TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance-Reference-Cited by-同舟云学术

TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance

Published:2023-09-29 Issue:12 Volume:220 Page:
ISSN:0022-1007
Container-title:Journal of Experimental Medicine
language:en
Short-container-title:

Author:

Çakan Elif¹^ORCID,Ah Kioon Marie Dominique²^ORCID,Garcia-Carmona Yolanda³^ORCID,Glauzy Salomé¹^ORCID,Oliver David²^ORCID,Yamakawa Natsuko¹^ORCID,Vega Loza Andrea¹,Du Yong²^ORCID,Schickel Jean-Nicolas¹^ORCID,Boeckers Joshua M.¹^ORCID,Yang Chao²^ORCID,Baldo Alessia¹^ORCID,Ivashkiv Lionel B.²⁴^ORCID,Young Ryan M.⁵^ORCID,Staudt Louis M.⁵^ORCID,Moody Krishna L.⁶,Nündel Kerstin⁶^ORCID,Marshak-Rothstein Ann⁶^ORCID,van der Made Caspar I.⁷^ORCID,Hoischen Alexander⁷^ORCID,Hayward Anthony⁸^ORCID,Rossato Marzia⁹^ORCID,Radstake Timothy R.D.J.¹⁰¹¹^ORCID,Cunningham-Rundles Charlotte³¹²^ORCID,Ryu Changwan¹³^ORCID,Herzog Erica L.¹³^ORCID,Barrat Franck J.²¹⁴^ORCID,Meffre Eric¹¹⁵^ORCID

Affiliation:

1. Yale University School of Medicine 1 Department of Immunobiology, , New Haven, CT, USA

2. HSS Research Institute and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery 2 , New York, NY, USA

3. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai 3 Department of Clinical Immunology, , New York, NY, USA

4. Weill Cornell Medical College of Cornell University 4 Department of Medicine, , New York, NY, USA

5. National Cancer Institute, National Institutes of Health 5 Lymphoid Malignancies Branch, , Bethesda, MD, USA

6. University of Massachusetts School of Medicine 6 Department of Medicine, , Worcester, MA, USA

7. Radboud University Medical Center 7 Department of Human Genetics, , Nijmegen, The Netherlands

8. Warren Alper School of Medicine, Brown University 8 , Providence, RI, USA

9. University of Verona 9 Department of Biotechnology, , Verona, Italy

10. University Medical Center Utrecht 10 Laboratory of Translational Immunology, , Utrecht University, Utrecht, The Netherlands

11. University Medical Center Utrecht 11 Department of Rheumatology and Clinical Immunology, , Utrecht University, Utrecht, The Netherlands

12. Icahn School of Medicine at Mount Sinai 12 Department of Medicine and Pediatrics, , New York, NY, USA

13. Critical Care and Sleep Medicine, Yale School of Medicine 13 Department of Internal Medicine, Section of Pulmonary, , New Haven, CT, USA

14. Weill Cornell Medical College of Cornell University 14 Department of Microbiology and Immunology, , New York, NY, USA

15. Allergy, and Clinical Immunology, Yale University School of Medicine 15 Section of Rheumatology, , New Haven, CT, USA

Abstract

Central B cell tolerance is believed to be regulated by B cell receptor signaling induced by the recognition of self-antigens in immature B cells. Using humanized mice with defective MyD88, TLR7, or TLR9 expression, we demonstrate that TLR9/MYD88 are required for central B cell tolerance and the removal of developing autoreactive clones. We also show that CXCL4, a chemokine involved in systemic sclerosis (SSc), abrogates TLR9 function in B cells by sequestering TLR9 ligands away from the endosomal compartments where this receptor resides. The in vivo production of CXCL4 thereby impedes both TLR9 responses in B cells and the establishment of central B cell tolerance. We conclude that TLR9 plays an essential early tolerogenic function required for the establishment of central B cell tolerance and that correcting defective TLR9 function in B cells from SSc patients may represent a novel therapeutic strategy to restore B cell tolerance.

Funder

National Institutes of Health

National Institute of Allergy and Infectious Diseases

Scleroderma Research Foundation

National Heart, Lung, and Blood Institute

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

Link

https://rupress.org/jem/article-pdf/doi/10.1084/jem.20230944/1918974/jem_20230944.pdf

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