Describe the TCR
- Short cytoplasmic tail
- Alpha and beta components (minority have gamma and delta chains)
- Diversity in variable region comes from VDJ recombination
- TCR is member of Ig superfamily
- CD3 IS A CONSTANT PART OF THE TCR
What are the CD3 polypeptides?
DEGZ
Delta
Epsilon
Gamma
Zeta
What are CD3 important for?
Delivering signal to T lymphocyte once antigen is recognised
CD3 has much longer cytoplasmic tails
Useful as a marker - present on all T cells
What do CD3 tails have?
Motifs with Tyrosine residues
Charged residues of the transmembrane Alpha and beta chain interact with oppositely charged residues in the transmembrane residues of CD3
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What happens when the TCR meets its antigen?
Tyrosine phosphorylated
Triggers other chemical cascades
What is ITAM
Immunoreceptor Tyrosine-based Activation Motif
What are the 2 major populations of T cells?
CD4 - MHC Class 2
CD8 - MHC Class 1
What does binding of the co-receptors (CD4/8) to the relevant MHC achieve?
Increased avidity of T cell-target cell interaction
Important in signalling
What do CD4 - T helper cells do?
- Secrete cytokines
- Recruit effector cells - activate macrophages
- Help/activate CTL and B cell responses
What do CD8 - Cytotoxic T lymphocyte do?
- Kill target cells
2. Induce apoptosis in target cells
Where do CD4 / CD8 bind?
TO THE SIDE OF THE MHC MOLECULE.
TCR BINDS TO THE ANTIGEN PRESENTED BY THE MHC
CD8+ = viral infected cells and viral proteins. MHC CLASS 1.
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Describe CD4+ Th1.
- Activates inflammatory responses.
2. Activates macrophages
Describe CD4+ Th2.
- Important in B cell response activation
Captures antigen on BCR - takes up antigen.
Antigen processed. Fragments presented on MHC Class 2.
Th2 binds and activates B cell - initiates response.
Describe mature thymocyte production.
- Progenitor cells move from bone marrow to thymus (NO CO RECEPTORS OR ANTIGEN SPECIFIC RECEPTORS AT THIS POINT).
- Initially immature thymocytes in cortex
- As the immature thymocytes develop, they move to the medulla - become mature thymocytes.
What determines if the thymocyte becomes CD4+ OR CD8+?
Depending on the type of MHC they recognise.
CD4 - MHC 2
CD8 - MHC 1
Describe thymocyte development in relation to the TCR.
B chain rearranged.
A chain rearranged.
Proper alpha-beta TCR formed
Describe Alpha / Beta chain rearrangement in TCR.
- BETA chain rearranged first. (VDJ)
2. Alpha chain rearranged second (VJ)
Talk to me about selection of T lymphocytes.
Checkpoint 1
- is the new beta chain functional?
- YES = survival and development to CD4/8, a/b TCR
- NO = DEATH BY APOPTOSIS
Checkpoint 2
- Is the a/b TCR functional? Is it auto reactive?
- If useful then proceed
Checkpoint 3
- Does TCR recognise self-MHC?
- Not recognising MHC is useless
- If it binds too tightly to MHC without antigen, then it is dangerous
- Want something in between
ONLY 5% OF THYMOCYTES SURVIVE SELECTION
Whats special about thymus epithelial cells?
Express both types of MHC molecule
What are the most important genes in controlling graft rejection?
MHC
What is MHC?
- Group of tightly packed genes
2. Important in specific immune responses
Describe MHC Class 1 structure.
2 different chains, Alpha (HEAVY) and B2-microglobulin (light).
3x Alpha chains.
1x B2-microglobulin chain
Alpha is polymorphic but B2-microglobulin chain is the same in everyone
Light chain (B2-microglobulin) binds non-covalently with Alpha chain.
B2-microglobulin is NOT TRANSMEMBRANE
Describe MHC Class 2 structure.
2x Alpha chains
2x Beta chains
Peptides bind between a1 and b1.
Which MHC Molecule presents shorter chain peptides (8-10 aa long)
MHC Class 1
What length does MHC Class 2 present?
13+ aa (longer peptides)
Describe how peptides bind to MHC.
- MHC has binding pockets.
- In the peptide, certain positions tend to have the same amino acid,
- This is known as a binding motif, whereby certain positions are a particular aa, other positions can be anything else.
- So MHC presents a substantial of peptides with some things in common where characteristics are conserved.
What is HLA?
Human Leukocyte Antigen., on Chromosome 6
HLA genes encode polypeptides that make up MHC molecules.
HLA Class 1 has 3 types; A, B, C.
HLA Class 2 has 3 types; DP, DQ, DR
In class 1, only the heavy chain is encoded by the HLA. (B2-Microglobulin is encoded on a different chromosome)
We are diploid, so we can have upto 6 different class 1 and class 2 molecules.
HUMAN VERSION OF MHC
MHC is polygenic and co-dominant. What is meant by this?
- Several Class 1 and Class 2 loci.
2. Maternal and paternal genes both expressed
Which type of MHC is expressed in nearly all cells?
MHC Class 1
Expression varies during infection or cytokines
Which type of MHC is expressed only in professional APCs?
MHC Class 2
Regulated by cytokines
What is the most polymorphic gene in the human genome?
MHC
What causes different immune responsiveness to different infections?
MHC is polymorphic.
We have 2 MHC haplotypes (We are diploid)
Which MHC Class is linked to autoimmune diseases?
MHC Class 2
There are over 4200 HLA genes
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Are MHC haplotypes randomly distributed?
NO
Define exogenous
Captured from the outside (e.g. phagocytosis)
Define Endogenous
synthesised within cells (e.g. virus)
Which MHC class is endogenous?
MHC Class 1
Which MHC Class is exogenous?
MHC Class 2
How are endogenous antigens presented?
Via MHC Class 1 to CD8+ T cells
How are exogenous antigens presented?
Via MHC Class 2 to CD4+ T cells
Explain endogenous antigen presentation via MHC Class 1
- Viral proteins in cytoplasm are processed by proteasome
- Peptides move into ER via TAP (Transporter associated with Antigen Processing)
- Newly synthesised MHC Class 1 moves into ER
- MHC Associates with chaperone proteins which aids its folding
- Class 1 heavy chain binds with peptide and B2-microglobulin
- All chains correctly folded. Then goes via golgi to cell surface. Awaits possible recognition by CD8 positive T cells
Explain exogenous antigen presentation via MHC Class 2.
- Proteins endocytosed and processed - peptides now in endocytic vesicles.
- Class 2 molecules enter ER.
- In the ER, Class 2 associates with INVARIANT chain. (iNVARIANT because not polymorphic - binds to all MHC Class 2).
- Invariant chain has targeting signal sequence which triggers molecules to go to the Golgi
- Invariant chain is chopped up and a small fragment remains - CLIP peptide.
- Finally, CLIP peptide swapped for peptide derived from antigen.
- MHC Class 2 then moves to cell surface for CD4+ T cell recognition