Cellular immunity and histocompatibility Flashcards
What do T cells do better than any other cells?
They are able to identity the difference between foreign and self antigens
Where do T cells arise from?
In the bone marrow
Where do these primary precursor T cells go to? What do they do there?
To the thymus gland
Undergo maturation
Where is the thymus?
Sits just above the heart
When is the thymus largest? Why does it change in size?
Largest at birth
When you are youngest is when the immune system needs the most maturation so as you get older it become smaller
What do the primary precursor T cells do once it gets to the thymus? What is this stage of development called?
It begins to express CD4+ and CD8+ antigens
Double positive T cell development
What is unique about the early T cell development?
It is the only time when BOTH CD4 and CD8 cells are produced
What is the T cell called when it is found in the thymus gland
Immature thymocyte
What does the immature thymocyte do in the thymus?
It migrates through the thymus
What does the migration of immature thymocyte cause it to do?
Causes it to come into contact with lots of other cells, in particular MHC (major histocompatibility complex) class I and II molecules
As the immature thymocyte comes into contact with other cells what does this cause it to do?
Causes it to decide if it will become a CD4+ or CD8+ cell (FYI + indicates cell and CD4 and CD8 are the antigens)
What is CD4+ referred to as? What does it do?
The helper population
Provide cytokines that drive type of immune response necessary for the type of pathogen
What are the functional subsets of CD4 helper T cells? What do they do?
Treg (T cell regulator) - produces cytokines that suppress immune response
Th1 - produce cytokines that promote cell-mediated immunity (lots of T cell reactivity, not much antibody production)
Th2 - produces cytokines that promote antibody mediated immunity (lots of antibody production, not much T cell production)
Th17 - produces cytokines that drive inflammation
When would Th1 be activated? Why this type?
During a viral infection
Need more cell mediated immunity to fight virus not antibodies
When would Th2 be activated? Why this type?
During a bacterial viral infection
Need more antibodies to fight bacterial infection not cell mediated immunity
What is the balance of Th1 and Th2 during an immune response called? Under what circumstances is a mixture of both used?
Polarised immune response
Pretty much always, it is very rare for just Th1 or 2 to be activated, normally a mix
What are Th17 associated with?
Autoimmune diseases
What is the CD8 population known as?
A cytotoxic T cell
What are CD8 cells filled with? What does this make them good at?
Filled with enzymes such as perforin and granzyme B
Very good at killing cells that are not normal
What is the thymus referred to as?
A primary lymphoid organ
What do T cells come from in the bone marrow?
Hematopoietic stem cells
What is the state of T cells in the thymus at an early age?
Why is this?
Dead or dying
They have been neglected as they have not responded appropriately to the antigens in the body
What happens to the T cells that survive in the thymus?
They ‘learn’ to recognise self MHC molecules in thymus tissue KEY SLIDE
What is the only thing that T cells recognise?
Changes in the MHC molecules
What do MHC molecules do?
They present antigens to the T cells
Which MHC molecules do CD4 and CD8 respond to?
CD4 responds to MHC class II, CD8 to MHC class I
What are the genes that code for MHC called in humans and mice?
Humans = HLA (Human leukocyte antigens)
Mice = H2 (2nd locus of histocompatibility)
What is a challenge when trying to fight viral infections for the immune system?
Viruses replicate inside the cells
What do cytotoxic T cells (CD8) recognise?
Only recognise MHC class I molecules
What do the cytotoxic cells do once a foreign antigen is recognised on a cell?
Release perforin which makes a pore into the cell then injects granzyme B which digests the cells
What does MHC restriction describe?
Describes how T cells must see two antigens at the same time for it to work: Foreign peptide antigen (non-self) and a MHC molecules (self)
What did experiments with congenic mice show about the immunes response to viral infection?
Mice that are genetically identical except for the genetic locus that control tissue rejection have T cells that do not respond to viral infection in the other mice’s tissue
What did the inbreeding of congenic mice demonstrate about CD8 cytotoxic T cells (CTL)?
Demonstrated that CLT are restricted by MHC and how viral immunity depended on MHC to present antigens
What are the two components to T cell immunity?
Self antigens are MHC
Non-self antigens come from viruses
What do HLA (human leukocyte cells) do?
Present peptide antigen to T cells
Where are HLA expressed?
On most cells in the body
How variable is the HLA molecule? What does this make this molecule?
It is highly variable
Makes them highly polymorphic
What are the molecules/genes that are expressed by Class I for HLA?
HLA A, HLA B and HLA C
What are the molecules/genes that are expressed by Class II for HLA?
HLA DR, HLA DP, HLA DQ
When the MHC is bonded to a self antigen, what is the affinity to its T cell? What is the T cells response?
Low affinity
No response
Where do Class I and II MHC molecules pick up antigens, what kind of pathogen do the detect then? What happens once the antigen is picked up?
Class I from inside the cells, Class II from outside the cell
Class I present to CD8, Class II present to CD4
Where do MHC class II molecules pick up non - self antigens?
goes through phagolysosome to pick up antigen from digested extracellular pathogens before being expressed on the cells
How do CD4 and CD8 initiate T cell signalling? What does this result in?
Through phosphorylation from their intracellular tyrosine kinases associated with their cytoplasmic tails
Causes phosphorylation cascade resulting in immune activation
Explain how CD4 is activated and what it does
1 - Extracellular pathogen (e.g. BACTERIA) are engulfed and broken down by components of the innate immune response (e.g. myeloid cell, macrophage etc.)
2 - MHC class II that is produced in the cell picks up bacterial antigens that are EXTRACELLULAR and present them onto the surface of the phagocytic cell
3 - CD4 cell, which has a TcR receptor that recognises combination of MHC class II and BACTERIAL antigen, binds to the cell surface and triggers help from other CD4 cells
4 - CD4 produce cytokines that HELP other cells such as initiating antibody production from B cells
What does AIDS stand for?
Acquired immune deficiency syndrome
What causes AIDS?
HIV virus
What does HIV target? What does HIV do to the CD4 cells? What happens to the CD4 count in someone with AIDS?
The CD4 receptor
Replicates inside the CD4 cells
It decreases to 0 over time
What does the reduction/elimination of CD4 cells do to the patient?
Makes them highly susceptible to pathogens which are normally treated very easily
Explain how CD8 is activated and what it does
1 - MHC class I picks ups INTRACELLULAR VIRAL antigens as they are synthesised
2 - MHC class I and VIRAL antigen are transported to the surface to the TcR on CD8
3 - CD8 then injects the cell CYTOTOXIC chemical perforin and granzyme B causing cell death
Why is it difficult to transplant tissue between two different people? Between what people is it very easy?
The MHC between two people are different, this means the T cells from the host recognise the MHC antigens on the donor tissue as foreign resulting in immune response
Identical twins share the same MHC so tissue transplantation is very easy
The variation of MHC can make it be described as….
…. polymorphic –> occurring in many different forms
What makes MHC polymorphic?
The three class I and three class II molecules are expressed co-dominantely by maternal and paternal genes resulting in 12 seperate polymorphic MHC molecules + there are hundred of different variation for each MHC gene locus = every person (except identical twins) has unique MHC (major histocompatibility complex FYI)
What is easier to transplant, internal organs or skin tissue? Why?
Organs because skin tissue has many antigen presenting cells that mount a very strong host vs grafted tissue response
How can the T cells in the donor tissue impact a transplant? What is this called?
T cells also mount a response against host
Called GVH (graft vs host)
What must people who receive a transplant take for their rest of their lives? What does it do?
Immunosuppressive drug, cyclosporine
Suppresses immune response
Why is MHC polymorphic?
Different populations experience different types of pathogens so develop different MHC to battle pathogens
Also it provides greater population protection as there is a greater statistical chance that some individuals have immunity
What are two major consequence of MHC polymorphism?
1 - Tissue transplantation is difficult except in identical twins (requires careful matching and immunosuppressive drugs (FYI))
2 - MHC polymorphic are strongly linked kWh susceptibility to many autoimmune disease
Why is MHC polymorphism strongly linked with autoimmune diseases?
It is the only polymorphic locus in the genome resulting in many variations some which causes diseases
What do these faulty MHC polymorphic molecules do to create autoimmune diseases?
MHC are presenting self antigens to T cells initiating an immune response against the body
