IL-7 Promotes CD95-Induced Apoptosis in B Cells via the IFN-γ/STAT1 Pathway

Sammicheli, Stefano; Phuong, Linh Dang Vu; Ruffin, Nicolas; Hong, Thang Pham; Lantto, Rebecka; Vivar, Nancy; Chiodi, Francesca; Réthi, Bence

doi:10.1371/journal.pone.0028629

Cited by 16 publications

(14 citation statements)

References 55 publications

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“…Our results are consistent with the elevated levels of BAFF (also known as BLyS) observed during HIV-1 infection, in association with hypergammaglobulinemia [58]. We also found that Fas expression on B cells is modulated by the release of interferon-g (IFN-g) from IL-7-treated T cells [55]. The increased Fas expression further sensitizes the B cells to undergo Fas-mediated apoptosis.…”

Section: Influence Of Cytokines On B-cell Homeostasissupporting

confidence: 88%

“…We showed recently that cytokines commonly associated with lymphopenia and increased T-cell activation might strongly influence B-cell homeostasis [55,11]. These studies suggested that IL-7, present in elevated concentrations in the circulation of several T-cell-depleted individuals [33], may interfere with B-cell proliferation and survival in novel and nonantigen-specific manners.…”

Section: Influence Of Cytokines On B-cell Homeostasismentioning

confidence: 99%

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Impairment of B-cell functions during HIV-1 infection

Amu

Ruffin

Réthi

et al. 2013

Aids

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A variety of B-cell dysfunctions are manifested during HIV-1 infection, as reported early during the HIV-1 epidemic. It is not unusual that the pathogenic mechanisms presented to elucidate impairment of B-cell responses during HIV-1 infection focus on the impact of reduced T-cell numbers and functions, and lack of germinal center formation in lymphoid tissues. To our understanding, however, perturbation of B-cell phenotype and function during HIV-1 infection may begin at several different B-cell developmental stages. These impairments can be mediated by intrinsic B-cell defects as well as by the lack of proper T-cell help. In this review, we will highlight some of the pathways and molecular interactions leading to B-cell impairment prior to germinal center formation and B-cell activation mediated through the B-cell receptor in response to HIV-1 antigens. Recent studies indicate a regulatory role for B cells on T-cell biology and immune responses. We will discuss some of these novel findings and how these regulatory mechanisms could potentially be affected by the intrinsic defects of B cells taking place during HIV-1 infection.

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Section: Influence Of Cytokines On B-cell Homeostasissupporting

confidence: 88%

Section: Influence Of Cytokines On B-cell Homeostasismentioning

confidence: 99%

Impairment of B-cell functions during HIV-1 infection

Amu

Ruffin

Réthi

et al. 2013

Aids

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“…These early IFNγ-dependent signals are required for subsequent proliferation and differentiation following stimulation with IL-21 and TLR7/8 ligand. IFNγ is not, in and of itself, a B cell mitogen and has, in fact, been reported to induce apoptosis of human B cells (64, 65). However, we find that IFNγ synergizes with TLR7/8 ligand signals to promote multiple rounds of B cell proliferation – an important prerequisite of ASC differentiation (66).…”

Section: Discussionmentioning

confidence: 99%

IFNγ induces epigenetic programming of human T-bet^hiB cells and promotes TLR7/8 and IL-21 induced differentiation

Zumaquero

Stone

Scharer

et al. 2019

Preprint

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34Although B cells expressing the IFNgR or the IFNg-inducible transcription factor T-bet drive autoimmunity 35 in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNg signaling in human 36 antibody responses is unknown. We show that elevated levels of IFNg in SLE patients correlate with 37 expansion of the T-bet expressing IgD neg CD27 neg CD11c + CXCR5 neg (DN2) pre-antibody secreting cell 38 (pre-ASC) subset. We demonstrate that naïve B cells form T-bet hi pre-ASCs following stimulation with 39 either Th1 cells or with IFNg, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is 40 significantly enhanced by IFNg or IFNg-producing T cells. IFNg promotes ASC development by 41 synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, 42 which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and 43 epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFNg signals poise B cells to 44 differentiate by increasing their responsiveness to 45 46 50 adaptive arms of the immune system, which ultimately leads to loss of immune tolerance in B and T 51 lymphocytes and the production of autoantibodies (Abs) by Ab-secreting B cells (ASCs) (1). The hallmark 52 SLE autoAbs recognize nuclear proteins and nucleic acids (2), which are also ligands for TLR7 and TLR9 53 that are expressed by innate immune cells and B cells (3). SLE autoAbs bound to their autoAgs form 54 immune complexes, which are responsible for many of the clinical manifestations of SLE, particularly 55 those associated with organ damage (2). Consistent with the important role for B cells and ASCs in SLE 56 pathogenesis (4), the only new drug approved to treat SLE in decades, Belimumab, targets B cells. 58Inflammatory cytokines and chemokines also contribute to SLE pathogenesis (5). SLE patient PBMCs 59 often exhibit a type I interferon (IFN) transcriptional signature and systemic IFNa is elevated in many 60 patients (6). It is less well appreciated that IFNg is also increased in some SLE patients (7-9) and that a 61 distinct IFNg transcription signature can be detected in PBMCs from a portion of SLE patients (10, 11). 62Interestingly, elevated serum IFNg can be observed years before IFNa or autoAbs are detected in SLE 63 patients and much earlier than clinical disease (12, 13). Consistent with these observations, B cells from 64 SLE patients can exhibit signs of prior IFNg exposure. For example, CXCR3 and T-bet, two IFNg-inducible 65 proteins (14), are more highly expressed by circulating B cells from SLE patients compared to healthy 66 controls (8,(15)(16)(17)(18)(19). Moreover, data from mouse SLE models show that clinical disease is dependent on 67 B cell-specific expression of the IFNgR and the IFNg-induced transcription factors and T-68 bet in some (23, 24) but not all (21, 25) models. Taken together, these data suggest that IFNg-driven 69 inflammation may contribute to SLE B cell-driven pathophysiology. 71Two populations of...

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“…Although such unresponsiveness is frequently achieved by loss of cytokine receptor expression , other mechanisms, including the abnormal activity of a negative regulator of cytokine signalling, may also play a role. SOCS1, in particular, might contribute to induce loss of responsiveness of tumour cells to HIV‐induced cytokines, for example, loss of responsiveness to INF‐γ, which causes B‐cell defects and apoptosis .…”

Section: Discussionmentioning

confidence: 99%

Alterations of negative regulators of cytokine signalling in immunodeficiency‐related non‐Hodgkin lymphoma

Capello

Gloghini

Baldanzi

et al. 2012

Hematological Oncology

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We investigated immunodeficiency-related non-Hodgkin lymphoma for the presence of molecular alterations affecting negative regulators of the Janus family protein tyrosine kinase/signal transducer and activator of transcription pathway. Protein tyrosine phosphatase, non-receptor type 6/Src homology 2-containing tyrosine phosphatase-1 epigenetic silencing was recurrent in primary effusion lymphoma (100%), and diffuse large B-cell lymphoma (63%), with a higher prevalence in the non-germinal centre subtype, and was associated with the activation of the Janus family protein tyrosine kinase/signal transducer and activator of transcription 3 pathway. Suppressor of cytokine signalling (SOCS)1 and SOCS3 epigenetic silencing were occasionally detected, whereas SOCS1 was frequently mutated in diffuse large B-cell lymphoma and polymorphic post-transplant lymphoproliferative disorders, possibly as a cause of aberrant somatic hypermutation. However, the mutation profile of the coding region of the gene was different from that expected from the aberrant somatic hypermutation process, suggesting that, at least in some cases, SOCS1 mutations may have been selected for their functional activity.

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IL-7 Promotes CD95-Induced Apoptosis in B Cells via the IFN-γ/STAT1 Pathway

Cited by 16 publications

References 55 publications

Impairment of B-cell functions during HIV-1 infection

Impairment of B-cell functions during HIV-1 infection

IFNγ induces epigenetic programming of human T-bet^hiB cells and promotes TLR7/8 and IL-21 induced differentiation

Alterations of negative regulators of cytokine signalling in immunodeficiency‐related non‐Hodgkin lymphoma

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IL-7 Promotes CD95-Induced Apoptosis in B Cells via the IFN-γ/STAT1 Pathway

Cited by 16 publications

References 55 publications

Impairment of B-cell functions during HIV-1 infection

Impairment of B-cell functions during HIV-1 infection

IFNγ induces epigenetic programming of human T-bethiB cells and promotes TLR7/8 and IL-21 induced differentiation

Alterations of negative regulators of cytokine signalling in immunodeficiency‐related non‐Hodgkin lymphoma

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IFNγ induces epigenetic programming of human T-bet^hiB cells and promotes TLR7/8 and IL-21 induced differentiation