Antigen-presenting autoreactive B cells activate regulatory T cells and suppress autoimmune arthritis in mice

Author:

Aoun Mike1ORCID,Coelho Ana1ORCID,Krämer Alexander1ORCID,Saxena Amit1ORCID,Sabatier Pierre2ORCID,Beusch Christian Michel2ORCID,Lönnblom Erik1ORCID,Geng Manman3ORCID,Do Nhu-Nguyen14ORCID,Xu Zhongwei1ORCID,Zhang Jingdian56ORCID,He Yibo1ORCID,Romero Castillo Laura1ORCID,Abolhassani Hassan7ORCID,Xu Bingze1ORCID,Viljanen Johan8ORCID,Rorbach Joanna56ORCID,Fernandez Lahore Gonzalo1ORCID,Gjertsson Inger9ORCID,Kastbom Alf10ORCID,Sjöwall Christopher10ORCID,Kihlberg Jan8ORCID,Zubarev Roman A.211ORCID,Burkhardt Harald412ORCID,Holmdahl Rikard13ORCID

Affiliation:

1. Karolinska Institute 1 Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, , Solna, Sweden

2. Karolinska Institute 2 Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, , Solna, Sweden

3. Precision Medicine Institute, The Second Affiliated Hospital of Xi’an Jiaotong University 3 , Xi’an, China

4. Fraunhofer Institute for Translational Medicine and Pharmacology, and Fraunhofer Cluster of Excellence for Immune-Mediated Diseases 4 , Frankfurt am Main, Germany

5. Karolinska Institute 5 Max Planck Institute Biology of Ageing—Karolinska Institute Laboratory, , Solna, Sweden

6. Karolinska Institute 6 Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, , Solna, Sweden

7. Karolinska Institutet, Karolinska University Hospital, Neo Building 7 Division of Clinical Immunology, Department of Biosciences and Nutrition, , Solna, Sweden

8. Uppsala University 8 Department of Chemistry, Biomedical Center, , Uppsala, Sweden

9. University of Gothenburg 9 Department of Rheumatology and Inflammation Research, , Gothenburg, Sweden

10. Linköping University 10 Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, , Linköping, Sweden

11. I.M. Sechenov First Moscow State Medical University 11 Department of Pharmacological and Technological Chemistry, , Moscow, Russia

12. University Hospital Frankfurt, Goethe University 12 Division of Rheumatology, , Frankfurt am Main, Germany

Abstract

B cells undergo several rounds of selection to eliminate potentially pathogenic autoreactive clones, but in contrast to T cells, evidence of positive selection of autoreactive B cells remains moot. Using unique tetramers, we traced natural autoreactive B cells (C1-B) specific for a defined triple-helical epitope on collagen type-II (COL2), constituting a sizeable fraction of the physiological B cell repertoire in mice, rats, and humans. Adoptive transfer of C1-B suppressed arthritis independently of IL10, separating them from IL10-secreting regulatory B cells. Single-cell sequencing revealed an antigen processing and presentation signature, including induced expression of CD72 and CCR7 as surface markers. C1-B presented COL2 to T cells and induced the expansion of regulatory T cells in a contact-dependent manner. CD72 blockade impeded this effect suggesting a new downstream suppressor mechanism that regulates antigen-specific T cell tolerization. Thus, our results indicate that autoreactive antigen-specific naïve B cells tolerize infiltrating T cells against self-antigens to impede the development of tissue-specific autoimmune inflammation.

Funder

Knut och Alice Wallenbergs Stiftelse

Vetenskapsrådet

Stiftelsen Konung Gustaf V:s 80-årsfond

Karolinska Institutet Foundation Grants for Rheumatology Research 2021

HORIZON EUROPE Marie Sklodowska-Curie Actions

Bundesministerium für Bildung und Forschung

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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