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Mechanisms of peripheral T cell tolerance
L van Parijs1, V L Perez, A K Abbas
1Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Novartis Foundation Symposium
|October 7, 1998
Summary
Peripheral tolerance prevents autoimmune disease through mechanisms like activation-induced cell death (AICD) and anergy. Defects in these pathways, such as in Fas or CTLA-4 signaling, lead to autoimmunity, highlighting lymphocyte regulation
Area of Science:
- Immunology
- Molecular Biology
- Autoimmunity Research
Background:
- Peripheral tolerance to self-antigens is crucial for preventing autoimmune diseases.
- Key mechanisms include activation-induced cell death (AICD) and T cell anergy.
- Dysregulation of these tolerance pathways can lead to autoimmune conditions.
Purpose of the Study:
- To elucidate the distinct molecular mechanisms underlying peripheral T cell tolerance.
- To investigate the roles of AICD and anergy in maintaining self-tolerance.
- To understand how defects in tolerance pathways contribute to autoimmune disease development.
Main Methods:
- Analysis of T cell responses under conditions promoting tolerance.
- Investigation of signaling pathways involved in AICD, including Fas/FasL and IL-2.
- Examination of anergy induction, focusing on B7 co-stimulators and CTLA-4 interactions.
Main Results:
- AICD in CD4+ T cells is mediated by Fas/FasL co-expression upon repeated stimulation and high IL-2 levels.
- Defects in Fas, FasL, or IL-2 receptor components impair AICD and result in autoimmune disease in mice.
- T cell anergy induction depends on CTLA-4 recognition of B7 co-stimulators; CTLA-4 deficiency causes fatal autoimmunity.
Conclusions:
- Peripheral tolerance is maintained by tightly regulated lymphocyte responses to self-antigens.
- Distinct pathways, including AICD and anergy, contribute to tolerance, with specific antigens potentially engaging different mechanisms.
- Single-gene defects causing autoimmunity often involve failures in lymphocyte regulatory pathways.