Lecture 8: T Cell Development Flashcards
Stages of T Cell Development
- Lymphocytes start as pluripotent stem cells in the bone marrow.
- Some stem cells develop into mature IgM+ B cells.
- Other stem cells develop into T cell precursors.
- T cell precursors migrate to the thymus.
- Somatic Recombination in the thymus generates a naive T cell with a unique TCR.
A naive thymocyte is made of:
Alpha chain locus
- V, J, C
Beta chain locus
- V, D, J, C
Allelic Exclusion
- 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.
- Prevents individual cells from expressing more than one TCR.
- The same event occurs during BCR rearrangement.
T Cell Receptor (TCR)
- is a heterodimer composed of an α and a β chain.
- each contains a variable 9V) 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.
TCR compared with an Ig molecule
- Both are composed of two chains that combine to form variable and constant domains.
- Both have flexible hinge regions.
- In contrast to an antibody, the TCR is directly and permanently anchored in the plasma membrane. Thus, the C-terminus has no effector functions, it is needed for signaling.
MHC-Peptide-TCR Complex
- Antigenic peptide is bound in the peptide binding groove formed by the α1 and α2 domains of the MHC I molecule.
- Both α and chains of the TCR interact with the peptide.
- Additional TCR residues interact with the MHC molecule.
The TCR interacts with the _______ and the _________
peptide and MHC
CD4 and CD8 do not interact with the antigenic peptide.
They interact with:
CD4 and CD8 interact with NON-POLYMORPHIC residues on MHC class II and I.
Features of TCR-mediated antigen recognition
- TCRs recognize peptides presented by MHC molecules.
- Each clone is specific for a single antigen.
- Antigen recognition is mediated by specific domains of the TCR.
- Signalling triggersT lymphocyte activation.
Positive selection (Identifying MHC recognition)
First stage in normal T cell development
Self-antigens
collection of thymus and non-thymus peptides
TCR development in the Thymus
- Thymic epithelial cell presents self antigen on MHC I and MHC II
- Self-antigens are a collection of thymus and non-thymus peptides
What dictates the type (ie. CD4 or CD8) of T cell it will be?
TRC-MHC interaction
In positive selection, what happens if TCR recognizes MHC II molecule?
The cell loses CD8 expression. Only CD4 molecules are on the surface.
In positive selection, what happens if TCR recognizes MHC I?
The cell loses CD4 expression. Only CD8 molecules are on the surface.
A double positive naive lymphocyte contains
both CD8 and CD4 on the surface.
What happens if the TCR does not recognize any MHC?
Failure of positive selection.
Non-reactive cell is removed from the thymus through apoptosis.
Negative Selection (Identifying TCR-MHC Affinity)
Second stage in normal T cell development
Auto-reactive, high affinity self recognizing TCR expressing T cell is removed from the thymus through __________.
apoptosis
In TCR development in the thymus, Positive selection along with negative selection generates:
Generation of a pool of CD4 and CD8 lymphocytes with low affinity for self peptide-self MHC complexes
Positive selection ensures __________
Negative selection ensures __________
Positive selection: ensures MHC restriction
Negative selection: ensures binding affinity
CD4 T cells restricted to ____________
CD8 T cells restricted to ____________
CD4 T cells: restricted to MHC II/ peptide
CD8 T cells: restricted to MHC I/ peptide
What happens after selection?
Naive CD4 and CD8 T cells migrate to peripheral lymphoid organs to look for antigen on MHC class I or II.
