MCB Lecture 48 Cooperative Immune Response Flashcards
What are the two different types of T lymphocyte?
T cytotoxic, CD8+
T helper, CD4+
Describe (and point out the differences) between antigen processing for MHC I and MHC II
MHC I: endogenous protein (synthesised inside the cell, may be viral DNA)
- MHC I synthesised in ER, protein degraded into peptide by proteosome and delivered via vesicle to ER
- Peptide binds to the cleft
- MHC I - pep exported to surface in a vesicle
MHC II: exogenous protein
- Protein endocytosed, and degraded into peptides by phagolysosome
- MHCII synthesised in ER
- Invariant chain binds in the cleft to prevent peptide binding there
- MHC II loaded into vesicle, which fuses with phagolysosome.
- Peptide loaded into MHC II cleft, invariant chain displaced
- Transported to the surface via a vesicle
Compare the different proteins found on T lymphocytes
CD8, binds to conserved alpha-3 of MHC I
Cd4, binds to conserved beta-2 of MHC II
Differentiate between the type of MHC that both types of lymphocyte interact with
CD8+: MHC I
CD4+: MHC II
What is the function of CD8+?
Bind to and kill cells that have been infected by a pathogen, or neoplasticism cells
What is the function of CD4+?
Help B cells and macrophages
Moderate immune response
Briefly describe the process of activation of lymphocytes
Naïve lymphocyte -> Effector cell
What is a dendritic cell?
It is a professional antigen presenting cell
What is the normal function of an APC?
How does it do this?
It samples the environment via:
Macro-pinocytosis
Mannose-R
FcR
The protein it takes in via this sampling is degraded and presented in MHC II
How are APCs activated?
- PAMP binds to PRR (Licensing)
2. Endocytosis of pathogen
Describe the steps involved in APC and T lymphocyte interaction
- APC undergoes licensing and expression of invader peptide in MHC
- APC moves to the lymph node via lymphatics
- Once in lymphatics, the peptide expressed in the MHC is recognised by TCR on T lymphocytes, activating them
Outline the post-Licensing maturation events of an APC
Increased MHC I and MHC II expression Stop sampling Migration to lymphoid tissue Expression of co-stimulatory and adhesion molecules Secretion of cytokines
What is licensing?
This is when an APC becomes active after binding a PAMP of an invading pathogen
What is signal one?
This is the binding of T lymphocyte and APC, via the TCR and MHC
What is signal 2?
APC cost insulate T cells, causing them to proliferate
What is signal 3?
This is release of cytokines onto T lymphocytes, causing them to differentiate
Outline the specific steps in APC - CD4+ interaction
- Adhesion: ICAM-1 + LFA-1
- Signal 1: MHC II-pep + TCR (CD4+)
- Signal 2: costimulation CD80, CD86 + CD28 –> proliferation
- Expression of CD40L by CD4+
- Autocrine signalling by CD4+: IL-2 and IL-2R
- Signal 3: cytokines released by APC stimulate CD4+ –> differentiation
How do APCs and CD4+ adhere to each other?
ICAM-1 and LFA-1
How do CD4+ perform autocrine signalling?
IL-2 and IL-2R
What causes the expression of CD40L on a CD4+?
What is the function of this molecule?
Co stimulation, interaction between APC and CD4+
This ligand then binds to CD40 on B cells, bringing about isotype switching
What is a super antigen?
What is the outcome when these occur?
This is an antigen that does not need to be specific for the alpha and beta parts of a TCR, instead, can bind directly to the MHC and TCR.
This results in a huge decrease in specificity, and up to 20% of T cells being activated at once
This huge immune response can have damaging effects on the body
Describe the outcome of cytokines signalling to CD4+ (Signal 3)
Differentiation of T helper cells: Eg. Th1: activate macrophages Th2: activate mast cells and eosinophils Tfh: aid B cell activation and proliferation Th17: recruit neutrophils Treg: regulation of "self-responses"
Describe how Cd4+ and B cells interact
- B cells are clonally selected by their complimentary antigen when in the lymph node
- Receptor mediated endocytosis of this antigen
- Presentation of peptide on MHC II
- T cell TCR binds to this antigen on MHC II
- Interaction between CD40 and CD40L –> isotype switching
- Cd4+ releases cytokines IL-4 and IL-5
How does a CD4+ recognise the B cell that it is going to ‘help’?
The B cell is presenting the antigen peptide in its MHC II with its BCR
What does ‘help’ from CD4+ result in for B cells?
Isotype switching Proliferation Increased antibody affinity Antibody secretion Memory
Outline how CD4+ help macrophages
- CD4+ becomes activated in the lymph node
- CD4+ returns to the infected tissue
- Here, it releases IFN-gamma
- IFN-gamma stimulates macrophages to undergo increased phagocytosis
Describe how CD8+ becomes activated
- Licensed APC moves to lymph node
- Co stimulatory molecules help CD8+ and APC interact
- MHC I - pep + TCR
- Activation and Proliferation of T cell
Once CD8+ is activated, what happens?
- Returns to the infected tissue
- TCR recognises epithelial cells presenting that antigen on their MHC I (eg. Virus inside has taken over the machinery and is making peptide)
- CTL releases granules: perforin and granzymes released
Perforin: puts holes in the epithelial cells -> lysis
Granzymes: induce apoptosis of the infected cells - Fas and Fas-L interact –> induction of apoptosis
Which molecules does Cd8+ release that kills cells? How does this happen?
Perforin –> lysis
Granzymes –> induction of apoptosis
What is the function of Fas and FasL?
Where are these located?
Fas and Fas-L are on the membrane of epithelial cells and CD8+
It causes apoptosis of the infected cell
List all the ways that a phagocyte can kill the bacterium once it is in the cell
- Acidic environment (pH 3-4)
- Competition: lactoferrin binds to the iron in the bacteria so it can’t function
- Enzymes: hydrolytic enzymes break down the structures
- Antimicrobial Peptides: cationic peptides, defensins
- Reactive oxygen species: superoxide, hydrogen peroxide
- Toxic nitrogen intermediates: Nitric oxide, NO
Describe how mycobacterium tuberculosis avoids intracellular killing
- Mycobacterium tuberculosis is taken up by alveolar macrophages
- Produces NH4 once in the phagosome to maintain pH around 6-7 (neutral)
- Inhibits the fusion of lysosomes with the phagosome by mycobacterium lipids in the cell wall
- Contains enzymes that neutralise reactive oxygen species
Now, it can survive and replicate
What does IL-2 autocrine signalling bring about?
Proliferation of the CD4+
Super antigens do not require … , unlike normal antigen
Processing
Once pathogens bind to the BCR bound to a B cell, what happens?
Receptor mediated endocytosis.
The pathogen is taken in, broken down and the antigen is presented on MHC II
How does a T helper cell interact with (bringing about activation) a macrophage back in the infected tissue?
The macrophage is displaying the antigen on its MHC II, which the T cell recognises with its TCR.
CD4+ releases IFN-gamma
