T cell Development - Receptor repertoire selection and CD4/CD8 lineage commitment Flashcards
Where do T cells come from?
- Multipotent Lymphoid Progenitors Migrate from the Bone Marrow to the Thymus
- In the Thymus, the 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
- T-cells will follow the trial cause by chemokines where they then enter the thymus.
Describe the structure of the thymus
The Thymus has a Capsule with Trabeculae. The trabeculae divide the thymus into Lobules. Per lobule you have an outer cortex and an inner medulla. The cortex is formed of dense lymphoid tissue which lacks nodules. Since the stroma of the medulla is less heavily infiltrated with lymphocytes than the cortex, the medulla stains more lightly than the cortex. Immature lymphoid cells enter the cortex proliferate, mature and pass on to the medulla. From the medulla mature T lymphocytes enter the circulation.
Describe what briefly happens when the immature double negative thymocytes enter the thymus
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Describe T cell development and migration
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What T cells are favoured during early development?
gamma delta thymocytes
Describe recognition of gamma delta thymocytes in the thymus
- T cells bearing specific receptors end up in skin (Vg5), gut (Vg2), uterus (Vg6), etc.
- T cells are not MHC restricted!
- Antigen is recognized directly, more like an antibody
- In some cases ligands for the TCR are self proteins upregulated under stress conditions
- In humans, circulating cells recognize a phospholipid antigen from Mycobacterium tuberculosis
- Play a role in cancer surveillance
What does a DP Thymocyte Needs to Progress to the SP Stage?
- Functional TCRa chain rearrangement
- CD4 and MHC II (To be a CD4+ cell)
- CD8, MHC I and TAP (To be a CD8+ cell)
- ERK signaling
- Calcineurin signaling
What happens to a double positive thymocyte?
DP look for MHC self-molecules in the thymus – which ever binds to the target first and has a higher affinity leads to the down regulation of the other molecule leading to positive selection. The rest die via neglect or apoptosis.
What genes encode the MHC cells
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Describe the process of positive selection
- Positive selection ensures that only T cells are that are useful and can and can engage in recognition areselected
- DP CD4/CD8 cells bind to MHC-I or MHC-II on thymic epithelial cells – it is a random event which one binds
- Following adequate binding of CD4:MHC-II, CD8 is downregulated and vice versa
- From here on, the SP CD4 or CD8 T cells are ready for negative selection Unselected cells die by apoptosis
Describe the process of negative selection
What gene is needed to perform this?
- Negative selection ensures that self-reactive cells are removed, as they would cause autoimmunity
- This is determined based on affinity of TCR for presented self-peptide: high – kill him, low – keep him
- This ensures that remaining T cells are only reactive to foreign peptides
- Self-reactive cells are not removed immediately but go through further TCR rearrangements (second chance) – before they are eventually removed if still self-recative
- A bit of a problem for T cells: thymus does not represent all self-antigens… but it has a transcription activator gene which can induce expression of other tissue specific proteins (kidney, heart etc)
- This gene is called AIRE (Autoimmune Regulator): this allows negative selection against most bodily self-proteins
How are T cells negatively selected against self-antigens not present in thymus?
- The Transcription Factor Autoimmune Regulator (AIRE) Mediates Ectopic Gene Expression in the Thymic Medullary Stroma – other tissue specific genes…kidney, heart, liver, lungs, gut, … apart from brain and testes
- This is known as promiscuous gene expression – about 10% of all genes in thymus are expressed this way
- This eliminates many self-reactive T cells
What cells in the thymus express MHC?
- DC
- Medullary Epithelial cells
- Cortical Epithelial cells
- Endothelial cells
CERTAIN CELL TYPEs CONTROL DIFFERENT T CELL DEVELOMENTAL FATES
• Positive selection
• Negative selection
• Receptor editing
How do regulatory T-cells develop?
- Do not proliferate in response to MHC self-peptide complexes
- T Regs accumulate in Hassall corpuscles and later migrate to different tissues
- Main role: dampen T cell response
- T cells that pass both positive and negative selection become conventional T cells
- They migrate to secondary lymphoid organs looking for their target antigen
- ‘Immunological synapse’
- If they encounter specific antigen, they get activated, proliferate and become effector T cells
- Some become memory T cells
- If they don’t find the target they, eventually die by apoptosis after period of circulation
