Central and peripheral tolerance
12 important questions on Central and peripheral tolerance
How is central tolerance achieved?
Apoptosis, receptor editing in B-cells, development of regulatory T-cells
How is peripheral tolerance achieved?
Apoptosis, Angery or Supression
How are cells in the thymus selected?
In the subcapsular region, immature double-negative thymocytes mature to be double positive thymocytes in the cortex. Here they are positively selected by cortical epithelial cells. They then migrate as mature thymocytes to the cortico-medullary junction where they are negatively selected by DCs. Then they can enter the periphery via venules.
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How do cortical epithelial cells positively select immature T-cells?
The epithelial cells express MHC II, which is recognized by the T-cells with low affinity. If they fail to do so, they undergo Apoptosis.
How are T-cells negatively selected in the thymus?
By thymic antigen-presentic cells (DCs) expressing MHCII. If the T-cell strongly binds to the APC, it will undergo apoptosis.
What is promoted by reaction of an immature T-cell with both MHC and a self peptide?
Survival and loss of irrelevant receptor, which is CD4+ when interacting with MHCI and CD8+ when interacting with MHCII
How are self-reactive B-cells regulated?
If they have a high affinity to self, they can either change the V-region of their epitope in the bone marrow or undergo apoptosis. If they have a low affinity to self, they undergo anergy
How is anergy initiated?
If an antigen is recognized without co-stimulator or an inhibiting signal like CTLA-4 is recognized, the cell becomes unresponsive.
How is supression mediated via T-regs?
The Treg secretes IL-10, IL-35 and TGF beta, which results in cell cycle arrest in FoxP cells.
They also consume IL-2, leading to Bim-mediated apoptosis.
Tregs may cause cytolysis via Granzymes to kill e.g. DCs.
Furthermore, its secreted or cell-surface molecules, like Galectin-1, may cause cell cycle arrest.
How can Tregs supress DCs?
- via CTLA4, which interacts with CD80, leading to downregulation of cofactors
- via LAG3 in immature DCs which interacts with MHCII, leading to ungoing immaturity
- via CD 39 which catches AMP and ATP to decrease costimulation
- via Nrp-1 in immature DCs which leads to reduced antigen-presentation
How are Tregs supressed?
Tregs are supressed by high TLR interaction and costimulation as well as high concentrations of IL-2 and IL-6
How are B-cells fully activated?
They require either ligation on CD40 with a T-cell or a signal from the specific MHC complex of an activated T-cell.
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