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

Zhian Chen^{1

2}, Yanfang Cui³, Yin Yao^{1

2

4}, Bo Liu⁵, Joseph Yunis^{1

2}, Xin Gao², Naiqi Wang¹, Pablo F Cañete¹, Zewen Kelvin Tuong^{6

7}, Hongjian Sun¹, Hao Wang², Siling Yang¹, Runli Wang², Yew Ann Leong⁸, David Simon Davis², Jiahuan Qin⁹, Kaili Liang⁹, Jun Deng⁹, Conan K Wang^{10

11}, Yen-Hua Huang¹⁰, Jonathan A Roco², Sam Nettelfield¹, Huaming Zhu^{12

13}, Huajun Xu^{12

13}, Zhijia Yu², David Craik^{10

11}, Zheng Liu⁴, Hai Qi⁵, Christopher Parish², Di Yu^{1

2

14}

Affiliations

¹ Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
² John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
³ Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Central China Normal University, Wuhan, China.
⁴ Department of Otolaryngology-Head and Neck Surgery, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
⁵ Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing, China.
⁶ Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK.
⁷ Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
⁸ Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC, Australia.
⁹ China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁰ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
¹¹ Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, University of Queensland, Brisbane, QLD, Australia.
¹² Department of Otolaryngology-Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
¹³ Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China.
¹⁴ Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.

PMID: 36800411
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 et al. Sci Immunol. 2023.

. 2023 Feb 24;8(80):eadd1728.

doi: 10.1126/sciimmunol.add1728. Epub 2023 Feb 17.

Authors

Affiliations

¹ Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
² John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
³ Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Central China Normal University, Wuhan, China.
⁴ Department of Otolaryngology-Head and Neck Surgery, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
⁵ Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing, China.
⁶ Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK.
⁷ Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
⁸ Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC, Australia.
⁹ China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁰ Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
¹¹ Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, University of Queensland, Brisbane, QLD, Australia.
¹² Department of Otolaryngology-Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
¹³ Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China.
¹⁴ Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.

PMID: 36800411
DOI: 10.1126/sciimmunol.add1728

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 up-regulated 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.

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

Affiliations

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

Authors

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Abstract

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LinkOut - more resources

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Research Materials

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