单位：[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.华中科技大学同济医学院附属同济医院耳鼻咽喉-头颈外科[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.
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.
基金：
Australian National Health and Medical Research Council grants
(GNT1085509, GNT1147769, and GNT2009554), a Bellberry-Viertel Senior Medical Research
fellowship (to D.Y.), and the National Natural Science Foundation of China (no. 21473065) (to
Y.C.).
第一作者单位：[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.
通讯作者：
通讯机构：[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.[14]Ian Frazer Centre for Children's Immunotherapy Research, Child Health Research Centre, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
推荐引用方式(GB/T 7714)：
Chen Zhian,Cui Yanfang,Yao Yin,et al.Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation[J].SCIENCE IMMUNOLOGY.2023,8(80):doi:10.1126/sciimmunol.add1728.
APA：
Chen Zhian,Cui Yanfang,Yao Yin,Liu Bo,Yunis Joseph...&Yu Di.(2023).Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation.SCIENCE IMMUNOLOGY,8,(80)
MLA：
Chen Zhian,et al."Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation".SCIENCE IMMUNOLOGY 8..80(2023)
医学