Tolerance Induction Flashcards
When do T cells begin to express TCR, CD4, and CD8 molecules?
- Must enter thymus and Migrate to cortex of thymus
- TCR alpha and beta chain rearrangement
- express CD3 TCR complex
- Finally express the good stuff
What puts the T cell in a vulnerable condition to be tested for self and MHC restriction?
- once T cell reaches thymic cortex and starts proliferating, it expresses lots of Fas on its surface, and little Bcl-2
- very easy to send into apoptosis
How does positive selection of T cells work?
- Testing for MHC restriction
- Tested by epithelial cells in thymic cortex
- If TCRs do not recognize any of the self MHC molecules (not antigens!), the T cell dies
How does testing of T Cells for tolerance of self work?
- T cells that recognize self MHC plus peptide proceed from thymic cortex to medulla
- tested for tolerance of self (negative selection)
- Tested by thymic dendritic cell displaying self peptides on MHC
- T cells that react to self antigens are killed
Why do thymic dendritic cells have a short lifespan?
- present only current self antigen
- if foreign antigens reach thymus (infection) then dentritic cells could falsely present them as self antigens
- short lifetime protects against this possibility
What two cell types perform negative selection of T cells in the thymus? Which MHC do they each use?
- Thymic dendritic cells (primarily MHC I)
- Medullary Thymic Epithelial cells (Primarily MHC II)
What do nTreg Cells do?
- work in secondary lymphoid organs
- express Foxp3
- suppress the activation of potentially self-reactive T cells that slipped through the cracks in the thymus
So nTreg cells keep self-reactive T cells from being activated in the secondary lymphoid organs, but what if that self-reactive T cell slips into random tissues of the body?
- still needs dual stimulation, usually provided by dendritic cells
- ordinary tissue cells do not expresss high levels of MHC or co-stimulatory molecules
- When a T cell recognizes its cognate antigen, but does not receive required costimulation, it is “anergized,” and dies by apoptosis
Ok, Ok, so what if the self-reactive T cells manage to slip into the tissues, and find a high enough density of its cognate to activate? What then?
- there is another layer of tolerance induction to save us
- activation-induced cell death
Enough about T cells, are B cells tolerized too?
Yes, in the bone marrow
How are B cells tolerized?
- in bone marrow
- tested to see if they recognize self antigens
- if they do, they are given a second chance at gene rearrangement
=Receptor Editing
After somatic hypermutation, what if the B cells have mutated their receptors to recognize self antigens?
- does not happen very often
- B cells in germinal centers are fragile and die by apoptosis unless they receive rescue signals
- also need costimulation from T cells, and it is very unlikely for a B cell to bump into a T cell that recognizes the same self antigen
Why is it unlikely that a self-recognizing B cell will find a self antigen on a follicular dendritic cell?
-FDC’s only display antigens that have been opsonized
What do Thymic dendritic cells do?
- Display self peptides in the thymus for presentation to maturing T cells
- Present only current self antigen
- T cell that react to self antigens are killed
What is the difference between nTregs and iTregs?
- nTregs provide protection against T cells which have the potential to react against self antigens and cause autoimmunity
- iTregs are tasked with restraining the immune system to keep it from overreacting to the foreign antigens of invaders
