Dev of T-cells

Question 1

Major site of T-cell dev

Answer 1

Thymus

-Occurs in ordered process via several CHECKPOINTS

Question 2

What checkpoints?

Answer 2

• Gene rearrangements generate a multitude of TCR
• In thymus T-cells become MHC-restricted and lineage committed
• Selection occurs at several stages
• -Positive
• -Negative

Question 3

What do each of us have?

Answer 3

A self-restricted TCR repertoire

–out T-cells recognize OWN self, but not necessarily others

Question 4

MHC restriction primer

Answer 4

T-cells recognize peptides derived from self/foreign Ags ONLY when bound to self MHC molecules

Question 5

MHC restriction?

Answer 5

T-cells recognize context - T-cell will recognize Ag only when bound to self MHC molecule

Question 6

What MHC do CD4+ and CD8+ recognize?

Answer 6

CD4+ = MHC class 2
CD8+ = MHC class 1

Question 7

What is the importance of thymus?

Answer 7

T-cell development

without it individuals are immunodeficient

Question 8

Parts of thymus

Answer 8

Cortex - densely packed
Medulla - loosely packed
Cortical-medullary junction - separates cortex from medulla

Question 9

How does T-cell move in thymus as developes

Answer 9

Cortex–>Medulla

Question 10

What occurs to function of thymus as increase in age?

Answer 10

Function declines

Question 11

What is the migration to and from thymus?

Answer 11

• T-cell precursors travel from BM to thymus for dev

- Mature T-cells leave thymus and travel to 2ndary lymphoid tissues

Question 12

Immigration and Emigration

Answer 12

• T-cell precursors (prothymocytes) derived from fetal liver and BM seed in thymus
• Thymus produces chemotatic factors to attract T-cell progenitors
• Cells that seed the thymus enter the cortico-medullary junction, via blood vessels
• Thymocytes that survive rigorous selection leave thymus

Question 13

What controls the migration process?

Answer 13

1. Chemokines

2. Sphigosine 1-phosphate receptors

Question 14

How is flow cytometry used to ID stages of TC dev?

Answer 14

By markers present on T-cell

Question 15

What are the 2 major classes of T-cells?

Answer 15

**alpha-beta

gamma-delta

Question 16

Lineage commitment

Answer 16

• All start as CD34+ uncommitted progenitor (DN)
• Then either go Alpha-Beta or Gamma-Delta based on gene rearrangement of beta,gamma,delta (uncommitted DP)
• If commits to beta, allows alpha chain to rearrange (committed)

Question 17

How do lineage choices occur?

Answer 17

TCR gene rearrangements

• depends on which of B,G,D are rearranged
• ->If beta–>Alpha beta – PRE-TCR
• ->if G andD –> Gamma delta

Question 18

How does pre-TCR know it works?

Answer 18

Pre-T-cell (mimics alpha chain) and interacts w/ beta chain to see if it workds
-if doesn’t - will undergo further rearrangement

Question 19

If don’t succeed at working TCR what happens?

Answer 19

Two attempts can be made to achieve a productive rearrangement of the Beta chain

Question 20

What if still not functional after rearrangement of Beta chain?

Answer 20

The alpha chain can sustain attempts at a functional rearrangement

Question 21

What occurs as a result of alpha chain rearrangement?

Answer 21

Eliminates delta chain locus

–>Now can’t go back to gamma-delta unit

Question 22

How do T-cells know self from non-self

Answer 22

Through + and - selection

Question 23

Positive selection

Answer 23

DP thymocytes recognize MHC in epithelial cells and undergo further dev
-MHC class 1 –>CD8
-MHC class 2–> CD4
If cant recognize they die

Question 24

Negative Selection

Answer 24

DP thymocytes bind to tightly to MHC and will die

Question 25

Ligands for + and - selection

Answer 25

Are self-peptides/MHC complexes expressed on stromal and hematopoetic cells

Question 26

How to prevent TCRs that would react with BM-derived cells in the periphery?

Answer 26

Presentation of self-peptides from hematopoetic cells play imp role in shaping the repertoire

Question 27

What protect peripheral tissue specific Ags?

Answer 27

The AIRE transcription factor - plays role in regulating the expression of some tissue specific Ags in medullary epithelial cells in the thymus

Question 28

What is the T-cell Repertoire?

Answer 28

The sum of all the specificities of the mature T-cells produced by the thymus
–>We all have diff MHCs so we will have diff T-cells