Selection of T cell receptor repertoire and CD4/CD8 lineage commitment Flashcards
Briefly explain development of T cells?
Multipotent lymphoid progenitors migrate from bone marrow to thymus
Lymphoid progenitors commit to T cell lineage by turning into pre-t Cells
Pre t cell educated to self and non-self
Thymic selection and positively selected T cell leave thymus
What cause lymphoid progenitors to migrate to the thymus from the blood marrow?
Chemokines travel through blood circulation and signals progenitors to follow to thymus
What are the names of the chemokines that cause migration of progenitors to the thymus?
Chemokines
- thymosin
- thymotaxin
- thymopoetin
- thymic factors
Which part of the thymus does late phase of T cell development take place in?
Medulla (lower lighter part)
What cells are in the medulla?
Cortical epithelial cell and medullary epithelial cells
Lymphocytes
Dendritic cells and macrophages
What is the hassal’s corpuscel?
Section of thymus where aggregation of mature lymphocytes occurs (esp Treg lymphocytes)
In which direction of thymus does maturation of T cells take place in?
From top to bottom (from cortex (double negative) down to medulla (single positive)
Double positive in the middle on way down
How do immature t cell become double positive?
Stromal cells interaction + singalled after beta cell rearrangment of TCR
What else is expressed when immature T cell becomes double positive for CD4 and CD8?
CD3
What does CD stand for?
Cluster differentiation
How does population od T cell population subsets vary in differet lymphoid tissue?
In thymus, most are double postive and in spleen most are double negative but alot are mature and single positive
Does positive or negative selection happen first?
Positive selection
When are gamma delta t cell made?
Favoured during foetal development, drops after gestation and alpha beta rises
What is different about gd T cells to ab T cells?
gd T cells aren’t MHC restricted, antigen can be recognised directly almost like an antibody
When do gd T cell levels rise in humans after gestation?
Upregulated during stress conditions
What do gd cells recongise in humans now’?
Phospholipid antigen on mycobacterium tuberculosis
+also role in cancer surveillance
Which part of T cell development does D-J gene reassortment take place?
Double negative pre-TCR and proliferation
Which part of T cell development does V-DJ gene reassortment take place?
Proliferation of pre T cells during double negative stage
Which part of T cell development does V-J gene reassortment take place?
Double positive stage before they become single positive (alpha rearrangment finishes off)
What events need to happen for a double positive thymocyte to become a single positive thymocyte?
Functional TCR alpha chain rearrangment
CD4 and MHC 2 complex formation (to become CD4+)
CD8 and MHC 1 complex formation (to become CD8+)
ERK signalling
Calcineurin signalling
What happens to cells that do not complete thymocyte maturation (from double to single positive)?
Become apoptotic (DNA disintegration) during +ve and -ve selection and cleared by macrophages
How many doubel positive T cells do not end up failing becoming single positive and apoptose?
95% of thymocytes
Why are failed thymyocytes killed by apoptosis?
Controlled cell death doesnt cause damage to other cells/tissue
What is the mechanism of apoptosis of failed thymyocytes?
Fas molecules on surface and Fas ligand (FasL)required before caspase cascade occurs causing chromatin disintegration and DNA break up
Where are MHC 1 bearing cells found in the thymus?
Thymic stromal cells and low level on antigen presenting cells(DC and macrophages)
Where are MHC 2 bearing cells found in the thymus?
Thymic medullary stromal cells and high level on antigen presenting cells
Which HLAs are MHC class 1?
HLA A, HLA B, HLA C
Which HLAs are MHC class 2?
HLR DR, HLA DQ, HLA DP
What molecules are present on a double positive T cell?
CD4 and CD8 and T cell receptor
What causes positive selection of T cells?
Double positive T cells bind to self MHC/HLA molecules, if strong there are positively selected
What cause negative selection of T cells?
Weak or no binding of T cell receptors to self MHC/HLA molecules
Where are the self MHC molecules that DP cells bind to?
Epithelial cells or APCs
Is MHC class 1 or MHC class 2 binding more common?
Random, whichever the double positive finds first e.g. CD4 binds to HLA DR on thymic epithelial cells or CD8 binds to HLA 1 on thymic epithelial cells
Why is positive selection important?
for self restriction - ensures only useful T cells that are able to recongise are selected
What happens after one of the 2 CD coreceptors bind to a HLA molecule?
The other CD coreceptor is downregulated
What happens to cells after positive selection?
Positively selected cells ready for negative selection whilst unselected cells dye via apoptosis
What is the purpose of negative selection?
exclude self reactive t cells - cant react to self antigens from the random gene arrangement formed TCRs
Which cells in thymus express self antigens?
Medulla - epithelial stromal cells or infiltrating dendritic cells/macrophages
What happens if T cells bind to a self antigen in the medulla?
Possibility of that T cell being self reactive so it is removed by apoptosis
If weak binding and not dangerous it is selected - so based on affinity
What happens to the selected cells from negative selection?
Some of them go onto become regulatory T cels
Why is it important to destory self reactive T cells?
Will cause autoimmunity otherwise
What happens to self reactive T cells before they are apoptosed?
Receptor editing - They go through further TCR rearrangments (mentioned earlier multiple gene rearrangments not just once), only removed if self reactive again
How are T cells made to be not self reactive to self antigens from other organs as well (not just thymus cells self antigens)?
AIRE gene (autoimmune regulator) - a transcription activator gene in thmys allows expression of other tissue specific proteins so negative selection done against most body self antigens
Which parts of bodies self antigens arent expressed by AIRE gene?
Brain and testes
What do regulatory T cells that develop in thymus express?
CD25 and Foxp3
How are Treg cells made?
In thymus but do not proliferate in response to self MHC peptide complexes,
Where are treg cell found?
In hassal’s corpuscles of thymus and later migrates to diff tissue for response once pathogen is gone and effector t cell is no longer needed
What is he role of Treg cells?
Dampen T cell response
What is an immunological synapse?
Interaction formed between T cells and antigen presenting cell( perhaps containing target antigen for T cell to become effective)
What happens to T cells in circulation if they don’t find a target antigen?
Die by apoptosis
