Lecture 6- t cell development Flashcards
where do T cells develop?
T cells mature in the thymus. The image at the top shows where the thymus is located in the body, the overall shape of the thymus and the last image shows that structure of the thymus - an outer cortex and inner medulla.
what are the key events in T cell development?
- Commitment to T cell lineage:
Generates Double Negative cells: no CD4, no CD8 expression - Generation of unique TCR molecules
Generates Double Positive cells: CD4+CD8+ - Positive selection: Removes cells that cannot recognise self-MHC
Generates Single Positive CD4+ OR CD8+ - Negative selection: Removes cells that strongly recognise self-peptides
Generates mature CD4 and CD8 T cells
what is the education of the T cell receptor?
Part 1: Learning to see self
part 2: Learning not to see self too strongly
what do the thymus T cells undergo?
-positive selection: only keep T cells that recognise self MHC molecules
-negative selection: remove self-reactive T cells
-regulatory T cell development (only some T cells)
how are T cell receptors generated?
by somatic gene rearrangement providing a huge number of different TCRs
what are most T cells?
Most T cells are conventional CD4 or CD8 T cells
The cartoon shows conventional CD4 T cells and CD8 T cells interacting with a dendritic cell. These conventional T cells have an antigen receptor made up of an alpha and beta TCR receptor. On CD4 T cells, the CD4 co-receptor helps the TCR bind to MHCII. For CD8 T cells, the CD8 co-receptor helps the TCR to bind to MHCI.
what are the unconventional T cells generated in the thymus?
Natural Killer T cells: found throughout the body. Majority express one particular TCRalpha chain and a limited selection of beta chains
Mucosal associated invariant T cells: mainly found in mucosal sites
Express restricted TCRα chains and limited selection of TCRβ chains
γδ T cells: often found in mucosal tissues and in the skin
Express a limited TCR repertoire
Are some of the first T cells to leave the thymus prenatally and early following birth
what are T cell receptors made up of?
diferent variable regions…
The animation shows how TCR diversity is generated during T cell development.
In the Beta chain: there are between 20-50 germline Variable regions, 12Junctional regions and 1-2Diversity regions.
In the alpha chain, there are between 50-100 Variable regions and 50Junctional regions.
There are additional nucleotides added that are called P and N nucleotides.
how does Double positive thymocytes undergo positive selection?
Double positive thymocytes (CD4+ CD8+) undergo positive selection in the cortex of the thymus where they interact with cortical thymic epithelial cells
T cells must recognise self MHC molecules on cortical thymic epithelial cells – this ensure they can recognise self-MHC presenting peptides from pathogens
The majority of cells fail to recognise self-MHC and die by apoptosis
T cells lose either CD4 or CD8 to become single positive thymocytes
what is an overview of T cells?
Conventional T cells: recognise peptides presented on MHC II or MHC I
Incoming progenitor cells migrate from bone marrow to the thymus
Unconventional T cells: recognise pathogen products on non-classical MHC molecules or as free antigens
what is Negative Selection?
removes T cells that recognise the body’s own proteins
Single positive T cells undergo negative selection in the thymic medulla
They interact with thymic medullary epithelial cells and DCs
Thymic medullary epithelial cells express many different self peptides that are found in organs throughout the body
This is co-ordinated by a molecule called AIRE
Cells that recognise self-peptide MHC molecules with high affinity usually undergo cell death by apoptosis
how are T cell receptors deconstructed sandwiches?
The genes that code for the different parts of the TCR are cut and pasted together in the DNA be a process called somatic rearrangement
Recognition of peptide-MHC – getting it just right
Fate of cells: apoptosis
Too cold:
Positive selection: binding of TCR to self-peptide too weak
Too hot:
Negative selection: binding of TCR to self-peptide MHC too strong
Fate of cells: released into periphery
Just right:
TCR recognises peptide-MHC with optimal affinity
But real life is more complicated than fairy stories!
Some CD4 T cells with TCRs that bind with moderate affinity to peptide-MHC become regulatory T cells
Regulatory T cells turn off immune responses
