Accelerated thymic atrophy as a result of elevated homeostatic expression of the genes encoded by the TNF/lymphotoxin cytokine locus

Liepinsh, Dmitry J.; Kruglov, Andrey; Galimov, A R; Shakhov, Alexander N.; Shebzukhov, Yuriy V.; Kuchmiy, Anna; Grivennikov, Sergei I.; Tumanov, Alexei V.; Drutskaya, Marina S.; Feigenbaum, Lionel; Kuprash, Dmitry V.; Nedospasov, Sergei A.

doi:10.1002/eji.200839191

Cited by 30 publications

(31 citation statements)

References 51 publications

(57 reference statements)

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“…Overexpression of TNF-a under control of its natural promoter has been reported to block early thymocyte development at the DN1 to DN2 stage, promoting accelerated thymic atrophy (49) and mirroring our own observations in the NOD thymus. This effect, similarly to the phenotypes we describe, is intrinsic to the hematopoietic cell compartment.…”

Section: Discussionsupporting

confidence: 88%

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

Ferreira

Palmer

Blake

et al. 2014

The Journal of Immunology

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The thymic natural regulatory T cell (Treg) compartment of NOD mice is unusual in having reduced TCR diversity despite normal cellularity. In this study, we show that this phenotype is attributable to perturbations in early and late stages of thymocyte development and is controlled, at least in part, by the NOD Idd9 region on chromosome 4. Progression from double negative 1 to double negative 2 stage thymocytes in NOD mice is inefficient; however, this defect is compensated by increased proliferation of natural Tregs (nTregs) within the single positive CD4 thymocyte compartment, accounting for recovery of cellularity accompanied by loss of TCR diversity. This region also underlies the known attenuation of ERK-MAPK signaling, which may preferentially disadvantage nTreg selection. Interestingly, the same genetic region also regulates the rate of thymic involution that is accelerated in NOD mice. These findings highlight further complexity in the control of nTreg repertoire diversity.

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Section: Discussionsupporting

confidence: 88%

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

Ferreira

Palmer

Blake

et al. 2014

The Journal of Immunology

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“…Tg Lck-LTαβ mice develop a fulminant thymus involution that is dependent on LTα 3 /TNFR1 and LTα 1 β 2 /LTβR signaling within the cTEC recapitulating virus infection-related thymic involution by activated LTαβ-overexpressing T cells. 44,45 Therefore, to assess the role of NIK in cell death of cTEC, we performed bone marrow (BM) reconstitution assays using WT or Tg Lck-LTαβ mice as donors and WT or aly/aly NIK-deficient recipient mice. 46 For phenotypic analyses, 8 weeks postreconstitution mice were killed and thymi were imaged and quantitatively and qualitatively analyzed.…”

Section: Resultsmentioning

confidence: 99%

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

et al. 2015

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NF-κB-inducing kinase (NIK) is well-known for its role in promoting p100/NF-κB2 processing into p52, a process defined as the alternative, or non-canonical, NF-κB pathway. Here we reveal an unexpected new role of NIK in TNFR1-mediated RIP1-dependent apoptosis, a consequence of TNFR1 activation observed in c-IAP1/2-depleted conditions. We show that NIK stabilization, obtained by activation of the non-death TNFRs Fn14 or LTβR, is required for TNFα-mediated apoptosis. These apoptotic stimuli trigger the depletion of c-IAP1/2, the phosphorylation of RIP1 and the RIP1 kinase-dependent assembly of the RIP1/FADD/caspase-8 complex.In the absence of NIK, the phosphorylation of RIP1 and the formation of RIP1/FADD/caspase-8 complex are compromised while c-IAP1/2 depletion is unaffected. In vitro kinase assays revealed that recombinant RIP1 is a bona fide substrate of NIK. In vivo, we demonstrated the requirement of NIK pro-death function, but not the processing of its substrate p100 into p52, in a mouse model of TNFR1/LTβR-induced thymus involution. In addition, we also highlight a role for NIK in hepatocyte apoptosis in a mouse model of virus-induced TNFR1/RIP1-dependent liver damage. We conclude that NIK not only contributes to lymphoid organogenesis, inflammation and cell survival but also to TNFR1/RIP1-dependent cell death independently of the alternative NF-κB pathway.

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“…The expression of Tg TNF/LT gene products led to thymic atrophy, suggesting that upregulation of LT and TNF might be responsible for thymic atrophy in infections (Liepinsh et al 2009). …”

Section: Discussionmentioning

confidence: 98%

Effects of Plasmodium berghei on thymus: High levels of apoptosis and premature egress of CD4+CD8+ thymocytes in experimentally infected mice

et al. 2011

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Accelerated thymic atrophy as a result of elevated homeostatic expression of the genes encoded by the TNF/lymphotoxin cytokine locus

Cited by 30 publications

References 51 publications

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

Effects of Plasmodium berghei on thymus: High levels of apoptosis and premature egress of CD4+CD8+ thymocytes in experimentally infected mice

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