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

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

doi:10.1126/sciimmunol.add1728

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

Zhian Chen, Yanfang Cui, Yin Yao, Bo Liu, Joseph Yunis, Xin Gao, Naiqi Wang, Pablo F. Cañete, Zewen Kelvin Tuong, Hongjian Sun, Hao Wang, Siling Yang, Runli Wang, Yew Ann Leong, David Simon Davis, Jiahuan Qin, Kaili Liang, Jun Deng, Conan K. Wang, Yen Hua HuangJonathan A. Roco, Sam Nettelfield, Huaming Zhu, Huajun Xu, Zhijia Yu, David Craik, Zheng Liu, Hai Qi, Christopher Parish, Di Yu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

Abstract

In antibody responses, mutated germinal center B (B_GC) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of B_GC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (T_FH) cell–derived signals, in particular costimulation through CD40. Here, we demonstrate that the T_FH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting B_GC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. B_GC cells, compared with non-B_GC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)–mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in B_GC cells and upregulated in ASC precursors, suggesting selective desensitization to IL-21 in B_GC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.

Original language	English
Article number	eadd1728
Journal	Science immunology
Volume	8
Issue number	80
DOIs	https://doi.org/10.1126/sciimmunol.add1728
Publication status	Published - Feb 2023

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Chen, Z., Cui, Y., Yao, Y., Liu, B., Yunis, J., Gao, X., Wang, N., Cañete, P. F., Tuong, Z. K., Sun, H., Wang, H., Yang, S., Wang, R., Leong, Y. A., Davis, D. S., Qin, J., Liang, K., Deng, J., Wang, C. K., ... Yu, D. (2023). Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation. Science immunology, 8(80), Article eadd1728. https://doi.org/10.1126/sciimmunol.add1728

@article{035b2186b34c464eab5000c42d11127b,

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

abstract = "In antibody responses, mutated germinal center B (BGC) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of BGC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (TFH) cell–derived signals, in particular costimulation through CD40. Here, we demonstrate that the TFH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting BGC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. BGC cells, compared with non-BGC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)–mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in BGC cells and upregulated in ASC precursors, suggesting selective desensitization to IL-21 in BGC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.",

author = "Zhian Chen and Yanfang Cui and Yin Yao and Bo Liu and Joseph Yunis and Xin Gao and Naiqi Wang and Ca{\~n}ete, {Pablo F.} and Tuong, {Zewen Kelvin} and Hongjian Sun and Hao Wang and Siling Yang and Runli Wang and Leong, {Yew Ann} and Davis, {David Simon} and Jiahuan Qin and Kaili Liang and Jun Deng and Wang, {Conan K.} and Huang, {Yen Hua} and Roco, {Jonathan A.} and Sam Nettelfield and Huaming Zhu and Huajun Xu and Zhijia Yu and David Craik and Zheng Liu and Hai Qi and Christopher Parish and Di Yu",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",

year = "2023",

month = feb,

doi = "10.1126/sciimmunol.add1728",

language = "English",

volume = "8",

journal = "Science immunology",

issn = "2470-9468",

publisher = "American Association for the Advancement of Science",

number = "80",

}

Chen, Z, Cui, Y, Yao, Y, Liu, B, Yunis, J, Gao, X, Wang, N, Cañete, PF, Tuong, ZK, Sun, H, Wang, H, Yang, S, Wang, R, Leong, YA, Davis, DS, Qin, J, Liang, K, Deng, J, Wang, CK, Huang, YH, Roco, JA, Nettelfield, S, Zhu, H, Xu, H, Yu, Z, Craik, D, Liu, Z, Qi, H, Parish, C & Yu, D 2023, 'Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation', Science immunology, vol. 8, no. 80, eadd1728. https://doi.org/10.1126/sciimmunol.add1728

TY - JOUR

T1 - Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation

AU - Chen, Zhian

AU - Cui, Yanfang

AU - Yao, Yin

AU - Liu, Bo

AU - Yunis, Joseph

AU - Gao, Xin

AU - Wang, Naiqi

AU - Cañete, Pablo F.

AU - Tuong, Zewen Kelvin

AU - Sun, Hongjian

AU - Wang, Hao

AU - Yang, Siling

AU - Wang, Runli

AU - Leong, Yew Ann

AU - Davis, David Simon

AU - Qin, Jiahuan

AU - Liang, Kaili

AU - Deng, Jun

AU - Wang, Conan K.

AU - Huang, Yen Hua

AU - Roco, Jonathan A.

AU - Nettelfield, Sam

AU - Zhu, Huaming

AU - Xu, Huajun

AU - Yu, Zhijia

AU - Craik, David

AU - Liu, Zheng

AU - Qi, Hai

AU - Parish, Christopher

AU - Yu, Di

PY - 2023/2

Y1 - 2023/2

N2 - In antibody responses, mutated germinal center B (BGC) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of BGC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (TFH) cell–derived signals, in particular costimulation through CD40. Here, we demonstrate that the TFH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting BGC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. BGC cells, compared with non-BGC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)–mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in BGC cells and upregulated in ASC precursors, suggesting selective desensitization to IL-21 in BGC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.

AB - In antibody responses, mutated germinal center B (BGC) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of BGC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (TFH) cell–derived signals, in particular costimulation through CD40. Here, we demonstrate that the TFH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting BGC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. BGC cells, compared with non-BGC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)–mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in BGC cells and upregulated in ASC precursors, suggesting selective desensitization to IL-21 in BGC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.

UR - http://www.scopus.com/inward/record.url?scp=85148330513&partnerID=8YFLogxK

U2 - 10.1126/sciimmunol.add1728

DO - 10.1126/sciimmunol.add1728

M3 - Article

SN - 2470-9468

VL - 8

JO - Science immunology

JF - Science immunology

IS - 80

M1 - eadd1728

ER -

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

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