Mature T lymphocyte apoptosis - Immune regulation in a dynamic and unpredictable antigenic environment

Apoptosis of mature T lymphocytes preserves peripheral homeostasis and tole rance by countering the profound changes in the number and types of T cells stimulated by diverse antigens. T cell apoptosis occurs in at least two ma jor forms: antigen-driven and lymphokine withdrawal. These forms of death a re controlled in response to local levels of IL-2 and antigen in a feedback mechanism termed propriocidal regulation. Active antigen-driven death is m ediated by the expression of death cytokines such as FasL and TNF. These de ath cytokines engage specific receptors that assemble caspase-activating pr otein complexes. These signaling complexes tightly regulate cell death but are vulnerable to inherited defects. Passive lymphokine withdrawal death ma y result from the cytoplasmic activation of caspases that is regulated by m itochondria and the Bcl-2 protein. The human disease, Autoimmune Lymphoprol iferative Syndrome (ALPS) is due to dominant-interfering mutations in the F as/APO-1/CD95 receptor and other components of the death pathway. The study of ALPS patients reveals the necessity of apoptosis for preventing autoimm unity and allows the genetic investigation of apoptosis in humans. Immunolo gical, cellular, and molecular evidence indicates that throughout the life of a T cell, apoptosis may be evoked in excessive, harmful, or useless clon otypes to preserve a healthy and balanced immune system.