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

被引：34

作者：

Chen, Zhian ^{[1
,2
]}

Cui, Yanfang ^{[3
]}

Yao, Yin ^{[1
,2
,4
]}

Liu, Bo ^{[5
]}

Yunis, Joseph ^{[1
,2
]}

Gao, Xin ^{[2
]}

Wang, Naiqi ^{[1
]}

Canete, Pablo F. ^{[1
]}

Tuong, Zewen Kelvin ^{[6
,7
]}

Sun, Hongjian ^{[1
]}

Wang, Hao ^{[2
]}

Yang, Siling ^{[1
]}

Wang, Runli ^{[2
]}

Leong, Yew Ann ^{[8
]}

Davis, David Simon ^{[2
]}

Qin, Jiahuan ^{[9
]}

Liang, Kaili ^{[9
]}

Deng, Jun ^{[9
]}

Wang, Conan K. ^{[10
,11
]}

Huang, Yen-Hua ^{[10
]}

Roco, Jonathan A. ^{[2
]}

Nettelfield, Sam ^{[1
]}

Zhu, Huaming ^{[12
,13
]}

Xu, Huajun ^{[12
,13
]}

Yu, Zhijia ^{[2
]}

Craik, David ^{[10
,11
]}

Liu, Zheng ^{[4
]}

Qi, Hai ^{[5
]}

Parish, Christopher ^{[2
]}

Yu, Di ^{[1
,2
,14
]}

机构：

[1] Univ Queensland, Frazer Inst, Fac Med, Brisbane, Qld, Australia

[2] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT, Australia

[3] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan, Peoples R China

[4] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Otolaryngol Head & Neck Surg, Wuhan, Peoples R China

[5] Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Sch Med, Lab Dynam Immunobiol, Beijing, Peoples R China

[6] Univ Cambridge, Dept Med, Mol Immun Unit, Cambridge, England

[7] Wellcome Sanger Inst, Wellcome Genome Campus, Cambridge, England

[8] Monash Univ, Ctr Inflammatory Dis, Sch Clin Sci Monash Hlth, Dept Med, Melbourne, Vic, Australia

[9] Shanghai Jiao Tong Univ, Renji Hosp, China Australia Ctr Personalised Immunol, Sch Med, Shanghai, Peoples R China

[10] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[11] Univ Queensland, Australian Res Council Ctr Excellence Innovat Pep, Brisbane, Qld, Australia

[12] Shanghai Jiao Tong Univ Affiliated Peoples Hosp 6, Dept Otolaryngol Head & Neck Surg, Shanghai, Peoples R China

[13] Shanghai Key Lab Sleep Disordered Breathing, Shanghai, Peoples R China

[14] Univ Queensland, Fac Med, Ian Frazer Ctr Childrens Immunotherapy Res, Child Hlth Res Ctr, Brisbane, Qld, Australia

来源：

SCIENCE IMMUNOLOGY | 2023年 / 8卷 / 80期

基金：

中国国家自然科学基金; 英国医学研究理事会;

关键词：

FOLLICULAR-HELPER-CELLS; PLASMA-CELL; TRANSCRIPTION FACTOR; AFFINITY MATURATION; CRYSTAL-STRUCTURE; VIRAL-INFECTION; DENDRITIC CELLS; ALPHA-RECEPTOR; INTERLEUKIN-21; ANTIGEN;

D O I：

10.1126/sciimmunol.add1728

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 demon-strate that the TFH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting BOc 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-sul-fation 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 bio-chemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and effi-ciency of GC selection.

引用

页数：17