Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells

Getahun, Andrew; Beavers, Nicole A.; Larson, Sandy; Shlomchik, Mark J.; Cambier, John C.

doi:10.1083/jcb.2133oia94

Cited by 8 publications

(9 citation statements)

References 22 publications

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“…62,63 Inducible deletion of PTEN is also sufficient to break tolerance of Ars/A1 B cells, although unlike anergic IgHEL B cells, PTEN itself is not overexpressed in this more modestly self-reactive model. 64 These findings may be generalizable to non-Tg B cells; Cambier and colleagues recently showed that PTEN expression varied continuously across the normal human B cell repertoire and correlated with increasing anergy and decreasing IgM expression. 65 More recently, Shlomchik and colleagues identified PTEN overexpression in GC B cells, which serves to redirect AKT kinase activity toward negative regulators of proximal BCR signaling, thereby engaging a negative feedback loop.…”

Section: Bcr Tg Mouse Modelsmentioning

confidence: 90%

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

Tan

Noviski

Huizar

et al. 2019

Immunological Reviews

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Efficient mechanisms of central tolerance, including receptor editing and deletion, prevent highly self-reactive B cell receptors (BCRs) from populating the periphery.Despite this, modest self-reactivity persists in (and may even be actively selected into) the mature B cell repertoire. In this review, we discuss new insights into mechanisms of peripheral B cell tolerance that restrain mature B cells from mounting inappropriate responses to endogenous antigens, and place recent work into historical context. In particular, we discuss new findings that have arisen from application of a novel in vivo reporter of BCR signaling, Nur77-eGFP, expression of which scales with the degree of self-reactivity in both monoclonal and polyclonal B cell repertoires. We discuss new and historical evidence that self-reactivity is not just tolerated, but actively selected into the peripheral repertoire. We review recent progress in understanding how dual expression of the IgM and IgD BCR isotypes on mature naive follicular B cells tunes responsiveness to endogenous antigen recognition, and discuss how this may be integrated with other features of clonal anergy. Finally, we discuss how expression of Nur77 itself couples chronic antigen stimulation with B cell tolerance. K E Y W O R D Sanergy, B cell, IgD, IgM, Nur77/Nr4a1, tolerance Previous work from our laboratory exploiting an in vivo reporter of antigen recognition, Nur77-eGFP BAC Tg, addresses this important point ( Figure 1A). 15 GFP expression in this reporter line is under the control of the regulatory region of Nr4a1/ Nur77. Nr4a1-3 encode a small family of orphan nuclear hormone receptors which were originally cloned as signal-dependent primary response genes (also known as immediate-early genes), and are highly upregulated by a range of mitogens, including antigen receptor stimulation. [16][17][18] Consequently, antigen stimulation rapidly triggers reporter expression in B and T cells in vitro ( Figure 1B), and GFP is also induced by infection or immunization in antigen-specific lymphocytes in

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Section: Bcr Tg Mouse Modelsmentioning

confidence: 90%

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

Tan

Noviski

Huizar

et al. 2019

Immunological Reviews

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“…33 Adoptive transfer of anergic B cells with subsequent induction of gene expression further showed that the inhibitory signaling pathways involved a tyrosine phosphatase SHP-1 and inositol phosphatase SHIP-1, which are both required to maintain anergy. 34 Activation events that disrupt anergy lead to rapid cell activation, proliferation, and short-lived plasma cells that reside in extrafollicular foci. 34 Previous studies by Goodnow and coworkers showed similar anergy loss in mice lacking Lyn, SHP-1, and CD22.…”

Section: Preg Erminal Center S Tag E B-cellmentioning

confidence: 99%

“…34 Activation events that disrupt anergy lead to rapid cell activation, proliferation, and short-lived plasma cells that reside in extrafollicular foci. 34 Previous studies by Goodnow and coworkers showed similar anergy loss in mice lacking Lyn, SHP-1, and CD22. The mechanistic basis was found to be phosphorylation of CD22 by Lyn, which then recruits SHP-1 to the CD22/BCR complex.…”

Section: Preg Erminal Center S Tag E B-cellmentioning

confidence: 99%

Autoreactive B cells in SLE, villains or innocent bystanders?

Hamilton

Hsu

Mountz

2019

Immunological Reviews

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Autoreactive B-cell development in SLE (systemic lupus erythematosus) is often considered in terms of the extrinsic stimuli and factors that drive B cells into autoantibody production. This review focuses on the novel concept that autoreactive B cells are initially programmed at the transitional stage for heightened susceptibility for development into autoantibody secreting plasmablasts (Figure 1). During peripheral B-cell development in the spleen, transitional B-cells expressing elevated levels of endogenous intracellular interferon-β (IFNβ) exhibit enhanced survival and activation through the B-cell receptor (BCR), a feature associated with more active SLE, particularly in African American (AA) patients. 1 Following passage through the transitional stage, a second major defect is the failure of B cells to maintain the integrity of tolerogenic splenic marginal zone macrophages (MZM), which normally function to remove apoptotic cell debris in a non-inflammatory fashion through upregulation of indoleamine-pyrrole 2,3-dioxygenase (IDO). 2 This failure is amplified by the type I IFN-driven migratory properties of marginal zone-precursor (MZ-P) B cells as they lose their tethering to sphingosine-1-phosphate (S1P) and drift across the follicular exclusion barrier. 3-8 Here they act as potent antigen-carrying, co-stimulatory cells expressing inflammatory cytokine IL-6 and low levels of the antiinflammatory cytokine IL-10. 9 In addition, Ag transporting MZ-P B-cells Abstract The current concepts for development of autoreactive B cells in SLE (systemic lupus erythematosus) focus on extrinsic stimuli and factors that provoke B cells into tolerance loss. Traditionally, major tolerance loss pathways are thought to be regulated by factors outside the B cell including autoantigen engagement of the B-cell receptor (BCR) with simultaneous type I interferon (IFN) produced by dendritic cells, especially plasmacytoid dendritic cells (pDCs). Later, in autoreactive follicles, B-cells encounter T-follicular helper cells (Tfh) that produce interleukin (IL)-21, IL-4 and pathogenic cytokines, IL-17 and IFN gamma (IFNɣ). This review discusses these mechanisms and also highlights recent advances pointing to the peripheral transitional B-cell stage as a major juncture where transient autocrine IFNβ expression by developing B-cells imprints a heightened susceptibility to external factors favoring differentiation into autoantibody-producing plasmablasts. Recent studies highlight transitional B-cell heterogeneity as a determinant of intrinsic resistance or susceptibility to tolerance loss through the shaping of B-cell responsiveness to cytokines and other environment factors.

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“…This defective BCR signalling results in reduced lifespan of the anergic B cells, altered migration and anatomical localization, and an inability to interact productively with helper T cells. Continuous inhibitory signalling pathways through tyrosine phosphatase Src homology region 2 1 domaincontaining phosphatase-1 (SHP-1) and the SH2-domaincontaining inositol phosphatase (SHIP-1) are required to maintain anergy, and inhibition of either of these pathways restored B cell activation, proliferation and generation of short-lived plasma cells [67]. Finally, anergic B cells have been reported as having an immature T3 [IgM mid , CD80 hi , CD95 hi , major histocompatibility complex (MHC) class II hi ] or a preplasma phenotype depending on the BCR specificity as well as ligand quality and quantity [60].…”

Section: Anergy and Regulation As Mechanisms Of B Cell Tolerancementioning

confidence: 99%

Transplantation tolerance: don't forget about the B cells

Chong

Khiew

2017

Clinical and Experimental Immunology

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SummaryEstablishing a state of transplantation tolerance that leads to indefinite graft survival without the need for lifelong immunosuppression has been achieved successfully in limited numbers of transplant recipients in the clinic. These successes led to studies aimed at identifying potential biomarkers that diagnose allograft tolerance and identify the patients most amenable to drug minimization, and implicated an enriched B cell signature of tolerance. The emergence of a specialized subset of regulatory B cell (B regs ), that possess immune-modulatory function in inflammation and autoimmune disease, raised the possibility that B regs play critical roles in the promotion of transplantation tolerance and that B regs are the underlying explanation for the B cell signature of tolerance. However, B cells are best known to play a key role in humoral immunity, and excessive production of donor specific antibodies has clear deleterious effects in transplantation. Thus, for tolerance to be persistent, alloantibody responses must also be curtailed, either through the suppression of T cell help or the induction of B cell-intrinsic dysfunction. Recent findings indicate a unique subset of follicular regulatory T cells (Tfr) that can suppress B cell function and induce epigenetic modifications that result in sustained defects in B cell differentiation and function. In this review, we summarize studies in animals and humans that suggest roles for B regs and dysfunctional B cells in transplantation tolerance, and discuss how these insights may provide a roadmap for new approaches to diagnose, and new therapies to induce allograft tolerance.

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Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells

Cited by 8 publications

References 22 publications

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

Autoreactive B cells in SLE, villains or innocent bystanders?

Transplantation tolerance: don't forget about the B cells

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