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SEMESTER 4 - M&I > L15 - T-cells: Generation of Receptor Repertoire Diversity > Flashcards

L15 - T-cells: Generation of Receptor Repertoire Diversity Flashcards

1
Q

Describe the stages of T-lymphocyte development?

A

COMMITMENT:
Multipotent progenitor become comitted precursors (pro- tcell)

PROLIFERATION:
Pro-tcells proliferate into pre-tcells

SELECTION:
t cells are selected for the type of receptor they express/produce

DIFFERENTIATION:
Differentiation into distinct functional effector subpopulations

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2
Q

What are the key factors that determine the process of lymphocyte development?

A

Stem cell factors (c-KIT)

Cytokines (IL-7 and IL-3)

Tissue specific signals (notch and thymic stromal cells)

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3
Q

Describe the different anatomic sites the T-cells pass through and the stages that they are at?

A

stem cells and pro-lymphocyte = bone marrow

pre-lymphocyte to immature lymphocyte = thymus

mature lymphocyte = peripheral lymphoid organs and tissue

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4
Q

Where do lymphocytes commit to the T-cell lineage?

A

In the Thymus

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5
Q

Describe the histology of the Thymus?

A

Cortex is the edge and medulla is within the cortex.

There is a dense network of stromal cells (specificlly epithelial cells) and T-lymphocytes

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6
Q

Describe the journey of t-cells through development

A
  • T-cell progenitors develop in the bone marrow and migrate to the thymus:

T-cell precursors rearrange its T cells receptor genes in the thymus

  • Positive and negative selection in the thymus:

Immature T-cells that recognise self-MHC recieve signals for survival. Those that interact strongly with self antigen are removed form the repertoire.

  • Mature T-cells migrate to the peripheral lymphoid organs:

Mature T-cells encounter foreign antigens in the peripheral lymphoid organ and are activated

  • Activated T-cells migrate to sites of infection:

Activated T-cells proliferate and eliminate the infection

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7
Q

Describe how the key factors play a role in T-cell development?

A

Notch signals from the thymic stroma - cells commit to the t- cell lineage and differentiate into early precursers

This induces transcription factor GATA3 which causes commitment to lineage

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8
Q

How long after entering Thymus, do T-cells commit to the lineage?

A

1 week after arrival of precursors into the thymus progenitors commit to the T cell lineage

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9
Q

What early markers are expressed on T cells?

A

(CD2 and Thy1)

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10
Q

What is the absence of CD8 and CD4 marker on T-cells called?

A

DN (double negatives)

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11
Q

What are developing T-cells called?

A

Thymocytes

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12
Q

How do we know T-cells are post DN stage?

A

They express both CD4 and CD8 and later just one or the other

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13
Q

Describe what the T cell receptor consists of?

A

T cells express high levels of TCR

TCR is a heterodimer consisting of two transmembrane polypeptide chains covelantly linked to each other by disulphide bonds

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14
Q

What are the two types of T- cell receptors?

A

One receptor has alpha-beta chains, and the other has gamma-delta chains

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15
Q

Describe what each chain on the T-cell receptor consists of?

A

has one Ig-like N terminal variable domain (V) and one Ig-like constant domain (C), a hydrophobic transmembrane region and a short signalling cytoplasmic region.

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16
Q

What do the Variable regions of the chains contain?

A

both contain short stretches of amino acids sequences that is highly variable between receptors.

These regions form the complementary determining regions. The 3 CDRS from alpha chain and the 3 from the beta chain form the peptide MHC binding site

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17
Q

Describe the other components of the membrane that help TCR?

A

charged amino acids allow the receptor to interact with accessory molecules like CD3.

Zeta chain also interacts with the TCR

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18
Q

How are other components bought together in the TCR complex.

A

The constant regions have cysteines residues that bring the chains together.

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19
Q

What is the entire structure of TCR, Zeta chain and CD3 together called?

A

TCR Signalling complex

20
Q

What is the function of CD3 and Zeta chain in the TCR complex?

A

Allow for the transduction of signals upon MHC- peptide binding

21
Q

What is an MHC and how many classes?

A

Major Histocopatibility Complex

MHC Class 1 and MHC Class 2

22
Q

What is a HLA?

A

• HLA Human Leukocyte Antigen

23
Q

What are MHC Class 1 Molecules?

A

MHC class I molecules present peptide
antigens derived from pathogens that
replicate inside the cell, such as viruses.

24
Q

What are MHC Class 2 Molecules?

A

MHC class II molecules present peptides from
pathogens and antigens that are present
outside the cell taken up by endocytic vesicles
of phagocytic cells.

25
Q

Why are MHC described as Polymorphic?

A

The MHC is highly polymorphic. There are multiple variants of each gene
within the population.

26
Q

Why are MHC described as Polygenic?

A 
The MHC is polygenic, it 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
27
Q

Describe the structure of MHC?

A

Has 1 extracellular peptide binding cleft

Ig like domain

Cytoplasmic tail

28
Q

Which binding site does MHC Class 2 have?

A

CD4 binding site

29
Q

Which binding site does MHC Class 1 have?

A

CD8 binding site

30
Q

Do MHC 2 or MHC 1 peptides bind to longer peptides?

A

MHC class 2

31
Q

What types of peptides can MHC molecules bind to?

A

they can bind and display foreign and self peptides

32
Q

Describe what cells express MHC class 1 and MHC class 2?

A

MHC Class 1 = all cells but erythrocytes

MHC Class 2 = Antigen presenting cells

33
Q

Describe the pathway of antigen processing and presentation on top of MHC Class 2?

A
  • Uptake of Extracellular protein antigens into vesicular compartments of APC
  • Proccessing of internalise proteins in lysosomal vesicles
  • APC Cell assembles MHC class 2 molecule.
  • Transport of class 2 MHC molecules to lysosome with antigen
  • Association of processed peptides with class 2 MHC molecules in vesicles
  • Export of vesicle and expression of peptide MHC complexes on cell surface
34
Q

How is the variable part of the chain formed?

A

composed of sequences chosen from a group of sequences that are encoded in the germ line

35
Q

By which order is the Rearranged B chain DNA formed from the germ line

A

A D fragment is joined with a J fragment, and it then adds a V fragment to the DJ Fragment

36
Q

Describe the properties of TCR on each T-cell?

A

only 1 form of TCR is expressed on each T-cell. When it prolifertaes, its daughter cells have only 1 TCR and specificity for antigen.

37
Q

What enzymes are T-cells receptor genes rearranged by?

A

Rag 1 and Rag 2

38
Q

Where do T-cells concentrate diversity?

A

in the 3rd Hyper-variable region called CDR3

39
Q

How are alpha-beta and gamma-delta T-cell receptors generated?

A

both by gene rearrangement

40
Q

Describe the TCR alpha chain gene rearrangement?

A
  • doesn’t have a D gene segment
  • They are arranged after the B-chain gene locus rearrangement
  • Successive rearrangements may be attempted until a productive rearrangement has been achieved (one that works with the Beta chain)
41
Q

How does the T-cell add extra diversity and what is it called?

A

Called Junctional Diversity

  • during the joining of different gene segments, addition or removal of nucleotides may create new sequences at junctions
42
Q

How is Junctional Diversity mediated?

A

TdT terminal Deoxynucleotidyl Transferase

43
Q

Where does Gene rearrangement of TCR take place?

A

Takes place in the Cortex of the Thyymus

44
Q

What do CD4- CD8- double negative cells express?

A

They both express CD44 and CD25

45
Q

Describe the 4 stages of CD44/CD25 expression?

A

DN1:
TCR germline - no rearrangment (high esoression of CD44, low expression of CD25.

DN2 AND DN3:
Rearrangment of Beta locus

DN4:
Successful beta arrangment and pre-TCR

46
Q

What happens after successful beta chain rearrangment?

A

It signals to the surrounding stromal thymus cells.

It sends the beta chain to the surface, with a surrogate chain (it mimicks the alpha chain).

 Signalling through the pre-TCR
suppresses expression of the
RAG genes.

 So, no more rearrangement at
this stage, this is allelic
exclusion.

 Allelic exclusion ensures that
only one TCRβ chain gene is
expressed.

 These events together are
known as β-selection

47
Q

What are the key points that suggest the successful signalling of a pre TCR?

A

Successful signaling of a PreTCR:
• Halts further b chain rearrangements

  • Induces expression of CD4 and CD8
  • Initiates alpha chain rearrangement

SEMESTER 4 - M&I (29 decks)

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