MATURE T LYMPHOCYTE APOPTOSIS—Immune Regulation in a Dynamic and Unpredictable Antigenic Environment

Abstract

Apoptosis of mature T lymphocytes preserves peripheral homeostasis and tolerance 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 major forms: antigen-driven and lymphokine withdrawal. These forms of death are controlled in response to local levels of IL-2 and antigen in a feedback mechanism termed propriocidal regulation. Active antigen-driven death is mediated by the expression of death cytokines such as FasL and TNF. These death cytokines engage specific receptors that assemble caspase-activating protein complexes. These signaling complexes tightly regulate cell death but are vulnerable to inherited defects. Passive lymphokine withdrawal death may result from the cytoplasmic activation of caspases that is regulated by mitochondria and the Bcl-2 protein. The human disease, Autoimmune Lymphoproliferative Syndrome (ALPS) is due to dominant-interfering mutations in the Fas/APO-1/CD95 receptor and other components of the death pathway. The study of ALPS patients reveals the necessity of apoptosis for preventing autoimmunity and allows the genetic investigation of apoptosis in humans. Immunological, cellular, and molecular evidence indicates that throughout the life of a T cell, apoptosis may be evoked in excessive, harmful, or useless clonotypes to preserve a healthy and balanced immune system.

TCR signaling inhibits glucocorticoid-induced apoptosis in murine thymocytes depending on the stage of development

“…If, under these conditions, elevated levels of GC inhibit AICD, they may preserve the survival of activated T cells. As soon as Ag levels fall below the threshold for production of cytokines, peripheral blood GC levels will decrease, and activated T cells may subsequently die by 'passive apoptosis' [48].…”

c‐Maf interacts with c‐Myb to down‐regulate Bcl‐2 expression and increase apoptosis in peripheral CD4 cells

“…When naive T cells are stimulated with antigen, they expand in number initially and later contract [34]. To determine if constitutive c-Maf expression affects cell death following TCR engagement, lymph node CD4 cells were stimulated with plate-bound anti-CD3 + anti-CD28 Ab and assessed for apoptosis 16 h later (Fig.…”

Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

“…At least two independent pathways for induction of AICD appear to exist. The better known pathway is initiated by activation of caspase 8 via signaling through cell surface receptors such as Fas or TNFR [1][2][3]. Activation of the Fas signaling pathway requires down-regulation of the FLICE-like inhibitor protein (FLIP), an IL-2-dependent event that occurs about 3 days after T cell activation [4].…”

“…Because caspases are involved in a number of apoptotic pathways, we have examined the role of several caspases in perforin-dependent AICD. Caspases such as caspase 8 that are activated downstream of death receptors such as Fas and TNFR ( [20], reviewed in [2,3]), are not likely to be involved, as perforindependent AICD occurs autonomously. Other apoptotic events act through compromise of mitochondrial activity and lead to activation of caspase 9 (reviewed in [21,22]).…”