B Cell Responses: Cell Interaction Dynamics and Decisions

Cyster, Jason G.; Allen, Christopher D.C.

doi:10.1016/j.cell.2019.03.016

Cited by 592 publications

(647 citation statements)

References 186 publications

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“…In vivo B cell responses to T-dependent stimuli such as haptenprotein conjugates are characterized by an initial phase of antigen-dependent events such as entry into cell cycle, upregulation of peptide-loaded MHC-II, adhesion, and costimulatory molecules, and secretion of chemokines that collectively facilitate recruitment of T cell help, along with migration away from the B cell follicle and toward the T-B border for the purpose of accessing such help. 136 Of necessity, there is a physiological delay between receipt of signal one (antigen), and acquisition of signal two in the form of T cell help (including components such as CD40L, the cytokines IL-4 and IL-21, as well as other co-stimulatory molecules on the surface of T cells).…”

Section: The T Wo -S I G Nal Model Of B Cell Ac Tivati On and S Elfmentioning

confidence: 99%

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: The T Wo -S I G Nal Model Of B Cell Ac Tivati On and S Elfmentioning

confidence: 99%

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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“…B cells with higher‐affinity BCRs have an advantage over lower‐affinity B cells because they can efficiently acquire antigens from follicular dendritic cells in the GC that act as antigen depots. Thus, high‐affinity B cells are more likely to receive CD40 signaling and cytokine help from T cells present in GCs to proliferate and differentiate into memory or plasma cells (PCs) . Somatic hypermutation is a process that enables these B cells to mutate their BCRs through the induction of the enzyme activation‐induced cytidine deaminase (AID).…”

Section: High‐affinity Ige In Allergies and Anaphylaxismentioning

confidence: 99%

“…Thus, high-affinity B cells are more likely to receive CD40 signaling and cytokine help from T cells present in GCs to proliferate and differentiate into memory or plasma cells (PCs). 39 Somatic hypermutation is a process that enables these B cells to mutate their BCRs through the induction of the enzyme activation-induced cytidine deaminase (AID). Typically, the higher the rate of mutation in a BCR, the higher the affinity it develops for a given antigen.…”

Section: High-affinity Ige Is Typically Generated Via Sequential Switmentioning

confidence: 99%

“…38 Much of the evidence for the GC selection-based models for affinity maturation comes from studying IgG. 6,39 Whether the GC-dependent selection model holds true for IgE has been an area of active investigation during the past decade. One of the main bottlenecks for studying IgE B cells has been their rarity in vivo.…”

Section: High-affinity Ige Is Typically Generated Via Sequential Switmentioning

confidence: 99%

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Regulation of IgE by T follicular helper cells

Gowthaman

Chen

Eisenbarth

2020

Journal of Leukocyte Biology

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Allergies to food and environmental antigens have steeply grown to epidemic proportions. IgE antibodies are key mediators of allergic disease, including life‐threatening anaphylaxis. There is now compelling evidence that one of the hallmarks of anaphylaxis‐inducing IgE molecules is their high affinity for allergen, and the cellular pathway to high‐affinity IgE is typically through sequential switching of IgG B cells. Further, in contrast to the previously held paradigm that a subset of CD4+ T cells called Th2 cells promotes IgE responses, recent studies suggest that T follicular helper cells are crucial for inducing anaphylactic IgE. Here we discuss recent studies that have enabled us to understand the nature, induction, and regulation of this enigmatic antibody isotype in allergic sensitization.

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“…We now understand that MBCs and LLPCs differentiate from naive B cells in specialized microenvironments in secondary lymphoid tissues. 45 Upon arrival in the secondary lymphoid organs from the peripheral circulation naive B cells rapidly increase expression of the CXCL13responsive chemokine receptor, CXCR5, which attracts these cells to the B cell follicle via a CXCL13 gradient maintained by follicular dendritic cell (FDC) and the follicle stroma (Figure 3). In the B cell follicles naive B cells encounter most antigens on the surfaces of FDC that were transported to and maintained on the FDC by various mechanisms.…”

Section: Under S Tanding At Ypic Al Mbc E Xpan S I On In the Contementioning

confidence: 99%

Exhaustion may not be in the human B cell vocabulary, at least not in malaria

Holla

Ambegaonkar

Sohn

et al. 2019

Immunological Reviews

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T cells exposed to persistent antigen in the inflammatory environment of chronic infections often show progressive loss of effector functions, high expression of inhibitory receptors and distinct transcriptional programs. T cells in this functional state are termed “exhausted” and T cell exhaustion is associated with inefficient control of infections. A remarkably similar scenario has been described for B cells during chronic infections in humans, including malaria, in which case a subpopulation of atypical memory B cells (MBCs) greatly expands and these MBCs show attenuation of B cell receptor signaling, loss of the B cell effector functions of antibody and cytokine production, high expression of inhibitory receptors and distinct transcriptional profiles. The expansion of these MBCs is also associated with inefficient control of infections. Despite the similarities with exhausted T cells we speculate that at least in malaria, atypical MBCs may not be exhausted but rather may be functional, possibly even beneficial. Our recent results suggest that we simply may not have known how to ask an atypical MBC to function. Thus, exhaustion may not be in the human B cell's vocabulary, at least not in malaria.

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B Cell Responses: Cell Interaction Dynamics and Decisions

Cited by 592 publications

References 186 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

Regulation of IgE by T follicular helper cells

Exhaustion may not be in the human B cell vocabulary, at least not in malaria

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