Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency

Abstract

Apoptosis is a form of programmed cell death that is controlled by aspartate-specific cysteine proteases called caspases. In the immune system, apoptosis counters the proliferation of lymphocytes to achieve a homeostatic balance, which allows potent responses to pathogens but avoids autoimmunity. The CD95 (Fas, Apo-1) receptor triggers lymphocyte apoptosis by recruiting Fas-associated death domain (FADD), caspase-8 and caspase-10 proteins into a death-inducing signalling complex. Heterozygous mutations in CD95, CD95 ligand or caspase-10 underlie most cases of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defective lymphocyte apoptosis, lymphadenopathy, splenomegaly and autoimmunity. Mutations in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryonic lethality in mice. Here we describe a human kindred with an inherited genetic deficiency of caspase-8. Homozygous individuals manifest defective lymphocyte apoptosis and homeostasis but, unlike individuals affected with ALPS, also have defects in their activation of T lymphocytes, B lymphocytes and natural killer cells, which leads to immunodeficiency. Thus, caspase-8 deficiency in humans is compatible with normal development and shows that caspase-8 has a postnatal role in immune activation of naive lymphocytes.

Transgenic overexpression of the Caspase‐8 inhibitor FLIPshort leads to impaired T cell proliferation and an increased memory T cell pool after staphylococcal enterotoxin B injection

“…4A). Several reports have suggested that caspases, in particular Caspase-8, not only play an essential role in apoptosis execution, but may also be important for T cell proliferation [25][26][27][28][29]. T cells lacking a functional FADD adaptor protein, either in FADD -/-knockout mice [12] or in transgenic animals overexpressing a dominantnegative FADD [16][17][18], exhibit a reduced proliferative capacity.…”

“…In addition, FLIP L expression has been reported to switch CD95-mediated glucose signaling in human pancreatic b cells from apoptosis to cell replication [24]. However, several groups have shown that caspase activity, in particular that of Caspase-8, plays an important role in promoting lymphocyte activation and proliferation [25][26][27][28][29]. In line with these findings and contrary to the study by Lens et al [23], transgenic overexpression of FLIP L in mouse T cells has also been reported to lead to suppression of T cell activation and proliferation as a consequence of FLIP L -mediated inhibition of FADD/Caspase-8 signaling [30].…”

Modifications and intracellular trafficking of FADD/MORT1 and caspase-8 after stimulation of T lymphocytes

“…8,10,12,15,16 Loss of FADD function diminished both the proliferative expansion of immature T cells stimulated through the pre-TCR complex 17 and the response of mature T cells to mitogens 8,10 or antigen. 18 Recently, two siblings exhibiting features of autoimmune lymphoproliferative syndrome (ALPS), a disease that is usually due to mutation in the fas gene, 1 were found instead to have a homozygous mutation in the caspase-8 gene.…”

“…18 Recently, two siblings exhibiting features of autoimmune lymphoproliferative syndrome (ALPS), a disease that is usually due to mutation in the fas gene, 1 were found instead to have a homozygous mutation in the caspase-8 gene. 15 The resulting instability of caspase-8 rendered lymphocytes resistant to Fas-induced apoptosis and surprisingly, B, T and NK cells were also refractory to mitogenic and antigenic stimulation. 15 An essential role for caspase-8 in T-cell activation was proven by the analysis of mice devoid of caspase-8 only in T cells.…”

“…15 The resulting instability of caspase-8 rendered lymphocytes resistant to Fas-induced apoptosis and surprisingly, B, T and NK cells were also refractory to mitogenic and antigenic stimulation. 15 An essential role for caspase-8 in T-cell activation was proven by the analysis of mice devoid of caspase-8 only in T cells. 12,16 While it is known that FADD transmits the apoptotic signal by recruiting caspase-8 and promoting its activation through conformational change, it is unclear how FADD and caspase-8 promote cell proliferation.…”