T cell Development, Receptor repertoire selection and CD4-CD8 lineage commitment Flashcards
Revision: Where do T cells come from
- Multipotent lymphoid progenitors migrate from bone marrow to thymus
- Positively selected T cells emigrate from the thymus to mediate and effect the cognate immune system
Describe the change in maturation of T cells across the thymus
- Increased T cell maturation the further you move from the cortex to the medulla
What can double negative T cells for CD4 and 8 be categorised into
- Double negatives can be grouped into relative expression of CD44 and CD25
How does fetal thymocytes differ from adult thymocytes
- Delta gamma thymocytes are favoured in fatal development
- Alpha beta thymocytes are favoured in adult life
How does antigen recognition for delta gamma differ from alpha beta
- delta gamma cells bearing specific receptors end up in the skin (Vg5), gut (Vg2), uterus (Vg6)
- Not MHC restricted
- Antigen is recognized directly, more like an antibody
- Unregulated ligands under stress conditions
- Recognise antigen from mycobacterium tuberculosis
- Role in cancer surveillance
What Arte the proportion in which T cells exist
- 90% Alpha-beta
- 10% gamma-delta
How are differences in T cell receptors acheived
- rearranged alpha and beta chain DNA when the receptor is produced
What does a double positive thymocyte need to progress to the single positive stage
Functional TCRalpha chain rearrangement
- CD4 and MHCII (to be a CD4+ cell)
- CD8, MHC I and TAP (To be a CD8+cell)
- ERK signalling
- Calcineurin signalling
What happens to unselected t cells
- Dies by apoptosis
- Macrophages collect dead cell material
What happens to double positive thymocytes
- Either one of the receptors CD4 or 8 is down-regulated to form the other receptor type cells
- If not the cell will die by neglect or negative selection
Where is MHC receptor expressed
- MHC I expressed on thyme stromal cells and low level on APC
- MHC II expressed one thyme medullary stroll cells and high level on APC
How does positive selection work
- Positive selection ensures that only T cells are that are useful and can and can engage in recognition are selected
- 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
What is the purpose of negative selection
- get rid of T cells that bind strongly to self-peptides to reduce chances of autoimmunity
How does negative selection work
- Determined based on the 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-reactive
What are the problems associated with negative selections
- The 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
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