Tolerance Induction

Question 1

When do T cells begin to express TCR, CD4, and CD8 molecules?

Answer 1

• Must enter thymus and Migrate to cortex of thymus
• TCR alpha and beta chain rearrangement
• express CD3 TCR complex
• Finally express the good stuff

Question 2

What puts the T cell in a vulnerable condition to be tested for self and MHC restriction?

Answer 2

• 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

Question 3

How does positive selection of T cells work?

Answer 3

• 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

Question 4

How does testing of T Cells for tolerance of self work?

Answer 4

• 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

Question 5

Why do thymic dendritic cells have a short lifespan?

Answer 5

• 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

Question 6

What two cell types perform negative selection of T cells in the thymus? Which MHC do they each use?

Answer 6

• Thymic dendritic cells (primarily MHC I)

- Medullary Thymic Epithelial cells (Primarily MHC II)

Question 7

What do nTreg Cells do?

Answer 7

• work in secondary lymphoid organs
• express Foxp3
• suppress the activation of potentially self-reactive T cells that slipped through the cracks in the thymus

Question 8

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?

Answer 8

• 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

Question 9

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?

Answer 9

• there is another layer of tolerance induction to save us

- activation-induced cell death

Question 10

Enough about T cells, are B cells tolerized too?

Answer 10

Yes, in the bone marrow

Question 11

How are B cells tolerized?

Answer 11

• 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

Question 12

After somatic hypermutation, what if the B cells have mutated their receptors to recognize self antigens?

Answer 12

• 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

Question 13

Why is it unlikely that a self-recognizing B cell will find a self antigen on a follicular dendritic cell?

Answer 13

-FDC’s only display antigens that have been opsonized

Question 14

What do Thymic dendritic cells do?

Answer 14

• 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

Question 15

What is the difference between nTregs and iTregs?

Answer 15

• 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