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

Autor: Chen Z; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia., Cui Y; Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Central China Normal University, Wuhan, China., Yao Y; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.; Department of Otolaryngology-Head and Neck Surgery, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China., Liu B; Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing, China., Yunis J; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia., Gao X; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia., Wang N; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia., Cañete PF; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia., Tuong ZK; Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK.; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK., Sun H; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia., Wang H; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia., Yang S; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia., Wang R; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia., Leong YA; Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC, Australia., Simon Davis D; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia., Qin J; China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Liang K; China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Deng J; China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wang CK; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, University of Queensland, Brisbane, QLD, Australia., Huang YH; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia., Roco JA; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia., Nettelfield S; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia., Zhu H; Department of Otolaryngology-Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China., Xu H; Department of Otolaryngology-Head and Neck Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China., Yu Z; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia., Craik D; Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, University of Queensland, Brisbane, QLD, Australia., Liu Z; Department of Otolaryngology-Head and Neck Surgery, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China., Qi H; Tsinghua-Peking Center for Life Sciences, Laboratory of Dynamic Immunobiology, School of Medicine, Tsinghua University, Beijing, China., Parish C; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia., Yu D; Frazer Institute, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.; John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.; Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
Jazyk: angličtina
Zdroj: Science immunology [Sci Immunol] 2023 Feb 24; Vol. 8 (80), pp. eadd1728. Date of Electronic Publication: 2023 Feb 17.
DOI: 10.1126/sciimmunol.add1728
Abstrakt: 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.
Databáze: MEDLINE