Nur77 Is Upregulated in B-1a Cells by Chronic Self-Antigen Stimulation and Limits Generation of Natural IgM Plasma Cells

Huizar, John; Tan, Chung-I; Noviski, Mark; Mueller, James L.; Zikherman, Julie

doi:10.4049/immunohorizons.1700048

Cited by 19 publications

(24 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3B, 3C). A similar phenomenon has been described in both Ig HEL Tg and anti-Thy-1 (ATA) Tg mice lacking Thy-1 Ag (12,35). This stands in marked contrast to the B2 compartment in B1-8i mice, which is populated almost exclusively by VH186.2 H chain-expressing cells (Fig.…”

Section: Development Of B1a Cells Expressing the B1-8i H Chain Transgsupporting

confidence: 79%

“…Selection into the innate-like B1a compartment requires the recognition of endogenous Ags sufficient to drive strong BCR signaling (12)(13)(14)(15). Consistent with the high self-reactivity of these cells, we recently showed that B1a cells express much higher levels of Nur77-eGFP reporter than B2 cells, and this was higher still among phosphatidylcholine-binding B1a cells that mark highly enriched, extremely self-reactive clones in this compartment (35). We first sought to determine whether NP + cells with low self-reactivity were indeed precluded from entering the B1a compartment in B1-8i mice.…”

Section: Development Of B1a Cells Expressing the B1-8i H Chain Transgmentioning

confidence: 53%

See 1 more Smart Citation

Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens

Noviski

Tan

Huizar

et al. 2019

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

It has long been appreciated that highly autoreactive BCRs are actively removed from the developing B cell repertoire by Agdependent receptor editing and deletion. However, there is persistent debate about whether mild autoreactivity is simply tolerated or positively selected into the mature B cell repertoire as well as at what stage, to what extent, under what conditions, and into which compartments this occurs. In this study, we describe two minor, trackable populations of B cells in B1-8i Ig transgenic mice that express the VH186.2 H chain and recognize a common foreign Ag (the hapten 4-hydroxy-3-nitrophenylacetyl) but differ in L chain expression. We use the Nur77-eGFP reporter of BCR signaling to define their reactivity toward endogenous Ags. The less autoreactive of these two populations is strongly counterselected during the development of mature B1a, follicular, and marginal zone B cells. By genetically manipulating the strength of BCR signal transduction via the titration of surface CD45 expression, we demonstrate that this B cell population is not negatively selected but instead displays characteristics of impaired positive selection. We demonstrate that mild self-reactivity improves the developmental fitness of B cell clones in the context of a diverse population of B cells, and positive selection by endogenous Ags shapes the mature B cell repertoire.

show abstract

Section: Development Of B1a Cells Expressing the B1-8i H Chain Transgsupporting

confidence: 79%

Section: Development Of B1a Cells Expressing the B1-8i H Chain Transgmentioning

confidence: 53%

Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens

Noviski

Tan

Huizar

et al. 2019

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Next, to test in vivo relevance of these in vitro observations, we probed immune response to a T-independent BCR stimulus, NP-Ficoll. We previously reported enhanced IgM responses to NP-Ficoll immunization of Nr4a1-/-hosts and here observe profoundly increased IgG3 responses to this immunogen across multiple time points (Fig 6A) 30 . NP-Ficoll responses are completely dependent upon intact BCR signal transduction 47 .…”

Section: Nur77/nr4a1 Restrains Humoral Responses To Ag In the Absencesupporting

confidence: 77%

“…More recently, we have identified a role for NUR77/Nr4a1 in imposing a novel layer of B cell tolerance in vivo by mediating competitive elimination of chronically Ag-stimulated self-reactive B cells in settings with a limiting supply of the B cell survival factor BAFF 28 . We have similarly shown that NUR77 is upregulated by Ag in the highly self-reactive innate-like B1a population where it functions to restrain generation of natural IgM plasma cells 30 . Although expression of Nr4a genes is rapidly and robustly upregulated in response to acute BCR stimulation, their function in this context is unknown, and redundancy among the family members has never been explored in B cells.…”

Section: Introductionmentioning

confidence: 68%

“A negative feedback loop mediated by the NR4A family of nuclear hormone receptors restrains expansion of B cells that receive signal one in the absence of signal two”

Tan¹,

Hiwa²,

Jl³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

CCL4Running title: NR4A family renders B cells dependent upon a second signal ABSTRACT Ag stimulation (signal 1) triggers B cell activation and proliferation, and primes B cells to recruit, engage, and respond to T cell help (signal 2). However, failure to receive signal 2 within a defined window of time results in an abortive round of proliferation, followed by anergy or apoptosis. Although the molecular basis of T cell help has been extensively dissected, the mechanisms that restrain Ag-stimulated B cells, and enforce dependence upon co-stimulation, are incompletely understood. Nr4a1-3 encode a small family of orphan nuclear receptors that are rapidly induced by B cell receptor (BCR) stimulation, yet little is known about their function in humoral immune responses. Here we use germline and conditional loss-of-function mouse models to show that Nr4a1 and Nr4a3 play partially redundant roles to restrain both the survival and proliferation of B cells that receive signal 1 in the absence of co-stimulatory signals, and do so in part by repressing expression of BATF and consequently c-MYC. Correspondingly, Ab responses to TI-2 immunogens are enhanced in the absence of Nr4a1, but are unaltered in response to immunogens that incorporate co-stimulatory signals.Unexpectedly, we also identify a role for the NR4A family in restraining B cell access to T cell help by repressing expression of the T cell chemokines CCL3/4, as well as CD86 and ICAM1, and show that this is relevant under conditions of competition for limiting T cell help. Our studies collectively reveal a novel negative feedback loop mediated by the NR4A family that increases B cell dependence upon T cell help and restrains stronglyAg-activated B cell clones from monopolizing limiting amounts of T cell help. We speculate that this imposes B cell tolerance and dampens immunodominance to facilitate preservation of clonal diversity during an immune response.were from The Jackson Laboratory 32-38 . TCRalpha-/-were obtained from the Weiss lab 39 . Nr4a3-/-mice were generated via electroporation of gRNA and Cas9 mRNA. In brief, Cas9 protein (40µM) and Nr4a3 gRNAs (80µM) were mixed and electroporated into C57BL/6 zygotes. The sequence of Nr4a3 exon 3 (containing start ATG) targeted for deletion is shown in Fig 4E. 15 founder lines with the targeted deletion were identified through a screen for PCR amplicon size, and confirmed via sequencing of cloned PCR products. Two founder lines were chosen for further analysis and were backcrossed for at least 4 generations onto the C57BL/6J genetic background. All other strains were fully backcrossed to the C57BL/6J genetic background for at least 6 generations. All mice were housed in a specific pathogen-free facility at UCSF according to University and National Institutes of Health guidelines.Antibodies and Reagents.

show abstract

“…133,134 Recently, we showed that Nur77-eGFP reporter expression was highly upregulated by chronic antigen stimulation in self-reactive B1a cells, particularly in highly self-reactive PtC-binding clones. 135 Unexpectedly, we found that deletion of Nr4a1 markedly increased the generation of B1a-derived natural IgM plasma cells, but did not expand the size of the B1a compartment. By contrast to ITIM-dependent inhibitory tone, Nur77 seems to regulate a distinct, downstream checkpoint by an unknown mechanism.…”

Section: Compe Titive Fitne Ss Of S Elf-re Ac Tive B Cell S In the mentioning

confidence: 61%

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

Tan

Noviski

Huizar

et al. 2019

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

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

show abstract

Nur77 Is Upregulated in B-1a Cells by Chronic Self-Antigen Stimulation and Limits Generation of Natural IgM Plasma Cells

Cited by 19 publications

References 35 publications

Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens

Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens

“A negative feedback loop mediated by the NR4A family of nuclear hormone receptors restrains expansion of B cells that receive signal one in the absence of signal two”

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

Contact Info

Product

Resources

About