How do T cells develop?

Question 1

T-cell Production

Answer 1

The Thymus as The Primary Site of
T-cell Production

T-cell progenitors develop in the bone marrow and migrate to the thymus where the cells complete their development by rearranging their antigen-receptor genes and undergoing repertoire selection

Mature T cells migrate to the peripheral lymphoid organs

Question 2

Structure of Thymus

Answer 2

HAEMOPOIETIC bone marrow/fetal liver derived
precursors which develop into T-cells

Non-haemopoietic STROMAL CELLS (Cortical Epithelium) (Medullary
Epithelium), that drive the
development of T-cell precursors

Question 3

Components of Thymus and how they are Organized

Answer 3

Thymus Epithelial Cells
From the blood vessel the DN T cell Progenitor cells move to the capsule and interact with the Subcapsular Epithelial cells
Then they move into the cortex and interact with Cortical Epithelial cells and become DP
Then they cross the corticomedulary junction into the medulla where they interact with the Medullary Epithelial cells and become SP
Then they undergo negative selection and leave the thymus

Question 4

T-cell Development

Answer 4

1st progenitors that enter Thymus are double negative
1. Lack expression of CD4 and CD8 Termed CD4-CD8- or ‘double negative’

2. Dual expression of CD4 and CD8
   Termed CD4+CD8+ or ‘double positive’
3. CD4 expression only
   ‘CD4 single positive’
   CD4+CD8-
   and
   CD8 expression only
   ‘CD8 single positive’
   CD4-CD8+

Question 5

Checkpoint 1- Maturation from the CD4-CD8- to CD4+CD8+ Stage

Answer 5

1. Commitment to the T-cell Lineage- Progenitors could be multipotent and have to be specified to enter T cell lineage.
   -Immature progenitor cells express receptor for Notch ligand
   -Thymic epithelial cells have a Notch ligand that binds to the receptor
   -Notch ligand interaction on cell surface forces ab T-cell lineage
2. Cellular expansion (proliferation)- Expand cells that enter Thymus any time (Thymus colonizing cells)
   Massive wave of proliferation driven by cytokines (IL-7, IL-15 and c-Kit) released by epithelial cells
3. Rearrangement of genes encoding the T-cell receptor- Most critical stage-Give the T cells a receptor that is essential for their function
   There are 2 genes that encode TCR- one that produces a chain and other the b chain
   T cell chooses individual building blocks from each region randomly and builds a fully rearranged gene

Question 6

Pre-T cell Receptor Complex

Answer 6

Expressed only on immature CD4-CD8- thymocytes
Consists of TCRb protein, CD3 complex, and pre-Ta
Signalling through pre-TCR is essential for the generation Of CD4+8+ thymocytes

IF the TCR beta chain is functional then
Stops TCRb rearrangement
CD4, CD8 expression
TCRa rearrangement
Cellular expansion

Question 7

Positive and Negative Selection in Thymus

Answer 7

Because rearrangement of TCR genes is random,
we need to select on the basis of MHC recognition:

USELESS: Don’t recognise peptide/MHC at all

USEFUL: Recognise peptide/MHC of low affinity or avidity (POSITIVE SELECTION)
Positive selection happens in the cortex through the cortical thymic epithelial cells

HARMFUL: Recognise peptide/MHC at high affinity or avidity (NEGATIVE SELECTION)

Question 8

The Cortex: Positive Selection

Answer 8

T cell learns to recognize MHC in Thymus and learns to become CD8 or CD4.

TCR and CD4 binds to MHC Class II on thymic epithelium
Loss of CD8 Expression

Question 9

The Medulla: Negative Selection

Answer 9

Negative selection happens after positive selection always
SP cells move to medulla and get screened for negative selection

Question 10

How Does The Thymus Control Tolerance To Self-Antigens Expressed
In All Tissues In The Body?

Answer 10

auto immune regulator gene AIRE
Transcription Factor expressed by medullary thymic epithelial cells
Regulates Promiscuous gene expression so that tolerance to
proteins expressed in peripheral tissues can occur in the thymus