T cell development, Generation of receptor repertoire diversity Flashcards
What are the main events in lymphocyte development
- Commitment
- Proliferation
- Selection
- Differentiation into distinct functional effector subpopulations
What cell lineage gives rise to B and T cells
Haematopoetic stem cells
What are the stages of T cell development
- Stem cell
- Pro-lymphocyte
- Pre-lymphocyte
- Immature lymphocyte
- Mature lymphocyte
Describe the anatomy of the thymus gland
- Gland located above the heart
- Lobular organ
- Comprised of a cortex and a medulla
- Has a dense network of stromal cells and lymphocytes
Describe the journey of T cells through their development
- Common lymphoid progenitor becomes Pro-T with the help of Notch signals by thyme storm and Induction of GATA3
- Intense proliferation in the thymus
How can T cell lineages be identified
- Receptor identification by flow cytometry
- Split into 4 quadrants comparing CD8 and CD4 receptor expression
Describe the structure of a T-cell receptor
- Heterodimer consisting 3 transmembrane polypeptide chains linked by disulphide bridges
- 2 types - alpha beta, gamma delta
What structures are present to aid the function of the TCR
- The C regions have cysteine residues that bring the chains together
- Charged residues in the transmembrane region bind to CD3 and the zeta chain to form the TCR signalling complex
- CD3 and zeta allow for the transduction of signals upon MHC-peptide binding
Explain how TCR binds to MHC
- Peptides bind to MHC receptors
- T cells recognise linear peptides and are not conformational determinants of protein antigens
- T cells recognise cell associates and not soluble antigens
- CD4 and CD8 cells recognise different classes of MHC
What is MHC (major histocompatibility complex)
- MHC class I molecules present peptide antigens derived from pathogens that replicate inside the cell, such as viruses.
- MHC class II molecules present peptides from pathogens and antigens that are present outside the cell taken up by endocytic vesicles of phagocytic cells.
Describe the structure of MHC receptor
- Extracellular peptide binding cleft
- Ig-like domain
- Cytoplasmic tail
- MHC class II has a conserved CD4 binding site
- MHC class I has a conserved CD8 binding site
How do MHC molecules achieve very high polymorphic and polygenic rates
- There are multiple variants of each gene within the population
- Contains several different MHC class I and class II genes. Thus every individual possesses a set of MHC molecules with different ranges of peptide binding specificities
How does the polymorphic residue location affect MHC-peptide interactions
- Each MHC has one cleft that binds one peptide at the
time but can bind different peptides - Peptides that bind one MHC share structural features
that promote binding - Minimal number of MHC-peptide complexes can
activate a T cell - MHC molecules can bind and display foreign and self
peptide - MHC class II binds to longer peptides than class I
What cells express MHC class 1 and 2
- MHC class I. All cells but erythrocytes
- MHC class II. Antigen presenting cells
Describe the process by which peptides are presented on MHC II
- Uptake of extracellular proteins into vesicular compartments
- Process of internalised proteins in endosome
- Biosynthesis and transport of MHC II molecules to endosome
- Peptide association with MHC II
- Expression of peptide-MHC complex on cell surface
Describe the properties of the T-cell receptor
- Only one form of TCR is expressed in each T cell.
- This means that each T cell and its daughter cells have only one TCR and one specificity for antigen
- However, there are an infinite number of different versions of the TCR each with a unique antigen binding site.
- A TCR has only one antigen binding site.
- A TCR is never secreted.
How are TCR genes re-arranged to make the receptor
- The T-cell receptor gene segments are arranged in a similar pattern to immunoglobulin gene segments and are rearranged by the same enzymes; Rag 1 and Rag 2
- T-cell receptors concentrate diversity in the third hypervariable region CDR3.
Describe the biosynthesis pathway of the T-cell receptor (TCRbeta)
- Creates multiple variabilities with a small number of genes
- RAG 1 and 2 genes mediate the recombination events leading to rearrangement
- This process is antigen-independent
What are T cell receptor chains made from (Beta chain)
- Made from different gene segments
- VDJC genes segments
Describe the formation of TCR alpha
- They do not have the D gene
segments - They are rearranged only after the TCRβ chain gene locus has been rearranged.
- Successive rearrangements may be attempted until a productive rearrangement has been achieved
What are T cell receptor chains made from (Alpha chain)
VJC gene segments
What is the purpose of junctional diversity
To provide extra diversity when forming TCR chains
How does junctional diversity work
- During the joining of different gene segments, the addition (or removal) of nucleotides may create new sequences at junctions.
- Mediated by TdT terminal deoxynucleotidyl transferase
When does gene rearrangement occur in the thymus
- Gene rearrangement and checkpoints occur within particular regions of the thymus
What are the effects of signalling through the pre-TCR-allelic exclusion
- Suppression of the RAG genes
- No more rearrangement at this stage - Allelic exclusion
- Allelic exclusion ensures that only one TCRB chain is expressed
- These events together are known as B-selection
How does Alpha chain rearrangements occur
Successful signalling of a PreTCR:
- Halts further b-chain rearrangements
- Induces expression of CD4 and CD8
- Initiates alpha chain rearrangement
