T Cell Development: Generation Of Receptor Repertoire Diversity Flashcards
What are the events in lymphocyte development?
Commitment
Proliferation
Selection
Differentiation into distinct functional effector sub populations
What are the key factors in lymphocyte development?
Stem cell factors (c-KIT)
Cytokines (IL-7, IL-3)
Tissue specific signals (notch and thymic stromal cells)
What do multipotent HSCs give rise to?
B and T cell lineages
What happens in the pro-lymphocyte stage of T cell maturation?
Growth factor mediated commitment, proliferation and initiation of antigen receptor gene arrangement all happen
What happens in the prelymphocyte stage of T cell maturation?
Selection of cells that express pre-antigen receptors
What does the thymus contain?
A dense network of stromal (epithelial) cells and lymphocytes
Where do T cell progenitors develop?
In the bone marrow and migrate to the thymus
What happens to T cell progenitors in the thymus?
Positive and negative selection (selects for non-self recognising cells)
What causes the T cells to mature?
Notch signals sent from the thymic stroma
Where do mature T cells migrate to?
Peripheral lymphoid organs
Where do activated T cells migrate to?
The site of infection
How do notch signals cause maturation and proliferation of T cells?
- > induction of GATA3
- > commitment to the T cell lineage
- > intense proliferation
How long after the arrival of precursors in the thymus do the progenitors commit to the T cell lineage?
1 week
What do T cell progenitors express when they first arrive in the thymus?
CD2 and Thy1
Why are early developing T cells called double negatives?
No CD4 or CD8
What happens in the double negative stage?
Developing T cells rearrange the TCR locus
What happens to the T cell after the double negative stage?
Go double positive
Resting stage
Split into single positives before going into the periphery
What do T cells express if they’re successfully rearranged and selected?
High levels of TCR
What is a TCR made up of?
A heterodimer consisting of two transmembrane polypeptide chains covalently linked to each other by disulphide bonds
What are the two types of TCR?
Alpha-beta and gamma-delta
What does each TCR chain have?
One Ig-like N terminal variable domain and one Ig-like constant domain
A hydrophobic transmembrane region and a short signalling cytoplasmic region
What does CDR stand for?
Complementary determining regions
What forms the peptide-MHC binding site?
3 CDRs of the alpha chain and 3 of the beta chain
What brings the chains together in the C regions?
Cysteine residues
What are the features of antigens recognised by T cells?
Linear peptides
Cell associated antigens
CD4+ recognise cells from the extracellular pool
CD8+ recognise cells from the cytosolic pool
What do MHC-I molecules present?
Peptide antigens derived from pathogens that replicate inside the cell (viruses)
What do MHC-II molecules present?
Peptides from pathogens and antigens that are present outside the cell and taken up by endocytotic vesicles of phagocytic cells
What is the structure of MHC class II molecules?
Extracellular peptide binding cleft
Ig-like domain
Cytoplasmic tail
Conserved CD4 binding site
What are some features of MHCs?
Highly polymorphic and polygenic
How many peptides can one MHC bind at a time?
One
What do different peptides that bind to the same MHC share?
Structural features that promote binding
How many MHC-peptide complexes are needed to activate a T cell?
Very small number
Do MHC-I or II bind the longer peptides?
MHC-II
Where are MHC-Is expressed?
On all cells apart from erythrocytes
Where are MHC-II molecules expressed?
APCs
What is the pathway for antigen processing and presentation on a MHC-II?
Extracellular protein uptake
Processing of proteins in vesicles
Biosynthesis and transport of class II MHC molecules to endosomes in the golgi
Association of processed peptides with MHC-II molecules in vesicles
Expression of peptide-MHC complex on cell surface
How are TCRs rearranged?
First a D fragment is joined with a J fragment and then the V fragment is joined to the DJ fragment
What are some properties of the TCR?
Only one TCR form is expressed on each T cell
They clone to get daughter cells
TCR only has one antigen binding site
Are there D regions on alpha TCRs?
No
How are the T cell receptor gene segments arranged?
In a similar pattern to the Ig gene segments and are rearranged by the same enzymes
Where do the TCRs concentrate their diversity?
The third hypervariable region CDR3
What mediates the recombination events in the biosynthesis of TCR?
RAG 1 and 2 gene
What happens before biosynthesis of TCR?
Beta chain rearrangement
Why would TCR alpha be rearranged many times?
Until a productive rearrangement is achieved
What is junctional diversity?
Addition or removal of nucleotides creating new sequences at junctions
What is junctional diversity mediated by?
TdT - terminal deoxynucleotidyl transferase
Where (physically) do gene rearrangement checkpoints occur?
Within particular regions of the thymus
What is allelic exclusion?
Signalling through the pre-TCR supresses expression of the RAG genes, so no more rearrangement at this stage
What does allelic exclusion ensure?
Only one beta chain is expressed
What happens when a successful pre-TCR rearrangement is formed?
Further beta chain rearrangement is halted
Induce expression of CD4 and CD8
Initiates alpha chain rearrangement
