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M&I: Overview of Immune System + Lymphocyte Development and Differentiation > T Cell Development and Generation of Repertoire Diversity > Flashcards

T Cell Development and Generation of Repertoire Diversity Flashcards

1
Q

After the commitment stage (commitment to lymhoid lineage then commitment to T cell lineage) what is the next event in the development of the T cell?

A

Proliferation - there is vigorous proliferation of the precurrosors and at later stages (red circles)

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2
Q

After the stages of Commitment and Proliferation there is a {?} stage

A

Selection

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3
Q

What is meant by selection in the context of T cell hematopoiesis?

A

Towards the final stages there is selection by the type of T cell receptor they produce

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4
Q

What is an effector cell in the context of T cell hematopoiesis?

A

A mature cell that has finished maturation and can now perform a particular immune function

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5
Q

What are the roles of stem cell factors (c-KIT), cytokines (IL7 and IL3) and tissue specific signals such as notch in T cell hematopoiesis?

A
  • early maintenance of progenitors (c-KIT)
  • commitment to T cell lineage so common lymphoid progenitor → T cell progenitor (notch)
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6
Q

How is the development of ILC cells slightly different than that of αβ or γδ \T cells

A
  • They branch off from the T cell lineage earlier
  • ILCs = innat lymphoid cells
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7
Q

Describe the stages of T cell maturation (development)

A
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8
Q

At what point in the development (maturation) of a T cell or B cell is a receptor present?

A
  • At a pre-lymphocyte.
  • Note that this receptor changes!
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9
Q

Name the 3 major events in lymphocyte development regarding the formation of the receptor on a mature cell

A
  • (As a stem cell and pro-lymohocyte) Initiation of T/B cell receptor gene rearrangement
  • (As a pre-lymphocyte) Selection of cells that express a T/B cell pre-antigen receptor
  • (As an immature lymphocyte) Selection of repetoire and acquisition of functional confidence (selected for it to work and also to not detect self antigens)
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10
Q

Where do the 2 types of selection a T cell undergoes in development (maturation) happen?

A

Thymus

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11
Q

What is meant by late development and mature T cells being antigen dependent?

A

Their survival is dependant on self antigen (not exogenous antigens from infection)

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12
Q

Do T cell progenitors commit to the T cell lineage before or after migrating to the Thymus?

A

After (so in the thymus)

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13
Q

Name the 2 layers of the Thymus

A

Cortex and Medulla

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14
Q

Within the thymus, what cells are found mostly?

A

A dense network of stromal cells (mostly epithelial)
- many dark purple small lymphocytes

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15
Q

Which 2 places can lymphocytes begin their development?

A
  • Bone marrow
  • Foetal liver
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16
Q

{?} and {?} are released by {?} to induce committment to the T cell lineage

A

Notch 1 and GATA3 are released by the thymic stromal cells to induce committment to the T cell lineage

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17
Q

{?} is a transcription factor induced by Notch signals essential for T cell commitment and early T cell precurosors

A

GATA3 is a transcription factor induced by Notch signals essential for T cell commitment and early T cell precurosors

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18
Q

Why is it that even though there is many waves of T cells undergoing intense proliferation in the Thymus, it does not change size?

A

As around 98% of T cells die as once they commit to the T cell lineage and proliferate, they may fail the production of a T cell receptor or the T cell receptor fails selection (so would fail one of the 2 selections)

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19
Q

How do we define successive stages in T cell development (how do we work out what stage a cell is in)?

A
  • By the surface markers expressed/not expressed
    early markers of T cell lineage is CD2 with NO expression of later markers such as CD3/4/8
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20
Q

Why are developing T cells called DN (double negative)?

A

Because of the lack of CD4 and CD8 markers (but will express CD2)

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21
Q

What are thymocytes and what do they do?

A

Thymocytes = DN (double negative) stage T cell progenitors.

They rearrange their T cell locus

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22
Q

Describe the expression of CD4 and CD8 in late stage T cells in development

A
  • First are double negative
  • Then express both (double positives)
  • Then express one or the other
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23
Q

Name a mature T cell that is not positive for CD4 or CD8

A
  • gamma delta T cell
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24
Q

Name the 2 components of the T cell receptor

A

α chain and β chain

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25
Q

What holds together the 2 components of a TCR?

A 
Covalent bonds (disulphide bridges) 
- heterodimer
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26
Q

Name the 2 types of TCRs

A

2 types: Alpha-beta and Gamma-delta

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27
Q

Name the 2 domains on each of the components (so 4 in total) on a TCR

A

Each chain has one lg-like N terminal variable domain (V) and one lg-like constant domain (C), a hydrophobic transmembrane region and a short signaling cytoplasmic

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28
Q

Explain what complimentary determining regions (CDRs) are

A
  • These are in the V (variable) domains of both chains
  • Are regions stretches of amino acid sequence that is highly variable between receptors
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29
Q

How many CDRs does each TCR have in total?

A

TCR has 2 chains (alpha and beta)

  • each chain has one V (variable) domain
  • each V domain has 3 CDRs
  • so 6 in total
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30
Q

What do all of the CDRs together form on a TCR?

A

The peptide-MHC binding site

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31
Q

Compare the structure of TCR to Ig (immunoglobulin)

A
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32
Q

Which, Ig or TCR can bind soluble antigens?

A

ONLY Ig (TCR has to bind membrane bound antigens)

33
Q

What allows TCR to interact with other molecules/complexes? (Not what receptor, but what property of the TCR)

A

Charged amino acids in the transmembrane domain

34
Q

The TCR complex is formed by TCR interacting with {?} and {?}, these 2 accessory complexes allow for the transduction of signals upon MHC-peptide binding

A

The TCR complex is formed by TCR interacting with CD3 and ζ chain, these 2 accessory complexes allow for the transduction of signals upon MHC-peptide binding

35
Q

Most T cells recognise {?} and no other molecules

A

Most T cells recognise peptides and no other molecules

36
Q

Explain why TCRs recongise only membrane bound antigens and not soluble

A

Because they need MHC

37
Q

CD4+ T cells preferentially recognise antigens sampled from the {?} as opposed to CD8+ T cells that recognise antigens from the {?}

A

CD4+ T cells preferentially recognise antigens sampled from the extracellular space as opposed to CD8+ T cells that recognise antigens from the {intracellular (cytosolic) space

38
Q

TCR interacts both with the {?} and also {?} exteremly specifically

A

TCR interacts both with the antigen presented by MHC and also the MHC itself exteremly specifically

39
Q

Describe the difference between the antigens Presented by MHC class 1 and class 2

A
  • MHC class | 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.
40
Q

Describe the structure of MHC class 2

A

Has an alpha and a beta chain, each has 2 chains within it (alpha 1, alpha 2 …)
- Is similar to Ig

41
Q

MHC class 2 has a conserved binding site for {?}

A

MHC class 2 has a conserved binding site for CD4

42
Q

MHC class 1 has a conserved binding site for {?}

A

MHC class 1 has a conserved binding site for CD8

43
Q

MHC molecules are poly{?} and poly{?}

A

MHC molecules are polymorphic and polygenic

  • Polymorphic = Multiple genes/forms
  • Polygenic = A polygenic trait is one whose phenotype is influenced by more than one gene.
44
Q

Can MHC bind multiple peptides or only 1?

A

Can bind multiple, but this is all in one celft
- binds a group of structurally similar peptides

45
Q

Can MHC molecules bind and display foreign and self peptides or only one or the other?

A

Can bind and display BOTH self and foreign peptides

46
Q

MHC class 2 binds to {?} peptides than class 1

A

MHC class 2 binds to longer peptides than class 1

47
Q

All cells apart from {?} express MHC class 1, only {?} cells express MHC class 2

A

All cells apart from erythrocytes express MHC class 1

only antigen presenting cells express MHC class 2

48
Q

So if we know which cells (CD8/CD4) sample the intracellular or extracellular space, which cell will bind to MHC class {?} to bind a viral antigen

A

So if we know which cells (CD8/CD4) sample the intracellular or extracellular space, which cell will bind to MHC class 1 to bind a viral antigen

49
Q

Describe the whole process leading up to the presentation of an antigen by MHC2

A
50
Q

Explain what the different components are in the image below and what is meant by germ-line alpha/beta chain DNA?

A

Germ line ___ DNA: is simply the inherited DNA, so how the DNA is in the cell
V is variable region
J is joint region
C is constant region

51
Q

Explain overall how TCR rearrangement works with the help of the image below

A

There are many V fragments of DNA in the germ line that the cell can chose to make a V domain, also many J fragments.

  • First step is the cell joins a D fragment with a J fragment (what is a D fragment?) are chosen at random
  • second step is to join a V fragment with this DJ fragment
  • this will be joined to a C fragment to make a chain
52
Q

Does one T cell progenitor make one mature T cell? And do they all have the same TCR?

A
  • No, makes many
  • NOOOOO! Each mature T cell would have a different receptor
53
Q

Which of the two TCR chains has no D segments in the locus?

A

Alpha

54
Q

What chromosomes are the alpha and beta TCR chains on?

A

Alpha (and delta)- 14
Beta (and gamma) - 7

55
Q

T cell receptor gene segments are arranged into a similar pattern to Ig gene segments and are rearranged by the same enzymes: {?}

A

T cell receptor gene segments are arranged into a similar pattern to Ig gene segments and are rearranged by the same enzymes: Rag1 and Rag 2

56
Q

The most variable of the hypervariable regions in a TCR is CDR{?} (??)

A

The most variable of the hypervariable regions in a TCR is CDR3

57
Q

In the process of gene rearrangement in the biosynthesis of a TCR, what is meant by the checkpoint

A

This is a checkpoint where if there is successful rearrangement of the beta chain, then the alpha chain can be rearranged

58
Q

Which of the two chains, alpha or beta, in a TCR undergoes D-J joining?

A
  • Beta
  • Alpha undergoes V-J joining
59
Q

Is the biosynthesis of a TCR antigen dependant or independant?

A

Antigen independant

60
Q

Which chain on a TCR receptor does not have D segments in its gene?

A

α (but also γ?)

61
Q

Describe the 2 mechanisms that TCR receptors create diversity in their structure (not too sure about this)

A

TCR receptor diversity (localised mostly in CDRs) is achieved by the selection of different segments (gene rearrangement) but also by modification in the junctional areas between those segments
- He says that we do not need to know this mechanism of recombination super well as we will be taught it in B cell receptor formation which is basically the same

62
Q

Example of a formation of β chain of a TCR

A
63
Q

Which chain in a TCR (α or β) is rearranged first?

A

β

64
Q

{?} chain rearangement in a TCR can happen multiple times in order to pair a good α chain with a {?} chain.

A

α chain rearangement in a TCR can happen multiple times in order to pair a good α chain with a beta chain.

65
Q

Explain what junctional diversity is

A
  • This is a second way for the TCR to add specificitiy/diversity in its TCR as well as gene rearrangement.
  • Is where during the joining of different gene segments, addition or removal of nucleotides may create new sequences at junctions
66
Q

What enzyme mediates junctional diversity?

A

Mediated by TdT terminal deoxyneucleotidyl transferase

67
Q

Compare which TCR chains show the most variability and compare with Ig

A
68
Q

In total, does Ig or TCR αβ have more potential for diversity?

A

TCR αβ (has 1016 but Ig has 1011)

69
Q

Name the 2 T cell markers that we can use to further characterise double negative T cells into 4 distinct categories of DN1-DN4

A

CD44 and CD25

70
Q

DN1 (double negative 1) T cells {?} begun TCR rearrangment

A

DN1 (double negative 1) T cells have/have not begun TCR rearrangment

71
Q

Describe the characteristics of the TCR in DN2 and DN3 cells

A

Are both undergoing TCR gene Beta chain rearrangement
- alpha chain will come later

72
Q

Describe the status of development of the TCR at DN4 stage

A

These cells have undergone successful TCR rearrangment in the beta chain only (remeber that alpha chain comes later)

73
Q

When is the first major checkpoint in T cell development in the thymus? What does it check?

A

Just after TCR β chain gene rearrangement, the DN4 cells need to go through the checkpoint
- checkpoint tells the body that the cell has undergone successful gene rearrangement

74
Q

Describe the mechanism of the first checkpoint in the thymus (is to check for TCR gene rearrangement)

A

The DN4 cell will export the beta chain and a temporary alpha chain to its surface

75
Q

What is the name of the temprary alpha chain exported to the surface of a DN4 T cell when undergoing the first checkpoint in the thymus?

A

pre T α

76
Q

Describe what happens when the molecules are exported to the surface of a DN4 cell in the first checkpoint for T cell development in the thymus - Explain how T cells only form one TCR
- what is allelic exclusion?

A
  • When the temporary alpha chain and the beta chain (forming the pre-TCR?) are exported to the surface of the DN4, signalling suppresses the expression of RAG genes so there is no more rearrangement of the Beta chain so the T cell can only form one specific TCR (so this is how T cells have one specificity)
  • This is allelic exclusion
  • The alpha chain still needs to be re-arranged
77
Q

Describe the process of how the T cell triggers rearragement of the alpha chain

A

After successful signalling of a pre-TCR, this

  • halts further b chain rearrangements
  • induces expression of CD4 and CD8 (so is now double positive instead of double negative)
  • initiates alpha chain rearrangement
78
Q

So when (after what event) does the T cell become double positive?

A

After successful rearrangement of the β chain of the TCR

79
Q

Summary of TCR and T cell development

A

M&I: Overview of Immune System + Lymphocyte Development and Differentiation (6 decks)

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