6 T-Lymphocytes And Antigen Recognition Flashcards
Q: Which immune system cells monitor what is happening inside cells?
A: T lymphocytes (regulatory)
Q: What main components make the T cell receptor? (2) Another subset? What else is present in all? role?
A: Has alpha and beta components which have short cytoplasmic tails
A small subset uses gamma and delta chains
There are charged residues in the transmembrane region of the alpha and beta chains that interact with oppositely charged residues in the transmembrane region of CD3 polypeptides
Q: What is CD3? Why is it important? Useful as? Tail type? length? contains?
A: CD3 polypeptides are a constant part of the TCR
- delivery of the signal to the T lymphocyte once the antigen has been recognised.
- useful as a marker because it is present on all T lymphocytes
They have much longer cytoplasmic tails that have motifs containing tyrosine residues
Q: What occurs to CD3 when TCR meets its antigen? (2)
A: PHOSPHORYLATION OF TYROSINE in the motifs occur -> This triggers several other chemical cascades
ITAM = Immunoreceptor Tyrosine-based Activation Motif
Q: What are the 2 major populations of T cells? What do they do? (3,2)
A: CD4 - antigen presented by MHC Class II - T helper cells (and reg)
Secretes cytokines
Recruit effector cells - activate macrophages
Help and activate CTL and B cell responses
CD8 - antigen presented by MHC Class I - Cytotoxic T Lymphocytes
Kill target cells
Induce apoptosis in target cells
Q: What are CD4 and CD8? role? important in? Key point.
A: CO-RECEPTORS WHICH BIND TO THE SIDE OF THE MHC MOLECULE and increase the avidity of T cell-target cell interaction and are important in signalling
THEY DO NOT BIND TO THE ANTIGEN PRESENTED BY THE MHC, TCR DOES THAT
Q: Describe the main 3 T cells subsets- their process of recognition of an antigen. Role?
A: ‘CD8+ T cell’ = CTL = cytotoxic T lymphocyte -> has CD8 co receptor and a TCR = T cell receptor
Viral infected cells have viral proteins which are processed and presented on MHC Class I for recognition by CD8+
TCR binds to the MHC and the CD8 binds to the side of the MHC
‘CD4+ Th1’ = T helper cells 1
Involved in inflammatory responses
Activates the macrophages so they can kill phagocytosed material
‘CD4+ Th2’ = T helper cells 2
Important in helping B cell response
It captures the antigen on the BCR and takes up the antigen
The antigen is processed an fragments are presented on the MHC Class II
Th2 binds and activates the B cell so it starts producing a response
Q: T cell progenitor cells are from? Begin as? Head to? Arrival they have? Process? (3) Result?
A: Progenitor cells move from the bone marrow to the thymus
They begin as immature thymocytes in the cortex
As they develop they move towards the medulla where they become mature thymocytes
When the precursors arrive at the thymus, they have NO TCR, CD4 or CD8 - there are no co-receptors or antigen specific receptors
1. Rearrangement of the gene segments takes place to form the antigen specific receptor In relation to the TCR: Beta chain is rearranged Alpha chain is rearranged Proper alpha-beta TCR is formed
- If it works thus far - it starts expressing both CD4 and CD8
- Final Selection Stage: You see which MHC molecule it recognises and dependent on this it ends up as either CD4+ or CD8+
Q: Describe alpha and beta chain rearrangement to form the TCR. How is diversity achieved?
A: germline DNA –recombination–> rearranged DNA -> mRNA -> protein (TCR) = occurs to both alpha and beta and comes together
Similar to how antibody diversity is generated but with different gene segments
Beta chain is rearranged FIRST
Beta chain has VDJ
Alpha chain is rearranged SECOND
Alpha chain has VJ
Diversity is achieved by randomly selecting from the gene segments available
Q: What are the 2 checkpoints during T lymphocyte maturation? 3 conclusions. 2 selection types.
A: 1- Pre TCR checkpoint- is the new beta chain functional?
Beta chain rearranges first
If functional it goes on to the next stage
If not, death by apoptosis
2- is the alpha beta TCR functional?/ dangerous?/autoreactive? (against own cells)
Does the TCR recognise self MHC?
If it doesn’t recognise the MHC then it is USELESS
If it binds too tightly to the MHC in the absence of antigen then it is DANGEROUS (NEGATIVE SELECTION= removes said cells that bind too strongly)
If you get something in between it is USEFUL (POSITIVE SELECTION= survival of cells whose TCR recognises self MHC
Q: What percentage of thymocytes survive selection?
A: 5
Q: What do T lymphocytes recognise? What receptor do they have? Where is the receptor derived? Where are they selected for usefulness? What are the 3 main subsets?
A: Recognise peptides presented on the cell surface by MHC molecules
Have an antigen specific receptor derived by rearrangement of gene segments during development in the thymus.
Are selected for usefulness in the thymus
Three Main Subsets:
CD4+ Th1
CD4+ Th2
CD8+ CTL
Q: What is the structure of MHC class I? Draw.
A: brackets below are domains
peptide binding region (alpha 1 and 2)
immunoglobin like region (beta2-microglobin and alpha 3)
transmembrane region
cytoplasmic region
Two Separate Chains: Alpha Chain (polymorphic) - Heavy and beta 2-microglobulin (same in everyone) - Light
The light chain (B2-microglobulin) associates NON-COVALENTLY with the alpha chain
Peptides bind between the alpha-1 and alpha-2 domains
NOTE: B2-microglobulin is NOT TRANSMEMBRANE
Q: What family are MHC a part of? Why?
A: Both domains are immunoglobulin like domains so MHC are part of the immunoglobulin superfamily
Q: What is the structure of MHC class II? Draw.
A: brackets below are domains
peptide binding region (alpha 1 and beta 1)
immunoglobin like region (alpha 2 and beta 2)
transmembrane region
cytoplasmic region
Similar in structure of MHC Class I
DIFFERENCE: There are two polypeptides of equal size which are BOTH transmembrane
There is an alpha chain and a beta chain which are equal in size
Peptide binds between alpha-1 and beta-1
Q: What type of peptide do MHC class I and II present?
A: MHC Class I presents peptides that are 8-10 amino acids long - SHORTER PEPTIDES
MHC Class II presents longer peptides (13+ amino acids) - LONGER PEPTIDES - Ends of the peptide often sticks out of the peptide binding site on the MHC
Q: How do peptides bind to MHC so that they can be presented? (2) Known as? Means that?
A: There are grooves within the MHC molecules where anchor residues from the polypeptide can bind to the MHC via binding pockets
Within the peptide there will be certain positions that are always more or less exactly the same amino acid.
This is known as a BINDING MOTIF - each MHC has a binding motif where certain positions tend to be particular amino acids and the other positions could be anything else.
This means that MHC presents a subset of peptides which have some things in common where characteristics are conserved
Q: How do MHC overcome the issue of having low diversity but needing to present a large number of different peptides?
A: They do this by having certain positions on the MHC that are relatively CONSERVED that anchor the peptide into BINDING POCKETS in the MHC.
Q: What is the HLA? AKA? Types? (2-3,3)
A: human leukocyte antigen
region on chromosome 6 that codes for the polypeptides that make up the MHC molecules
HLA = human MHC
Three types of Class I = A, B and C
Three types of Class II = DP, DQ and DR
Q: In class I MHC, what encodes the heavy chain and what encodes the B2-microglobulin?
A: only the heavy chain that is encoded within HLA - B2-microglobulin is encoded on a different chromosome
Q: Describe MHC gene expression. Which cells express the 2 types? Regulated by?
A: MHC is polygenic - there are several class I and class II loci
It is CODOMINANT - maternal and paternal genes are both expressed
MHC Class I - nearly ALL CELLS - expression varies during infection or by cytokines
MHC Class II - only on PROFESSIONAL APCs - regulated by cytokines
Q: Describe MHC polymorphism. What does it result in?
A: Highly polymorphic
MHC Haplotype - group of MHC alleles linked together on a single chromosome
We have two MHC haplotypes because we are diploid - we can have up to SIX different class I and class II molecules This variability means that we all have slightly different immune responsiveness to different infections - different susceptibility to different infections
Some haplotypes are more common than others - they are NOT randomly distributed
We all have different TCR repertoires and different combinations of MHC molecules
Q: What is MHC class II linked to?
A: Particular alleles of MHC Class II are linked with susceptibility to autoimmune disease
Q: Define exogenous. What presents these type of antigens? to?
A: antigens captured from outside (extracellular) e.g. via phagocytosis
Exogenous antigens are presented via MHC Class II to CD4 T cells
Q: Define endogenous. What presents these type of antigens? to?
A: antigens synthesised within cells (intracellular) e.g. virus
Endogenous antigens are presented via MHC Class I to CD8 T cells
Q: How are antigens presented via MHC Class I?
A: endogenous ones
There are viral proteins in the cytoplasm which are processed by a multisubunit proteolytic system - proteasome
The peptides then move into the ER via TAP (transporter associated with antigen processing)
Newly synthesised MHC Class I moves into the ER (it has a signal sequence) and associates with chaperone proteins which aids its folding
The class I heavy chain binds to the peptide and b2-microglobulin
Once all three are correctly folded, it can go via the golgi to the cell surface for possible recognition by CD8 positive T lymphocytes
Q: How are antigens presented via MHC Class II?
A: exogenous ones
Proteins are endocytosed and processed into peptides in endocytic vesicles
The class II molecules get into the ER (as they have signal sequences) -> Once in the ER it associates with INVARIANT CHAIN (invariant because it is always the same - it is not polymorphic)
Once they enter the endocytic pathway, the invariant chain is digested away
You end up with a small peptide fragment derived from the invariant chain bound to the MHC Class II known as the CLIP peptide (Class II Associated Invariant Chain Peptide)
Last Step - swapping the CLIP peptide for the antigenic peptide
The antigenic peptide is then loaded onto MHC Class II and moves to the cell surface for recognition by CD4 T lymphocytes
Q: What does the invariant chain do?
A: stops peptides that need to be loaded onto MHC Class I from being loaded onto Class II. It also has a targeting signal sequence so the molecules go to the endocytic pathway via golgi
in relation to how antigens presented via MHC Class II
Q: Compare and differentiate between antigen recognition by B and T lymphocytes and by CD4+ and CD8+ T lymphocytes.
A: B- direct recognition of intact, extracellular antigens T- recognition of processed (intracellular) antigens presented at the surface by MHC molecules only (specialised self molecules): class I to CD8+ and class II to CD4+ T cells
