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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, Siling; Wang, Runli; Leong, Yew Ann; Simon Davis, David; Qin, Jiahuan; Liang, Kaili; Deng, Jun; Wang, Conan K; Huang, Yen-Hua; Roco, Jonathan A; Nettelfield, Sam; Zhu, Huaming; Xu, Huajun; Yu, Zhijia; Craik, David; Liu, Zheng; Qi, Hai; Parish, Christopher; Yu, Di.
Affiliation
  • Chen Z; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
  • Cui Y; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
  • Yao Y; Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Central China Normal University, Wuhan, China.
  • Liu B; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
  • Yunis J; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
  • Gao X; Department of Otolaryngology-Head and Neck Surgery, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
  • Wang N; Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing, China.
  • Cañete PF; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
  • Tuong ZK; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
  • Sun H; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
  • Wang H; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
  • Yang S; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
  • Wang R; Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK.
  • Leong YA; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
  • Simon Davis D; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
  • Qin J; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
  • Liang K; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
  • Deng J; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
  • Wang CK; Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC, Australia.
  • Huang YH; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
  • Roco JA; China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Nettelfield S; China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zhu H; China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Xu H; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
  • Yu Z; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, University of Queensland, Brisbane, QLD, Australia.
  • Craik D; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
  • Liu Z; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
  • Qi H; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
  • Parish C; Department of Otolaryngology-Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • Yu D; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China.
Sci Immunol ; 8(80): eadd1728, 2023 02 24.
Article in En | MEDLINE | ID: mdl-36800411
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 up-regulated 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: T-Lymphocytes, Helper-Inducer / Germinal Center Language: En Journal: Sci Immunol Year: 2023 Document type: Article Affiliation country: Australia Country of publication: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: T-Lymphocytes, Helper-Inducer / Germinal Center Language: En Journal: Sci Immunol Year: 2023 Document type: Article Affiliation country: Australia Country of publication: Estados Unidos