Cell cycle regulation by FasL and Apo2L/TRAIL in human T-cell blasts. Implications for autoimmune lymphoproliferative syndromes

Bosque, Alberto; Aguilo, Nacho; Rey, Manuel; Paz-Artal, Estela; Allende, Luis M.; Naval, Javier; Anel, Alberto

doi:10.1189/jlb.0108043

Cited by 18 publications

(17 citation statements)

References 49 publications

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“…The same group confirmed this concept using Jurkat T cells (45). In a later study (4), Fas binding of human T cell blasts reduced their proliferation with a concomitant increase in p21, a finding that directly associates p21 with the antiproliferative mechanism of the Fas/FasL system. These studies reinforce the view that the Fas/FasL system attenuates proliferation, although Fas cross-linking in vitro could entail questions regarding the physiological relevance of these data.…”

Section: Etiology Of In Vivo Lpr T Cell Proliferationmentioning

confidence: 86%

“…In a previous study, T cell blasts from ALPS patients with higher responses than controls showed lower p21 expression (4). We therefore overexpressed the cell cycle inhibitor p21 in B6/ lpr and MRL/ lpr mice in a T cell-specific manner.…”

Section: Reduction Of T Cell Hyperproliferation Regulates Lymphadenopmentioning

confidence: 86%

“…The hyperproliferative T cell phenotype of lpr mice is also observed in patients with autoimmune lymphoproliferative syndrome (ALPS) (2–4), an autoimmune disease also characterized by defective Fas/FasL signaling. ALPS patients are classified by distinct disease types, depending on the underlying genetic defect (5).…”

Section: Phenotype and Characteristics Of Fas-deficient Micementioning

confidence: 99%

“…T cell hyperproliferation is also observed in patients with ALPS (2, 4), an autoimmune disease characterized by defective Fas/FasL signaling or by other genetic defects associated with the Fas/FasL pathway. The major features of this syndrome are DN T cell accumulation, lymphadenopathy development, autoimmunity, and increased lymphoma risk (5).…”

Section: Hyperproliferation Of All Lpr Mouse T Cell Subsetsmentioning

confidence: 99%

“…To explain the lymphoproliferative and autoimmune lpr phenotype, we suggested that Fas deficiency also leads to T cell proliferation abnormalities (30), a view previously proposed based on studies of ALPS patients (4). Indeed, treatment of ALPS patients includes drugs that target the activation/proliferation aspects of accumulating T cells, such as mycophenolate mofetil and sirolimus (rapamycin) (31).…”

Section: Hyperproliferation Of All Lpr Mouse T Cell Subsetsmentioning

confidence: 99%

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On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice

et al. 2017

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Fas induces massive apoptosis in T cells after repeated in vitro T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (lpr) mice. Although the in vitro Fas apoptotic mechanism has been defined, there is a large conceptual gap between this in vitro phenomenon and the pathway that leads to in vivo development of lymphadenopathy and autoimmunity. A striking abnormality in lpr mice is the excessive proliferation of CD4+ and CD8+ T cells, and more so of the double-negative TCR+CD4−CD8−B220+ T cells. The basis of lpr T cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all lpr T cell subtypes and lymphadenopathy in lpr mice. p21 controls expansion of repeatedly stimulated T cells without affecting apoptosis. These results confirm a direct link between hyperactivation/hyperproliferation, autoreactivity, and lymphadenopathy in lpr mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control lpr T cell hyperproliferation. lpr T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated lpr T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause lpr T cell hyperactivation/hyperproliferation in vivo. We propose that Fas/Fas ligand (FasL) acts as an activation inhibitor of recurrently stimulated T cells, and that its disruption causes overexpansion of T cells in lpr mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of lpr mice and lead to therapeutics for related human syndromes.

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Section: Etiology Of In Vivo Lpr T Cell Proliferationmentioning

confidence: 86%

Section: Reduction Of T Cell Hyperproliferation Regulates Lymphadenopmentioning

confidence: 86%