA-4 (inhibitory) has a stronger affinity for CD80/86 and will compete effectively with activating receptor CD28.
- The engagement of CTLA-4 with CD80/86 will lead to T cells anergy.
- A similar effect is triggered by the interaction of inhibitory receptor PD-1 on T cells with its ligand programmed death 1/2 ligand (PD-L1/2) expressed on antigen-presenting cells.
- In fact, immune checkpoints can be hijacked by cancer cells to escape immunity by causing T cell anergy.
20
Q
What activates cytotoxic T-cells?
A
- dendritic cells
- In this case, the DCs are presenting antigen from the cytosol, for example from viral proteins, loaded onto MHC class I.
- CD28 is providing the second signal and cytokines such as IL-12 provides the third signal.
21
Q
Describe when exogenous antigens are presented on MHC class I
A
- There is also a possibility for exogenous antigens to be presented on MHC class I
- A subtype of dendritic cells (cDC1 where c stands for conventional) is specialised to divert some exogenous antigens into the MHC class I pathway, and activate cytotoxic T cells to pathogens that have been phagocytosed, as illustrated in the image below.
22
Q
Where in the body are T-cell activated?
Where do they go after?
A
- they are activated in the lymph node
- after activation, they leave and circulate to where there is an infection
23
Q
After T-cells are at the site of infection, what happens to them there?
A
- T-cells will receive another signal from their TCR from MHC expressing cells
- e.g. virus-infected and tumour cells
- they will start exerting their effector functions
24
Q
What are the functions of T helper (TH) cells?
A
- they promote or suppress the function of other cells of the immune system e.g.
- licencing dendritic cells to activate cytotoxic T-cells
- stimulate cytotoxic T-cells to kill infected target cells
- stimulation of B-cells to secrete antibodies
- stimulate macrophages to destroy the ingested microbes
25
Q
What determines the type of cytokine released and what effect they have on helper T cells?
A
- The image shows several types of pathogens PAMPs, including bacteria, fungi, viruses, parasites, binding to PRRs expressed by DCs
- The activation of a particular PRR, for example, a TLR, will result in the transcription of genes encoding for a specific cytokine.
- When DCs present the antigen to T cells in the lymph node they not only provide a sample of the pathogen antigen, but they are also providing extra information about the type of pathogen causing the infection by releasing specific cytokines.
- The type of cytokine released will determine how T helper cells will polarise (differentiate) and respond to the ongoing infection.
27
Q
Observe the complexity and versatility of T-helper cells effector functions
A
29
Q
Define antibody
A
- An antibody is a large, Y-shaped protein used by the immune system to neutralise pathogens.
- The antibody recognises a unique pathogen’s antigen, as shown in the following diagram.
39
Q
Observe this diagram of how cytotoxic T-lymphocytes recognise and destroy target cells
A
41
Q
Use this figure to review the main characteristic of the adaptive immune system
A
42
Q
What human diseases is the bacteria, Streptococcus pyogenes responsible for?
A
- scarlet fever
- strep throat
44
Q
What happens after our surface defences have failed to contain S. pyogenes infection?
A
- this internal invasion will cause the secretion of cytokines and chemokines from infected cells, thus initiating the process of inflammation
- Phagocytes (mostly neutrophils followed by monocytes/macrophages) will migrate to the area and attack the invading S. pyogenes
- -* S. pyogenes will start to secrete several proteins that are toxic to the phagocytes (such as pore-forming toxins leukocidins) but despite the resistance, many pathogens will be killed by your neutrophils and macrophages.
- Nonetheless, due to the slow rate of phagocytosis, bacteria will keep on proliferating.
- Your body will attempt to confine the infection by wrapping S. pyogenes in a fibrin clot, but streptokinase produced by the microbe will dissolve the clot, further advancing the infection.
- Your innate response was not sufficient to contain the bacteria attack!
45
Q
What happens after innate response has failed to contain S. pyogenes infection?
A
- the more the microbes proliferate, the more the neutrophils will penetrate the area.
- As neutrophils phagocytose bacteria, they will die and make up the pus that runs down the back of your throat.
- Macrophages and dendritic cells (DCs) will now start killing the bacteria and displaying on the cell membrane the pathogenic protein fragments that have been processed and coupled with the MHC Class II.
- Dendritic cells (DCs) will then move to the lymph node where they will present the bacterial antigens to T helper (TH) cells.
- Upon interaction of the MHC Class II complex with the TCR, costimulation and the cytokines that the DCs release the T cells will get activated.
- In the meantime, IL-1 and IL-6 production will cause an increase in your body temperature.
- Receptors on your B cells will begin to encounter antigens that flow in the lymph fluid from the infected area into the lymph node.
- Some of those antigens will be processed by B cells and presented on MHC Class II to T cells residing in the lymph nodes.
- Previously activated TH cells will recognise this antigen and secrete IL-1 beta, IL-4 and IL-5 that will stimulate B cells to multiply (a fraction of TH cells will remain as memory cells).
- As the numbers of B cells and APCs carrying antigen increase, a germinal centre will form, and the B cells will compete for binding to antigen.
- Only the B cells with the highest affinity for antigen will survive.
- TH cells will start secreting IL-2, IL-4 and IL-6 which will cause the differentiation of some of these B cells into plasma cells, while others remain to undergo more rounds of affinity selection.
- Mature plasma cells will migrate to the centre of the lymph node and begin secreting antibodies specific to the antigen.
- Antibodies will travel through the lymphatic system and enter into the bloodstream where eventually will come in contact with S. pyogenes.
- They will bind to and neutralise the toxins secreted by the microorganism, as shown in the following figure.
- Phagocytes will now rapidly engulf and kill S. pyogenes due to opsonisation by antibodies that bind to antigens on the surface of the bacterium.
- Entry into the phagocyte will be rapidly lethal for S. pyogenes.
- The end result of antibody production will be the rapid clearing of pathogens in the area of infection.
- Microbial numbers will begin to decrease rapidly and within a few days, the infection and its symptoms dissipate.
- As antigen diminishes, the B cells remaining in the germinal centre will leave, becoming long lived memory B cells.
46
Q
What is the initial response after viral infection?
A
- Imagine that a person is ill with the flu, sneezes in the room where you are.
- By breathing that contaminated air you can easily pick up droplets containing millions of flu viruses.
- Some of them then will make their way to the back of your throat.
- The low pH and the hostile environment created by the normal flora will inactivate most of the viruses.
- Those that will survive, will enter the throat epithelial cells by receptor-mediated endocytosis and will release genomic fragments of RNA into the cell as depicted in the next diagram.
- Up until this point, the immune system has no indication that anything is unusual.
- Infected cells synthesise viral proteins, which allow the virus to start replicating its genome.
- Like all other proteins synthesised in the cell, some of the viral proteins are degraded and the peptide fragments are transported to the cell surface in combination with MHC class I molecules.
48
Q
What is the adaptive response to viral infection?
A
- Secondary and tertiary signals will promote the differentiation of TH cells into TH1, most commonly induced by IL-12.
- TH1 cells begin to secrete IL-2 (promotes T cell proliferation) and IFN-γ (antiviral) for their effector functions.
- The T cells leave the lymph nodes and cytotoxic T lymphocytes (CTLs) detect infected cells presenting viral antigens on their MHC class I molecules and – upon recognition via MHC Class I-TCR interactions – start killing them.
- Most of these CTLs will be activated under the influence of the TH1 cells but a fraction of them remain as memory cells, which make them ready to attack during the next encounter!
- CTLs elicit a form of programmed cell death (apoptosis) in the target cell and also secrete cytokines like IFN-γ and tumour necrosis factor (TNF), which attract phagocytes and activate them to more efficiently kill infected cells, and clear the debris left behind by viral particle.
- Antigen collected by dendritic cells from virus-infected cells and taken to the germinal centre also stimulates B cells to expand, undergo affinity maturation, and differentiate into plasma cells, which can now secrete antibodies against viral antigens.
- As the virus infection is cleared, a fraction of the highest affinity B cells will remain as B memory cells.
50
Q
Learn the different steps and outcomes of TH cell activation
A
51
Q
Label the diagram
A
52
Q
What determines the polarisation of helper T-cells?
A
- the cytokine released by DC upon sensing
58
Q
What are the immunological synapses?
A
- the primary, secondary and tertiary signals are the immunological synapses
- The primary signal is represented by touch of the hands in the bottom panel cartoon, the secondary signal by the kiss and the tertiary signal by the hearts.
60
Q
Observe this table of the properties of major histocompatibility complex (MHC) molecules and genes
A
61
Q
Observe this diagram of the steps in the maturation and selection of MHC-restricted T lymphocytes
A
62
Q
Observe this table of the features of peptide binding to MHC molecules
A
