Immune Tolerance and Recognition Flashcards
What is a possible side effect of random and diverse TCR diversity?
Self-reactivity, as there may be a CD8 cytotoxic T-cell produces which recognises a normal body peptide fragment displayed on a MHC 1 class molecule in antigen presenting cells. This may lead to the destruction of these cells and this is the basis of autoimmune disease.
What is the process of T-cell production? Where are they formed? Where do they move to?
Initially synthesised in the bone marrow. They exit this as T-cell precursors called thymocytes and travel to the thymus gland for further training. This is when they become either CD4 or CD8 T-cells.
What is name of the educating process given to thymocytes in the thymus gland?
Thymine education
What happens to T-cells in the thymus during thymocytes education to determine which class of T-cell they will become (CD4 or CD8)?
They start to express a TCR and also an accessory protein (either CD4 or CD8 = the one which helps them attach to MHC-peptide complexes) which helps them differentiate.
What is the first step in thymic education?
What do the T-cells that arise from this stage look like?
In the first stage of thymic education, TCR genes are rearranged to be closer together to aid TCR synthesis.
The T-cells produced co-express both CD4 and CD8 receptors at this stage.
What is the second step in thymic education?
How does this process occur?
What do the T-cells that arise from this stage look like?
The thymocytes are screened for positive selection for MHC affinity.
This is done via specialised MHC class 1 and 2 co-presenting cells in the thymic cortex which screen if cells can weakly bind to MHC 1, MHC2 or neither.
- At least weak affinity for MHC1 = become CD8 cytotoxic T-cells (loses expression of its CD4 accessory molecule)
- At least weak affinity for MHC2 = become CD4 T-helper T-cells (loses expression of its CD8 accessory molecule)
- Weak affinity for neither = cell is destroyed via apoptosis
What is the third step in thymic education?
How does this process occur?
What do the T-cells that arise from this stage look like?
This is a negative selection stage for those T-cells which have passed stage 2 and have shown positive affinity for MHC. Thos stage removes those cells which show high affinity for self MHC-peptide complexes and takes place in the thymic medulla on thymic medullary epithelial cells (TMEC’s).
High affinity showing T-cells have are self reactive and therefore need killing via activation induced death.
What do TMEC’s express?
A wide variety of TRA’s (tissue restricted antigens) which are major proteins found elsewhere in the body (e.g. insulin, trypsin, thyroglobulin) in order to check which T-cells in the negative selection stage of thymic education show high self reactivity and need destroying.
What percentage of thymocytes pass the X3 stages of thymic education and enter the peripheral circulation?
<1%
What is an alternative name for the thymic education process?
The central mechanism of tolerance as it occurs centrally in the thymus.
Why is a peripheral mechanism of tolerance also needed as well as a central one (thymic education)?
As some thymocytes can escape the central mechanism of tolerance.
What are the X2 processes which are peripheral mechanisms of tolerance?
1) anergy
2) T-reg cells
What is anergy?
How does this occur?
Anergy is where the high self-affinity T-cells remain in the circulation but are non-active and non-responsive to stimulation due to no second signal (co-stimulators signal) being expressed on antigen presenting cell surfaces due to it having interacted with a self-peptide-MHC complex.
What types of normal processes is anergy important for?
- food antigen tolerance (food proteins are non-self antigens after all!)
- antigens not expressed in the thymus (not all are expressed)
- friendly/commensalism bacteria tolerance
What are the two ways T-regs can control high affinity self-MHC T-cells?
1) they can stop their proliferation and stop their cytokine production (CD8 cytotoxic T-cells) to reduce their killing.
2) they can stop the co-stimulatory second signals to reduce it and therefore halt the killing of self.
