What happens to T cells that are recognise their peptide of MHC but don't get the second signal (CD80/86)
They fail to proliferate > inactivate > anergy
What is the difference between nTregs and iTregs?
nTregs develop in the thymus
iTreg differentiate in the periphery from naive T cells in response to TGFbeta
What is the transcription factor for Tregs?
How does CTLA-4 would to tone down the T cell response?
Activated T cells express CTLA-4, this binds strongly to B7 on APCs. When these two interact, a inhibitory signal is sent to the T cells in order to tone down IL-2 production
What anti-inflammatory mediators do Tregs produce?
What are the 3 key factors that lead to autoimmunity?
Genetic susceptibility (mainly via HLA)
Loss of self-tolerance
Where does central tolerance occur for B cells?
What signal causes differentiation of naive T cells into Tregs?
What is an important cause of loss of central tolerance?
Loss of AIRE
What is the function of AIRE?
Facilitates expression of self-ag's that wouldn't otherwise be found in the thymus so that new TCRs can be tested for self-reactivity.
Do autoimmune response always lead to autoimmune disease?
No, sometimes they are self-limiting
What is positive selection?
Only TCRs that can recognise self-MHC are selected to survive. If they can't, they die by neglect
What is the bystander effect?
Infectious agent causes damage releasing self ag and activating DCs > nearby self reactive T cell can receive both signals from a DC
What happens to B cells that exhibit extensive self reactivity in the bone marrow?
They are killed
What is molecular mimicry?
A foreign ag has a similar structure to a self ag so that ab's against the foreign ag also targets the self ag.
Eg M protein from strep causing rheumatic heart disease
Why don't all autoreactive lymphocytes get activated?
They do see their antigen
They don't get the co-stim signal for APCs
They (B cells) don't get the signal from T cells
What are some important causes of loss of peripheral tolerance?
Defect in FoxP3
Loss of Tregs and peripheral tolerance mechanisms
At what development stage do T cells undergo positive and negative selection?
Double positive T cells
When can B cell peripheral tolerance break down?
When T cells are also self reactive
Which cells express AIRE?
Thymic epithelial cells
What is negative selection of T cells?
TCR that have too strong affinity to self-MHC are selected against. Die by apoptosis
How does peripheral B cell tolerance work?
B cells requires CD40L from T cells for full activation otherwise antigen cross-linking causes the development of only short lived plasma cells. So generally, B cells will only be activated fully in the presence of a foreign antigen that is recognised by the BCR and TCR
What is the goldilocks theory?
Only TCRs that are moderately reactive with self-MHC are allowed to survive
Where does T cell development occur?