T Cell Defelopment, Reeptor Repertoire Selection And CD4/CD8 Lineage Commitment Flashcards
Describe the journey of T cell maturation in the body?
- Multi-potent lymphoid progenitors migrate from the bone marrow to the thymus
- In the thymus, lymphoid progenitors differentiate to pre-T cells and are educated to differentiate self from non-self
- Positively selected T cells emigrate from the thymus to mediate and effect the cognate immune response
Describe the structure of the thymus
Capsule
Cortex
- cortical epithelial cells
medulla
= medullary epithelial cells
Hassails corpuscle
What parts of the thymus are different developmental stages of thymocytes found?
Subcapsular reigon
- immature CD3,4,8
- double negative thymocytes
Cortex
- immature CD3,4,8
- double positive thymocytes
Cortico-medullary junction
- mature CD4,8
- positive and negative thymocytes
What does CD stand for in CD4,CD8?
Cluster of differentiation
What does MHC stand for?
Major histocompatibility complex
How can we characterise cells in T cell development?
By using flow cytometry
CD4 - left
- top left is posative
- bottom left is double negative
CD8 in bottom right
- top right is double posative
- bottom left is dingle posatve
When are gamma delta T cells favoured during development?
During early fetal development
Number reduces after 8 weeks gestation
How is antigen recognition by gamma-delta T cells different from alpha-beta?
The cells bare specific receptor that end up in skin, gut uterus
Not MHC restricted
Antigen is recognised directly - mor like a antibody
In some cases can be unregulated under stress conditions
Play a role in cancer surveillance
What proportion of generated T cells are alpha-beta?
90%
What proportion of generated T cells are gamma-delta?
10%
What does a DP thymocytes need to progress to the SP stage?
Functional TCR-alpha chain rearrangement
CD4 and MHC2 — to be CD4 postive cell
CB8, MHC 1 and TAP - to be CD8 positive cell
ERK signalling
Calcineurin signalling
What percentage of cells fail to complete thymoyte maturation?
95%
What fates await DP cell thymocyte?
Posative selection - become CD4 SP or become CD8 SP
Death by neglect
Negative selection
Where are MHC1 genes expressed?
On thyme stromal els an low level on APC (DC and macrophages)
Where are MHC2 gees expressed?
On thymic medullary stromal cells and high level on APC
Describe what occurs during posative selection of DC
alpha-beta T cells bind to HLA molecules
If binding is strong enough the cell will be selected and allowed to continue development
Ensuring that only useful T cells that can engage in recognition are selected
Following adequate binding of CD4-MHC2, CD8 is down regulated and vice versa
The CD4 and CCD8 cells re ready for negative selection - unselected cells die by apoptosis
Describe what cures during negative selection
If the binding to the TRA peptide is strong , then this could pose a problem for the host because t could become a elf destructive T cell.
Ensures self reactive cells re removed as they would cause autoimmunity
Determined based on affinity of TCR for presented self-peptide
This ensures that remaining T cells are only reactive too foreign peptides
Self reactive cells are not removed immediately but go through further TCR rearrangements - before they eventually re removed if still self reactive
What is a problem for negative selection?
Thymus does not represent all self antigens
But it has a transcription activator gene which allows expression of other tissue specific proteins (apart from brain and testies) - promiscuous gene expression
This gene is called AIRE
This eliminates any self reactive T cells n
What controls thymocyte selection?
Antigen presentation and MHC expression
Wha happens to the T cells that remain in the thymus?
Express high levels of CD25 and foxp3
Do not proliferate in response to MHC sel-peptide complexes
Accumulate in the hassall corpuscle
Main role is t dampen T cell response
What happens T cells that pass both positive and negative selection?
Become conventional T cells
They migrate to secondary lymphoid organs looking for their target antigen.
Then form a immunological synapse - lead to the activation nod proliferation of effector T cells
If they don’t find they’re target they eventually die by apoptosis
