Lecture 8 - T Cell Developement

Question 1

Stages of T Cell Development

Answer 1

1. Lymphocytes start as pluripotent stem cells in the bone marrow.
2. Some stem cells develop into mature IgM+ B cells (last lecture).
3. Other stem cells develop into T cell precursors which migrate to the thymus
4. Somatic Recombination in the thymus generates a naive T cell with a unique TCR

Question 2

Allelic Exclusion

Answer 2

Each individual inherits maternal AND paternal α chain genes.

Recombinase rearranges V and J gene segments to form an alpha chain.
If the recombination reaction is productive, recombinase is shut off at the other alpha chain locus. This prevents individual cells from expressing more than one TCR.

The same event occurs during BCR rearrangement

Question 3

T Cell Receptor (TCR)

Answer 3

A heterodimer composed of an α and a β chain
Each chain contains a variable (V) and a constant (C) region

The V and C regions are similar in structure to the V and C regions of Antibodies. Likewise, the V regions contribute most to antigen recognition

Question 4

TCR vs Ig

Answer 4

Both are composed of two chains that combine to form variable and constant domains.

Both have flexible hinge regions

Unlike antibodies, the TCR is directly and permanently anchored in the plasma membrane. Thus, the C-terminus has no effector functions, it is needed for signaling

Question 5

The MHC-Peptide-TCR Complex

Answer 5

1. Antigenic peptide is bound in the peptide binding groove formed by the α1 and α2 domains of the MHC I molecule
2. Both the α and β chains of the TCR interact with the peptide.
3. Additional TCR residues interact with the MHC molecule

Interactions:
CD4 and CD8 do NOT interact with the antigenic peptide.
CD4 and CD8 interact with NONPOLYMOPHRIC residues on MHC class II and I

Question 6

Features of TCR-Mediated Antigen Recognition

Answer 6

1. TCRs recognize peptides presented by MHC molecules.
2. Each clone is specific for a single antigen.
3. Antigen recognition is mediated by specific domains of the TCR.
4. Signalling triggers T lymphocyte activation

Question 7

TCR Development in the Thymus

Answer 7

Thymic Epithelial cell presents self-antigen on MHCI and MHCII

TCR-MHC interaction dictates the type of T cell it will be (ie. CD4 or CD8). If TCR recognizes MHC-II molecule then the cell loses CD8 expression and vise versa

Question 8

Self-Antigens

Answer 8

a collection of thymus and non-thymus peptides

Question 9

Failure of Positive Selection

Answer 9

The TCR recognizes no MHC and the non-reactive T cell is removed from the thymus through apoptosis

Question 10

Positive Selection

Answer 10

First stage of T cell differentiation

In Thymic Cortex

MHC recognition. Determines Class I or Class II MHC. TCR-MHC interaction dictates the type of T cell it will be (ie. CD4 or CD8)

Question 11

Double negative T cell

Answer 11

CD4- & CD4-

Lymphocyte precursor

Question 12

Double positive T cell

Answer 12

CD4+ & CD8+

Found in naive T lymphocytes. Must differentiate depending on MHC interaction

Question 13

Single Positive T cell

Answer 13

Either CD4+ & CD8-
Or CD4- & CD8+

Differentiates depending on MHC interaction

Question 14

Negative Selection

Answer 14

Second stage of T cell differentiation

In Thymic Medulla

Identifying TCR-MHC Affinity

Too high an affinity will cause self-peptide recognition, which is removed through apoptosis. Too low and it will not recognize MHC and will also be removed

Question 15

TCR self-peptide recognition

Answer 15

Auto-reactive, high affinity self recognizing TCR expressing T cell is removed from the thymus through apoptosis

Too high an affinity is as bad as no affinity

Question 16

Positive Selection with Negative Selection

Answer 16

Generation of a pool of CD4 and CD8 lymphocytes with low affinity for self peptide-self MHC complexes

Positive Selection: Ensures MHC Restriction Negative Selection: Ensures binding affinity

Ensures that:
— CD4 T cells are restricted to MHCII/peptide
— CD8 T cells are restricted to MHCI/peptide

Question 17

After Selection

Answer 17

Naive CD4 and CD8 T cells migrate to peripheral lymphoid organs to look for antigen on MHC class I or II