IL-4 downregulates BCL6 to promote memory B cell selection in germinal centers

Shehata, Laila; Thouvenel, Christopher D.; Hondowicz, Brian D.; Pew, Lucia A.; Rawlings, David J.; Choi, Jinyong; Pepper, Marion

doi:10.1101/2023.01.26.525749

Cited by 3 publications

(5 citation statements)

References 86 publications

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“…In the present work investigating how IL-4Rα blockade impacts the B cell repertoire beyond avoidance of IgE production, we found that loss of IL-4/IL-13 signaling in vivo broadly suppresses gene expression, particularly relating to metabolic processes and BCR signaling. Intriguingly, Ag re-exposure could still elicit Ag-specific GC activity in the absence of IL-4/IL-13, an issue which has remained contentious ( 27 , 49 , 50 ).…”

Section: Discussionmentioning

confidence: 99%

Pathogenic IgE-fated B cell memory retains functional plasticity

Bruton,

Phelps,

Ariaz

et al. 2023

Preprint

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Long-lived immunoglobulin (Ig) E responses against innocuous environmental and dietary antigens (Ags) are maintained by an IgG1-dominant memory B cell (MBC) compartment primed for IL-4 responsiveness. In this work, we investigated the plasticity of the MBC compartment fated for IgE class switch recombination upon Ag re-exposure. Antibody-mediated IL-4R( blockade augmented the germinal center response and uncovered an IL-4/IL-13 dependency within the type 2 memory B cell (MBC2) skewed phenotype. In the absence of IL-4/IL-13 signaling during the recall response, a long-lived Ag-specific IgG2c MBC population emerged, shifting the MBC response away from a type 2 phenotype and towards type 1. The emergence of this IgG2c response was dependent on IFN-( signaling and arose from both unswitched and class-switched Ag-specific B cells in vivo. We further demonstrated that a type 1-polarizing adjuvant can augment the redirection of type 2-polarized class-switched MBCs, suggesting with the correct cues pathogenic MBCs can be functionally reprogrammed.One Sentence SummaryB cell responses to allergens can be reprogrammed away from a pathogenic fate through IL-4/IL-13 signaling blockade.

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Section: Discussionmentioning

confidence: 99%

Pathogenic IgE-fated B cell memory retains functional plasticity

Bruton,

Phelps,

Ariaz

et al. 2023

Preprint

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“…While B-cell-directed therapies inherently impact B cells, it is intriguing that the interleukin-4 receptor (IL-4R) blockade, initially not designed to specifically target B cells, has emerged as a potential regulator of B cell responses and humoral immunity ( 76 , 146 – 149 ) ( Figure 2B ).…”

Section: Current Therapeutics For Inflammatory Skin Diseases and Pote...mentioning

confidence: 99%

“…This assumption allows activated B cells to remain within the GC, preventing them from exiting GC and becoming MBC. To bridge the gap between these conflicting conclusions on whether IL-4 promotes or inhibit MBC differentiation, a recent study has proposed a plausible explanation ( 149 ). They demonstrated that IL-4 can prompt GC B cell selection and exit through differential regulation of BCL6 expression, depending on the preexisting levels of BCL6 in a given cell.…”

Section: Current Therapeutics For Inflammatory Skin Diseases and Pote...mentioning

confidence: 99%

From neglect to spotlight: the underappreciated role of B cells in cutaneous inflammatory diseases

Lee,

2024

Front. Immunol.

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The skin, covering our entire body as its largest organ, manifests enormous complexities and a profound interplay of systemic and local responses. In this heterogeneous domain, B cells were considered strangers. Yet, recent studies have highlighted their existence in the skin and their distinct role in modulating cutaneous immunity across various immune contexts. Accumulating evidence is progressively shedding light on the significance of B cells in maintaining skin health and in skin disorders. Herein, we integrate current insights on the systemic and local contributions of B cells in three prevalent inflammatory skin conditions: Pemphigus Vulgaris (PV), Systemic Lupus Erythematosus (SLE), and Atopic Dermatitis (AD), underscoring the previously underappreciated importance of B cells within skin immunity. Moreover, we address the potential adverse effects of current treatments used for skin diseases, emphasizing their unintentional consequences on B cells. These comprehensive approaches may pave the way for innovative therapeutic strategies that effectively address the intricate nature of skin disorders.

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“…Interestingly, FDC can limit GC IL-4 availability through IL-4Ra expression, enhancing memory B cell generation ( 50 ). IL-4 also triggers a negative autoregulatory mechanism of Bcl6 expression in GC B cells, although it initially enhances Bcl6 in naive B cells to facilitate the generation of GC ( 51 ). This reduction in Bcl6 by IL-4 contributes to a selective process: pre-memory GC B cells with access to supplementary survival signals are granted permission to exit the GC, while those devoid of such signals undergo apoptosis ( 51 ).…”

Section: Cytokines Produced By Tfh and Their Regulationmentioning

confidence: 99%

“…IL-4 also triggers a negative autoregulatory mechanism of Bcl6 expression in GC B cells, although it initially enhances Bcl6 in naive B cells to facilitate the generation of GC ( 51 ). This reduction in Bcl6 by IL-4 contributes to a selective process: pre-memory GC B cells with access to supplementary survival signals are granted permission to exit the GC, while those devoid of such signals undergo apoptosis ( 51 ). These findings suggest that IL-4 acts on B cell differentiation at multiple stages, including GC B cell and memory B cell differentiation.…”

Section: Cytokines Produced By Tfh and Their Regulationmentioning

confidence: 99%

Cytokines in Follicular Helper T Cell Biology in Physiologic and Pathologic Conditions

Choi,

Crotty,

Choi

2024

Immune Netw

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Follicular helper T cells (Tfh) play a crucial role in generating high-affinity antibodies (Abs) and establishing immunological memory. Cytokines, among other functional molecules produced by Tfh, are central to germinal center (GC) reactions. This review focuses on the role of cytokines, including IL-21 and IL-4, in regulating B cell responses within the GC, such as differentiation, affinity maturation, and plasma cell development. Additionally, this review explores the impact of other cytokines like CXCL13, IL-10, IL-9, and IL-2 on GC responses and their potential involvement in autoimmune diseases, allergies, and cancer. This review highlights contributions of Tfh-derived cytokines to both protective immunity and immunopathology across a spectrum of diseases. A deeper understanding of Tfh cytokine biology holds promise for insights into biomedical conditions.

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IL-4 downregulates BCL6 to promote memory B cell selection in germinal centers

Cited by 3 publications

References 86 publications

Pathogenic IgE-fated B cell memory retains functional plasticity

Pathogenic IgE-fated B cell memory retains functional plasticity

From neglect to spotlight: the underappreciated role of B cells in cutaneous inflammatory diseases

Cytokines in Follicular Helper T Cell Biology in Physiologic and Pathologic Conditions

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