Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation

Chen, Zhian; Cui, Yanfang; Yao, Yin; Liu, Bo; Yunis, Joseph; Gao, Xin; Wang, Naiqi; Cañete, Pablo F.; Tuong, Zewen Kelvin; Sun, Hongjian; Wang, Hao; Yang, Si-Ling; Wang, Runli; Leong, Yew Ann; Davis, David S.; Qin, Jiahuan; Liang, Kai‐Li; Deng, Jun; Wang, Conan K.; Huang, Yen‐Hua; Roco, Jonathan A.; Nettelfield, Sam; Zhu, Huaming; Xu, Huajun; Yu, Zhijia; Craik, David J.; Liu, Zheng; Qi, Hai; Parish, Christopher R.; Yu, Di

doi:10.1126/sciimmunol.add1728

Cited by 26 publications

(27 citation statements)

References 85 publications

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“…The ability of IL-21 to synergize with CD40 in inducing S6 phosphorylation in GC B cells in vitro was further confirmed in recent studies by the Shlomchik and Yu groups ( 60 , 61 ). Notably, Dvorscek et al .…”

Section: Il-21 Promotes Gc Expansion and Shapes Gc B-cell Polarizationsupporting

confidence: 53%

“…GC with reduced or no IL-21 signaling (left) have reduced dark zone compartments and yield fewer plasma cells than GC with normal IL-21 levels (middle) ( 25 , 26 , 38 , 54 , 58 , 64 ). Elevated IL-21 levels (right) lower the B-cell positive selection threshold and allow more B-cell clones to enter the GC dark zone ( 54 , 60 , 61 ). Exacerbated IL-21 production favors GC B-cell differentiation over GC maintenance ( 61 ).…”

Section: Il-21 Promotes Gc Expansion and Shapes Gc B-cell Polarizationmentioning

confidence: 99%

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T-cell help in the germinal center: homing in on the role of IL-21

Petersone,

Walker

2024

International Immunology

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Interleukin 21 (IL-21) is a pleiotropic cytokine that is overproduced in multiple autoimmune settings. Provision of IL-21 from follicular helper T cells is an important component of T cell help within germinal centers (GC), and the last few years have seen a resurgence of interest in IL-21 biology in the context of the GC environment. While it has been more than a decade since T cell-derived IL-21 was found to upregulate B cell expression of GC master transcription factor Bcl-6 and to promote GC expansion, several recent studies have collectively delivered significant new insights into how this cytokine shapes GC B cell selection, proliferation, and fate choice. It is now clear that IL-21 plays an important role in GC zonal polarization by contributing to light zone GC B cell positive selection for dark zone entry as well as by promoting cyclin D3-dependent dark zone inertial cycling. While it has been established that IL-21 can contribute to the modulation of GC output by aiding the generation of antibody secreting cells, recent studies have now revealed how IL-21 signal strength shapes the fate choice between GC cycle reentry and antibody secreting cell differentiation in vivo. Both provision of IL-21 and sensitivity to this cytokine are finely tuned within the GC environment, and dysregulation of this pathway in autoimmune settings could alter the threshold for germinal center B cell selection and differentiation, potentially promoting autoreactive B cell responses.

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Section: Il-21 Promotes Gc Expansion and Shapes Gc B-cell Polarizationsupporting

confidence: 53%

Section: Il-21 Promotes Gc Expansion and Shapes Gc B-cell Polarizationmentioning

confidence: 99%

T-cell help in the germinal center: homing in on the role of IL-21

Petersone,

Walker

2024

International Immunology

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“…The identification of these specific roles of IL-21 is an important mechanistic and conceptual step forward in our understanding of selection in the GC. The laboratory of D. Yu has also made similar findings about the ability of CD40 and IL-21R signals to induce c-MYC in GCBCs ( 49 ).…”

Section: Discussionmentioning

confidence: 73%

IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells

et al. 2023

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Both B cell receptor (BCR) and CD40 signaling are rewired in germinal center (GC) B cells (GCBCs) to synergistically induce c-MYC and phosphorylated S6 ribosomal protein (p-S6), markers of positive selection. How interleukin-21 (IL-21), a key T follicular helper (T FH )–derived cytokine, affects GCBCs is unclear. Like BCR and CD40 signals, IL-21 receptor (IL-21R) plus CD40 signals also synergize to induce c-MYC and p-S6 in GCBCs. However, IL-21R plus CD40 stimulation differentially affects GCBC fate compared with BCR plus CD40 ligation—engaging unique molecular mechanisms—as revealed by bulk RNA sequencing (RNA-seq), single-cell RNA-seq, and flow cytometry of GCBCs in vitro and in vivo. Whereas both signal pairs induced BLIMP1 in some GCBCs, only the IL-21R/CD40 combination induced IRF4 hi /CD138 + cells, indicative of plasma cell differentiation, along with CCR6 + /CD38 + memory B cell precursors. These findings reveal a second positive selection pathway in GCBCs, document rewired IL-21R signaling in GCBCs, and link specific T FH - and Ag-derived signals to GCBC differentiation.

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“…A recent study has provided insights into how IL-21 regulates the positive selection of GC B cells by modulating its availability and signal strength ( 13 ). Reduced IL-21 signals, possibly due to partial expression of the IL-21 receptor, can impede the differentiation of Ab-secreting PCs.…”

Section: Cytokines Produced By Tfh and Their Regulationmentioning

confidence: 99%

“…Reduced IL-21 signals, possibly due to partial expression of the IL-21 receptor, can impede the differentiation of Ab-secreting PCs. In contrast, stronger IL-21 signals, which can be achieved through exogenous IL-21 treatment, appear to favor PC differentiation and concurrently reduce the total population of GC B cells ( 13 ). Collectively, the development of GC zones as a function of time and B cell proliferation highlights IL-21 as a key regulator of these intricate processes.…”

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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Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation

Cited by 26 publications

References 85 publications

T-cell help in the germinal center: homing in on the role of IL-21

T-cell help in the germinal center: homing in on the role of IL-21

IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells

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

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