Immunological Tolerance

Question 1

What does central tolerance involve?

Answer 1

• B cell selection
• T cell selection
Both occur in primary lymphoid organs- bone marrow and thymus

Question 2

Outline B cell selection

Answer 2

• Occurs in bone marrow
• Survival requires generation of a functional antigen receptor. If an immature B cell binds a self antigen:
-> Receptor editing (change specificity)
-> OR Deletion (negative selection)- cell killed

Question 3

Outline T cell selection

Answer 3

• Occurs in thymus- T cells are educated

1. Stem cell
   - > double negative (CD4-CD8-) Pro T cell
   - > Pre T cell (+ Pre-TCR)
   - > double positive (CD4+CD8+) immature T cell- thymocyte

2. T cell selection:
• weak recognition of class II MHC+peptide-> positive selection CD4+
• weak recognition of class I MHC+peptide-> positive selection CD8+
• no recognition-> failure of positive selection and death by neglect- apoptosis
• strong recognition of class I/II MHC+peptide-> negative selection- apoptosis/ becomes Treg

AIRE- autoimmune regulator- transcription factor in thymus that switches on expression of tissue-restricted antigens so they can be seen during T cell selection (insulin)
AIRE deficient thymus-> autoimmunity

Question 4

What does peripheral tolerance involve?

Answer 4

• Cell Intrinsic mechanisms
-ignorance
-anergy 
-phenotypic skewing
-apoptosis
• Cell extrinsic mechanisms
-Tregs

Question 5

Outline cell Intrinsic mechanisms of peripheral tolerance

Answer 5

1. Ignorance- T cell never encounters self antigen
2. Anergy- Costimulator required for clonal expansion- Increased expression when APCs are activated-> B7 expressed on APC surface binds to CD28 on T cell and APC secretes cytokines
3. Phenotypic skewing- T cells in periphery with potential to cause harm must differentiate in a certain way- otherwise the cell responds but won’t cause pathology
4. Apoptosis- T cell dies because it hasn’t received correct signals (like anergy)

Question 6

Outline cell extrinsic mechanisms of peripheral tolerance

Answer 6

Regulatory T cells
• Develop in thymus, some in periphery
• Express FOXP3 (transcription factor) and CD25 (IL-2 receptor α)

Importance- mice lacking thymus reconstituted with total T cells were healthy, with CD25 depleted T cells-> autoimmunity

Mechanisms of action:
• Secrete inhibitory cytokines (IL-10, TGFβ)
• Use the regulatory protein CTLA-4 to modify APC- block or remove costimulatory ligands
• Bind and consume IL-2 (gf for T cells)

-> control many other cell types