Lecture 3 Flashcards
T cell receptor (TCR) genes:
- TCR polypeptides are also encoded by rearranging genes
- variable regions encoded by V, (D) & J segments
- gene segments rearrange during T cell development in the thymus
- mechanism similar to Ig gene rearrangement: similar recombination signal sequences and enzymes involved (explains some SCIDs)
Generation of diversity of TCR:
Similar mechanisms to that seen in BCR/Ig
• multiple V, (D) & J gene segments
• combinatorial diversity: between V, (D) & J
• junctional diversity
Difference between BCR and TCR
Unlike BCR however, TCR is never secreted
Additionally, unlike that seen in the generation of BCR/Ig diversity, no somatic hypermutation occurs in the TCR genes
TCR generation is very similar to the DNA rearrangement process seen in BCR/Ig generation
Remember TCR recognize Ag in groove of MHC molecules
MHC diversity
- no gene rearrangement occurs
- genes located within MHC (HLA in humans, on chromosome 6)
- co-dominantly expressed
- class I expressed by all nucleated cells
- class II expressed on particular cell types e.g. B cells, macrophages, dendritic cells (antigen presenting cells, APC)
up regulated and induced by interferon (inflammation)
Co-dominant expression of MHC molecules:
three MHC class I molecules (HLA-A, HLA-B and HLA-C)
if heterozygous at each loci, one person can express six different class I molecules
similarly, for class II (HLA-DP, HLA-DQ and HLA-DR)
What’s the reason for such high levels of MHC polymorphism?
• allows the binding of a vast range of peptides that can be presented to T cells - provides a clear evolutionary advantage to the population
• however, downside with highly polymorphic MHC increases risk of many immune-mediated diseases e.g. autoimmune diseases (i.e. presenting self-antigens)
makes selection of suitable donor organs for transplantation very complex and inefficient
BCR and TCR Summary
- huge diversity within an individual
- rearranging genes
- clonally distributed (i.e. each B/T cell has a unique BCR/TCR)
MHC class I and II Summary
- highly polymorphic (diverse at population level)
- individual has a limited number of different forms
- influence which peptides can be presented
List 2 similarities between BCR and TCR generation
Multiple V, D, and J gene segments. Combinatorial diversity between V, D, and J and junctional diversity
List 2 differences
TCR is never secreted unlike BCR.
No somatic hypermutation occurs in the TCR genes
What are the main structural differences between MHC class I and II molecules?
Class 1 expressed by all nucleated cells; class 2 expressed on particular cell type (B cells, macrophages, dendritic cells (APC))
Describe how polymorphisms seen in MHC affect their function
It allows the binding of a vast range of peptides that can be presented to T cells - provides a clear evolutionary advantage to the population
• Which gene segments encode the variable region of the TCRα chain?
V, J, C
What’s the reason for such high levels of MHC polymorphism?
allows the binding of a vast range of peptides that can be presented to T cells provides a clear evolutionary advantage to the population
How do peptides end up on the surface of cells bound to MHC molecules?
It depends:
peptides from protein Ag synthesized in the cytoplasm of a cell (endogenous antigens) are usually presented by class I MHC molecules: e.g. Ag from an intracellular pathogen e.g. a virus
peptides derived from exogenous Ag (taken up from the outside of the cell) are generally presented by class II MHC molecules:
e.g. Ag from an extracellular bacteria
in both cases, the protein Ags need to be processed into peptides that are capable of binding MHC molecules
Ag processing and presentation by MHC class I molecules:
1) Ag (e.g. viral protein) synthesised in cytoplasm
2) protein cleaved to peptides by proteasome
3) peptides transported to endoplasmic reticulum by TAP transporter
4) peptides bind to MHC class I molecules
5) MHC-I/peptide complex then transported to cell surface
proteasomes carry out functions in all cells
Cytoplasmic protein turnover
proteasomes in cells receiving inflammatory cytokines signals are modified to produce altered peptides
TAP is a component of a multi-protein assembly, the peptide loading complex
also includes tapasin and calreticulin
Antigen processing and presentation by MHC class II molecules:
1) Ag (e.g. bacteria) endocytosed into intracellular vesicles inside the cell
2) protein cleaved to peptides by acid proteases in vesicles
3) vesicles fuse with vesicles containing MHC class II molecules
4) peptides bind MHC class II molecules
5) MHC-II/peptide complex then transported inside vesicles to cell surface
Antigen processing and presentation by MHC class II molecules (cont.)
- MHC class II molecules bind to invariant chain in the ER
- this prevents peptides binding in the groove
- in endocytic pathway lysosomal enzymes degrade this leaving CLIP peptide associated with the binding groove
- peptides from antigen displace CLIP when they bind
- HLA-DM, a class II-like molecule, is required for loading of peptides into the groove
Important to remember…
…that in normal healthy uninfected cells, MHC class I and MHC class II molecules will bind and present peptides from self-proteins
Accessory molecules involved in antigen processing and presentation are also encoded within the MHC
TAP and LMP (class I pathway) HLA-DM (class II pathway)
Antigen presenting cells (APC):
• as all nucleated cells express MHC class I molecules, any cell infected by a virus can present viral peptides on MHC class I molecules and be recognised and killed by cytotoxic CD8+ T cells • only specialized cells express MHC class II molecules: these include “professional APC”
(e.g. macrophages, dendritic cells, B cells) which take up and present extracellular Ag to activate helper CD4+ T cells
