Extreme lymphoproliferative disease and fatal autoimmune thrombocytopenia in FasL and TRAIL double-deficient mice

Abstract

To delineate the relative roles of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand in lymphocyte biology and lymphoproliferative disease, we generated mice defective in both molecules. B6.GT mice develop severe polyclonal lymphoproliferative disease because of accumulating CD3 ؉ CD4 ؊ CD8 ؊ B220 ؉ T cells, CD4 ؉ and CD8 ؉ T cells, and follicular B cells, and mice die prematurely from extreme lymphocytosis, thrombocytopenia, and hemorrhage. IntroductionApoptotic cell death is mediated primarily by 2 distinct pathways: the intrinsic mitochondrial-sensed, Bcl2-family regulated pathway and the extrinsic death-ligand/receptor pathway. Members of the tumor necrosis factor (TNF) family of death-inducing ligands, such as Fas ligand (FasL), TNF, and TNF-related apoptosis-inducing ligand (TRAIL), compose the extrinsic pathway, and these molecules bind to specific receptors that contain a "death-domain" signature in their cytoplasmic region. For FasL and TRAIL, ligand binding results in recruitment of Fas-associated death domain adaptor protein to the receptor's death domain enabling subsequent recruitment and activation of procaspase-8 and/or procaspase-10. Apical caspases then act on downstream effector caspases that leads to degradation of the inhibitor of the caspase-activated DNase, with cleavage of dsDNA causing apoptotic cell death. 1 To date, however, the specific roles and redundancies of the multiple death TNF-family death ligands and receptors are unclear.Despite the conservation in intracellular death receptor signaling, the biologic functions of TNF/TNFR molecules in vivo appear to be divergent. TNF-␣ is an important mediator of inflammation 2 and a key cause of apoptosis of virus-infected cells, 3 and FasL/Fas plays a critical role in the elimination of self-reactive lymphocytes and in regulating T cell homeostasis. 4 In contrast, the physiologic role of TRAIL in vivo is still emerging. TRAIL specifically kills transformed 5 and virally infected cells 6 and controls tumor growth and metastasis contributing to tumor surveillance. [7][8][9][10] The inert properties of LZ-TRAIL on normal cells 5,11 has led to Apo2L/ TRAIL protein and agonistic receptor-specific antibodies being trialed for the treatment of human cancers. However, it is debatable whether TRAIL's tumoricidal activity provides sufficient evolutionary pressure for its existence as the fourth death ligand/receptor system in humans. That cancer most frequently occurs in persons after child-bearing age and that TNF-␣ and FasL also have tumorigenic properties 12,13 suggest that TRAIL/TRAIL-Rs mediates biologic functions that remain to be defined. Curiously, the study of TRAIL Ϫ/Ϫ mice revealed little about the roles of TRAIL in vivo as these mice are essentially physiologically normal. 7 It is now apparent that, because most cells that express TRAIL also express FasL 14 and because TRAIL and FasL initiate a death-signaling pathway that is almost identical, 15 attempts to define the physiologic role of TRAIL/TRAIL-Rs in vi...

Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia

“…In a word, the total TRAIL expression on the platelet surface of group A might be in a much lower level, which may enhance the role of TRAIL in impaired megakaryocyte apoptosis through the TRAIL/ TRAIL-R2 pathway. Recently, Sedger et al 44 have reported that FasL and TRAIL double deficient mice develop extreme lymphoproliferative disease and fatal autoimmune thrombocytopenia, which is a little different from the results of our study. However, severe lymphoproliferative disease is the result of maximal resistance of lymphocytes to activation-induced cell death, and dysregulated lymphocyte homeostasis resulted in the production of antiplatelet IgM and IgG causing thrombocytopenia.…”

Functional TRAIL receptors in monocytes and tumor-associated macrophages: A possible targeting pathway in the tumor microenvironment

“…TRAIL-deficient mice have been reported to have defects in the thymic negative selection and control of central tolerance, with consequences for the development of autoimmune diseases [37, 38] although not confirmed in other studies [39]. Sedger et al reported that control of aberrant lymphocyte expansion requires both FasL and TRAIL and only the double KO mice show a marked lymphoproliferative disease and severe autoimmunity [40]. Thus TRAIL in tandem with FasL are important to control lymphocyte homeostasis and to limit autoimmunity.…”

TRAIL–Receptor Costimulation Inhibits Proximal TCR Signaling and Suppresses Human T Cell Activation and Proliferation

“…The TRAIL-R/TRAIL system was previously described to contribute to T cell homeostasis because blocking Abs against TRAIL reduced the efficiency of activation-induced cell death (31), and mice deficient for CD95L and TRAIL developed a more severe lymphoproliferative disease than mice deficient for CD95L alone (32). Also, "helpless" CD8 + Ag-activated T cells generated in the absence of CD4 + T cells die by TRAIL-mediated, activationinduced cell death upon restimulation (33).…”