T Cell Defelopment, Reeptor Repertoire Selection And CD4/CD8 Lineage Commitment

Question 1

Describe the journey of T cell maturation in the body?

Answer 1

1. Multi-potent lymphoid progenitors migrate from the bone marrow to the thymus
2. In the thymus, lymphoid progenitors differentiate to pre-T cells and are educated to differentiate self from non-self
3. Positively selected T cells emigrate from the thymus to mediate and effect the cognate immune response

Question 2

Describe the structure of the thymus

Answer 2

Capsule

Cortex
- cortical epithelial cells

medulla
= medullary epithelial cells

Hassails corpuscle

Question 3

What parts of the thymus are different developmental stages of thymocytes found?

Answer 3

Subcapsular reigon
- immature CD3,4,8
- double negative thymocytes

Cortex
- immature CD3,4,8
- double positive thymocytes

Cortico-medullary junction
- mature CD4,8
- positive and negative thymocytes

Question 4

What does CD stand for in CD4,CD8?

Answer 4

Cluster of differentiation

Question 5

What does MHC stand for?

Answer 5

Major histocompatibility complex

Question 6

How can we characterise cells in T cell development?

Answer 6

By using flow cytometry

CD4 - left
- top left is posative
- bottom left is double negative

CD8 in bottom right
- top right is double posative
- bottom left is dingle posatve

Question 7

When are gamma delta T cells favoured during development?

Answer 7

During early fetal development

Number reduces after 8 weeks gestation

Question 8

How is antigen recognition by gamma-delta T cells different from alpha-beta?

Answer 8

The cells bare specific receptor that end up in skin, gut uterus

Not MHC restricted

Antigen is recognised directly - mor like a antibody

In some cases can be unregulated under stress conditions

Play a role in cancer surveillance

Question 9

What proportion of generated T cells are alpha-beta?

Answer 9

90%

Question 10

What proportion of generated T cells are gamma-delta?

Answer 10

10%

Question 11

What does a DP thymocytes need to progress to the SP stage?

Answer 11

Functional TCR-alpha chain rearrangement

CD4 and MHC2 — to be CD4 postive cell

CB8, MHC 1 and TAP - to be CD8 positive cell

ERK signalling

Calcineurin signalling

Question 12

What percentage of cells fail to complete thymoyte maturation?

Answer 12

95%

Question 13

What fates await DP cell thymocyte?

Answer 13

Posative selection - become CD4 SP or become CD8 SP

Death by neglect

Negative selection

Question 14

Where are MHC1 genes expressed?

Answer 14

On thyme stromal els an low level on APC (DC and macrophages)

Question 15

Where are MHC2 gees expressed?

Answer 15

On thymic medullary stromal cells and high level on APC

Question 16

Describe what occurs during posative selection of DC

Answer 16

alpha-beta T cells bind to HLA molecules

If binding is strong enough the cell will be selected and allowed to continue development

Ensuring that only useful T cells that can engage in recognition are selected

Following adequate binding of CD4-MHC2, CD8 is down regulated and vice versa

The CD4 and CCD8 cells re ready for negative selection - unselected cells die by apoptosis

Question 17

Describe what cures during negative selection

Answer 17

If the binding to the TRA peptide is strong , then this could pose a problem for the host because t could become a elf destructive T cell.

Ensures self reactive cells re removed as they would cause autoimmunity

Determined based on affinity of TCR for presented self-peptide

This ensures that remaining T cells are only reactive too foreign peptides

Self reactive cells are not removed immediately but go through further TCR rearrangements - before they eventually re removed if still self reactive

Question 18

What is a problem for negative selection?

Answer 18

Thymus does not represent all self antigens

But it has a transcription activator gene which allows expression of other tissue specific proteins (apart from brain and testies) - promiscuous gene expression

This gene is called AIRE

This eliminates any self reactive T cells n

Question 19

What controls thymocyte selection?

Answer 19

Antigen presentation and MHC expression

Question 20

Wha happens to the T cells that remain in the thymus?

Answer 20

Express high levels of CD25 and foxp3

Do not proliferate in response to MHC sel-peptide complexes

Accumulate in the hassall corpuscle

Main role is t dampen T cell response

Question 21

What happens T cells that pass both positive and negative selection?

Answer 21

Become conventional T cells

They migrate to secondary lymphoid organs looking for their target antigen.

Then form a immunological synapse - lead to the activation nod proliferation of effector T cells

If they don’t find they’re target they eventually die by apoptosis