Central vs. Peripheral Tolerance

Tolerance

• Tolerance is a state of unresponsiveness in which the lymphocytes remain alive but cannot exert effector functions against a particular antigen.

Central Tolerance

• Lymphocytes with receptors specific for self-antigens are deleted at an early stage in lymphoid cell development. This process is called central tolerance and allows self-reactive B and T cells to be removed.
• Lymphocytes that do not receive survival signals undergo apoptosis.
• The subset of T cell receptors that receive the correct antigen signals will leave the thymus and circulate in the periphery.
• Some CD4+ T cells receive signals in the thymus that select them to differentiate into "natural" T regulatory cells (nTregs), which express the FoxP3 transcription factor and suppress the immune response by both direct and indirect mechanisms.

Used with permission from Macmillan Publishers Ltd: Nature Reviews Genetics 7, 917-928, copyright 2006.

Peripheral Tolerance

• When self-reactive T cells escape into the periphery, peripheral tolerance ensures that they are deleted or become anergic (functionally unresponsive to antigen).
• Peripheral tolerance can occur through one of three mechanisms:
  1. Induction of anergy (a state of inactivation in which the lymphocytes remain alive but are unable to respond to antigen).
     • Example: If dendritic cells are not appropriately activated and present self-antigen to T cells without signals 2 and 3 (costimulation and cytokine signals), they will produce T cells that are tolerant or anergic to that self-antigen.
     • Note: Anergy is a reversible state.  
      
  2. Deletion of autoreactive T cells via apoptosis.
  3. Development of "induced" regulatory T cells (Tregs) 
     • T cells exposed to the cytokine TGF-beta can differentiate into "induced" T regulatory cells in the peripheral tissues.
     • "Induced" T regulatory cells have similar effector functions as natural T regulatory cells, but they are produced in the periphery rather than in the thymus.