T Cell Development: Generation Of Receptor Repertoire Diversity

Question 1

What are the events in lymphocyte development?

Answer 1

Commitment
Proliferation
Selection
Differentiation into distinct functional effector sub populations

Question 2

What are the key factors in lymphocyte development?

Answer 2

Stem cell factors (c-KIT)
Cytokines (IL-7, IL-3)
Tissue specific signals (notch and thymic stromal cells)

Question 3

What do multipotent HSCs give rise to?

Answer 3

B and T cell lineages

Question 4

What happens in the pro-lymphocyte stage of T cell maturation?

Answer 4

Growth factor mediated commitment, proliferation and initiation of antigen receptor gene arrangement all happen

Question 5

What happens in the prelymphocyte stage of T cell maturation?

Answer 5

Selection of cells that express pre-antigen receptors

Question 6

What does the thymus contain?

Answer 6

A dense network of stromal (epithelial) cells and lymphocytes

Question 7

Where do T cell progenitors develop?

Answer 7

In the bone marrow and migrate to the thymus

Question 8

What happens to T cell progenitors in the thymus?

Answer 8

Positive and negative selection (selects for non-self recognising cells)

Question 9

What causes the T cells to mature?

Answer 9

Notch signals sent from the thymic stroma

Question 10

Where do mature T cells migrate to?

Answer 10

Peripheral lymphoid organs

Question 11

Where do activated T cells migrate to?

Answer 11

The site of infection

Question 12

How do notch signals cause maturation and proliferation of T cells?

Answer 12

• > induction of GATA3
• > commitment to the T cell lineage
• > intense proliferation

Question 13

How long after the arrival of precursors in the thymus do the progenitors commit to the T cell lineage?

Answer 13

1 week

Question 14

What do T cell progenitors express when they first arrive in the thymus?

Answer 14

CD2 and Thy1

Question 15

Why are early developing T cells called double negatives?

Answer 15

No CD4 or CD8

Question 16

What happens in the double negative stage?

Answer 16

Developing T cells rearrange the TCR locus

Question 17

What happens to the T cell after the double negative stage?

Answer 17

Go double positive
Resting stage
Split into single positives before going into the periphery

Question 18

What do T cells express if they’re successfully rearranged and selected?

Answer 18

High levels of TCR

Question 19

What is a TCR made up of?

Answer 19

A heterodimer consisting of two transmembrane polypeptide chains covalently linked to each other by disulphide bonds

Question 20

What are the two types of TCR?

Answer 20

Alpha-beta and gamma-delta

Question 21

What does each TCR chain have?

Answer 21

One Ig-like N terminal variable domain and one Ig-like constant domain
A hydrophobic transmembrane region and a short signalling cytoplasmic region

Question 22

What does CDR stand for?

Answer 22

Complementary determining regions

Question 23

What forms the peptide-MHC binding site?

Answer 23

3 CDRs of the alpha chain and 3 of the beta chain

Question 24

What brings the chains together in the C regions?

Answer 24

Cysteine residues

Question 25

What are the features of antigens recognised by T cells?

Answer 25

Linear peptides Cell associated antigens CD4+ recognise cells from the extracellular pool CD8+ recognise cells from the cytosolic pool

Question 26

What do MHC-I molecules present?

Answer 26

Peptide antigens derived from pathogens that replicate inside the cell (viruses)

Question 27

What do MHC-II molecules present?

Answer 27

Peptides from pathogens and antigens that are present outside the cell and taken up by endocytotic vesicles of phagocytic cells

Question 28

What is the structure of MHC class II molecules?

Answer 28

Extracellular peptide binding cleft Ig-like domain Cytoplasmic tail Conserved CD4 binding site

Question 29

What are some features of MHCs?

Answer 29

Highly polymorphic and polygenic

Question 30

How many peptides can one MHC bind at a time?

Answer 30

One

Question 31

What do different peptides that bind to the same MHC share?

Answer 31

Structural features that promote binding

Question 32

How many MHC-peptide complexes are needed to activate a T cell?

Answer 32

Very small number

Question 33

Do MHC-I or II bind the longer peptides?

Answer 33

MHC-II

Question 34

Where are MHC-Is expressed?

Answer 34

On all cells apart from erythrocytes

Question 35

Where are MHC-II molecules expressed?

Answer 35

APCs

Question 36

What is the pathway for antigen processing and presentation on a MHC-II?

Answer 36

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

Question 37

How are TCRs rearranged?

Answer 37

First a D fragment is joined with a J fragment and then the V fragment is joined to the DJ fragment

Question 38

What are some properties of the TCR?

Answer 38

Only one TCR form is expressed on each T cell They clone to get daughter cells TCR only has one antigen binding site

Question 39

Are there D regions on alpha TCRs?

Answer 39

No

Question 40

How are the T cell receptor gene segments arranged?

Answer 40

In a similar pattern to the Ig gene segments and are rearranged by the same enzymes

Question 41

Where do the TCRs concentrate their diversity?

Answer 41

The third hypervariable region CDR3

Question 42

What mediates the recombination events in the biosynthesis of TCR?

Answer 42

RAG 1 and 2 gene

Question 43

What happens before biosynthesis of TCR?

Answer 43

Beta chain rearrangement

Question 44

Why would TCR alpha be rearranged many times?

Answer 44

Until a productive rearrangement is achieved

Question 45

What is junctional diversity?

Answer 45

Addition or removal of nucleotides creating new sequences at junctions

Question 46

What is junctional diversity mediated by?

Answer 46

TdT - terminal deoxynucleotidyl transferase

Question 47

Where (physically) do gene rearrangement checkpoints occur?

Answer 47

Within particular regions of the thymus

Question 48

What is allelic exclusion?

Answer 48

Signalling through the pre-TCR supresses expression of the RAG genes, so no more rearrangement at this stage

Question 49

What does allelic exclusion ensure?

Answer 49

Only one beta chain is expressed

Question 50

What happens when a successful pre-TCR rearrangement is formed?

Answer 50

Further beta chain rearrangement is halted Induce expression of CD4 and CD8 Initiates alpha chain rearrangement