Topic 5: T and B Cell Receptors, development and tolerance Flashcards
1
Q
What are the similarities between B and T cell receptors?
A
- Both contain a constant region
- Both contain a variable region
- Both contain invariant membrane proteins
2
Q
What are the differences between B and T cell receptors?
A
- The TCR is made up of 1 alpha chain and a 1 beta chain while the BCR is made up of 2 light chains and 2 heavy chains
- BCRs have 12 CDRs (3 per chain) whilst TCRs only have 6 CDRs
- TCRs have 1 antigen binding site while BCRs have 2
- TCRs are never secreted while some isotypes of BCR are
- The TCR has no effector function while BCRs do
- The TCR can only recognise antigen in the form of peptide displayed in the groove of MHC while BCRs can recognise the whole structure of antigens and bind to epitopes
3
Q
IgA:
- Structure:
- Location:
- Function:
- Secretion?
A
- Structure: monomer or secreted as a dimer (2 monomers joined by Fc regions by J chains with a secretory component
- Location: lumen of gastrointestinal and respiratory tracts (also in breast milk)
- Function: Mucosal immunity- neutralising antibody
- Can it be secreted? Yes
4
Q
IgM:
- Structure:
- Location:
- Function:
- Secretion?
A
- Structure: monomer on cell surface, secreted as a pentamer
- Location and function: B cell surface (acts as receptor) in all body fluids (classical complement activation pathway)
- Secretion? Yes
5
Q
IgG:
- Structure:
- Location:
- Function:
- Secretion?
A
- Structure: monomer
- Location: body fluids (also can cross placenta)
- Function: opsonisation of antigens, neutralisation of microbes and toxins, complement activation, very long halflife
- Secretion? Yes
6
Q
IgD:
- Structure:
- Location:
- Function:
- Secretion?
A
- Structure: membrane bound monomer
- Location: B cell surface
- Function: naive B cell antigen receptor
- Secretion? No
7
Q
IgE:
- Structure:
- Location:
- Function:
- Secretion?
A
- Structure: monomer
- Location: body fluids
- Function: defence against helminths, intermediate hypersensitivity reactions
- Secretion? Yes
8
Q
What common steps in early development do B and T cells share?
A
- Haematopoietic stem cells commit to being T or B cells
- Proliferation of progenitor cells
- Rearrangement and expression of antigen receptor genes (VDJ recombination and junctional diversity)
- Selection event to identify and expand lymphocytes with potentially useful
9
Q
What are the two mechanisms resulting in the diversity of antigen receptor binding sites?
A
- V(D)J recombination/combinatorial diversity: each antigen receptor can contain a number of different combination of V(D) and J segments which confers combinatorial diversity to the CDR1, CDR2 and CDR3 regions
- Junctional diversity: arises from the addition and subtraction of nucleotides at the points where the V and J regions (in light/alpha chains) and the V,D and J regions (in heavy/beta chains) come together. This section encodes CDR3 which means that CDR3 is the most variable
- This generates enormous diversity as it can induce frameshifts etc.
10
Q
How does junctional diversity occur?
A
- Exonucleases can remove nucleotides from V (D) and J gene segments at the sites of recombination
- Terminal deoxyribonucleotidyl tranferase (TdT) add nucleotides to V (D) and J segments at the site or recombinatinion
- Ligases join these segments
11
Q
How is a mature B cell made?
A
- Stem Cell: A haematopoietic stem cell becomes comitted to become a B-Cell and becomes a pro-B Cell
- Pro-B cell: Pro-B cell then proliferates with activation by Il-7
- The Pro-B cell recombines VDJ segments of the heavy chain variable region and this is joined to a µ constant region (giving the isotype IgM)
- A few of these rearranged IgM heavy chains will be combined with surrogate light chains and they will associate with invariant membrane proteins forming a pre-BCR complex on the cell surface
- If the pre-BCR complex is not expressed the cell will die by apoptosis- if it is expressed the cell will survive and proliferate into pre-B cells
- Pre-B cells: The pre-BCR complex triggers the cell to make a light chain via VJ recombination and prevents the successful heavy chain variable region from being altered
- The Pre-B cell will produce a kappa light chain (or if this is unsuccessful a lambda light chain) if the light chains associate with the heavy chain the complete antigen receptor will be expressed on the surface and the cell will survive and mature into a immature B cell (VDJ recombinase is shut off)
- Immature B Cell: a cell expressing the recombined antigen receptor with the heavy chain region µ (isotype IgM)
- The antigen receptor variable regions undergo alternative splicing with delta heavy chain regions producing IgD isotype receptors
- Mature B cell: expresses both IgM and IgD isotype receptors (required for naive B cell antigen recognition)
12
Q
How is a mature T cell made?
A
- Haematopoietic stem cells commits to becoming a T-Cell and develops into a pro-T cell (CD4- and CD8-)/a double negative T cell
- Pro T Cell: The TCR variable region genes will undergo VDJ recombination and if successful a beta chain will be produced.
- Pre T Cell: The beta chain is expressed on the cell surface with a pre-T alpha chain forming a pre-T complex which means the cell will recieve signals to survive and differentiate and produce an alpha chain by VJ combination
- Double positive T cell: if the alpha chain is produced successfully the cell will not die by apoptosis and the alpha chain will be expressed with the beta chain as the complete TCR along with both CD4 and CD8 markers (making the cell double positive)
- The double positive T cells undergo positive selection: to test whether the TCR can recognise MHC; and depending on which it binds more strongly will down regulate its expression of either CD4 or CD8 to beecome a single positive T cell
- The immature T cells also undergo negative selection because if the cell recognises and binds MHC too strongly it will be killed
13
Q
What are the processes and outcomes of positive selection/negative selection?
A
Double positive T cells undergo positive selection: to test whether the TCR can recognise MHC; there are 3 outcomes:
- if the TCR does not bind either MHC it will die by apoptosis
- if the TCR weakly binds MHC class II it will down regulate CD8 and become a CD4+ cell (positive selection as a T helper cell)
- if the TCR weakly binds MHC class I it will down regulate CD4 and become a CD8+ cell (positive selection as a cytotoxic T cell)
- If the cell strongly binds either MHC class too strongly it will die by apoptosis in a process called negative selection
14
Q
What is tolerance?
A
- The ability for immune cells to discriminate between self and non-self cells
15
Q
What is central tolerance? Where does it occur?
A
- Central tolerance is tolerance that occurs during development
- It involves the apoptosis of lymphocytes that have the potential to recognise self-antigen
- It occurs in the thymus (T cells) or in the bone marrow (B cells)
