Low-dose IL-2 Enhances the Generation of IL-10-producing Immunoregulatory B Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Apr 12

PMID 37045832

Authors

Akimichi Inaba

Zewen Kelvin Tuong

Tian X Zhao

Andrew P Stewart

Rebeccah Mathews

Lucy Truman

Rouchelle Sriranjan

Jane Kennet

Kourosh Saeb-Parsy

Linda Wicker

Frank Waldron-Lynch

Joseph Cheriyan

John A Todd

Ziad Mallat

Menna R Clatworthy

Affiliations

Soon will be listed here.

Abstract

Dysfunction of interleukin-10 producing regulatory B cells has been associated with the pathogenesis of autoimmune diseases, but whether regulatory B cells can be therapeutically induced in humans is currently unknown. Here we demonstrate that a subset of activated B cells expresses CD25, and the addition of low-dose recombinant IL-2 to in vitro stimulated peripheral blood and splenic human B cells augments IL-10 secretion. Administration of low dose IL-2, aldesleukin, to patients increases IL-10-producing B cells. Single-cell RNA sequencing of circulating immune cells isolated from low dose IL2-treated patients reveals an increase in plasmablast and plasma cell populations that are enriched for a regulatory B cell gene signature. The transcriptional repressor BACH2 is significantly down-regulated in plasma cells from IL-2-treated patients, BACH2 binds to the IL-10 gene promoter, and Bach2 depletion or genetic deficiency increases B cell IL-10, implicating BACH2 suppression as an important mechanism by which IL-2 may promote an immunoregulatory phenotype in B cells.

Citing Articles

Genetic insights into the relationship between immune cell traits and abnormal uterine bleeding: A Mendelian randomization study.

Ou W, Du P, Bai X, He Y Medicine (Baltimore). 2025; 104(8):e41609.

PMID: 39993130 PMC: 11856939. DOI: 10.1097/MD.0000000000041609.

Expansion of B10 cells : Pathways, techniques and applications in transplantation (Review).

Zhao D, Huai G, Yuan Y, Cui Y, Yuan Y, Zhao G Int J Mol Med. 2024; 55(2).

PMID: 39670296 PMC: 11670864. DOI: 10.3892/ijmm.2024.5470.

Characterization of class-switched B cells in chickens.

von La Roche D, Schumacher M, Kohn M, Trapp J, Schusser B, Rautenschlein S Front Immunol. 2024; 15:1484288.

PMID: 39640270 PMC: 11617357. DOI: 10.3389/fimmu.2024.1484288.

Metabolic impact of low dose IL-2 therapy for primary Sjögren's Syndrome in a double-blind, randomized clinical trial.

Feng R, Xiao X, Wang Y, Huang B, Chen J, Cheng G Clin Rheumatol. 2024; 43(12):3789-3798.

PMID: 39482484 PMC: 11582071. DOI: 10.1007/s10067-024-07165-2.

Atherosclerosis antigens as targets for immunotherapy.

Raposo-Gutierrez I, Rodriguez-Ronchel A, Ramiro A Nat Cardiovasc Res. 2024; 2(12):1129-1147.

PMID: 39196152 DOI: 10.1038/s44161-023-00376-x.

References

Popescu D, Botting R, Stephenson E, Green K, Webb S, Jardine L . Decoding human fetal liver haematopoiesis. Nature. 2019; 574(7778):365-371. PMC: 6861135. DOI: 10.1038/s41586-019-1652-y. View

Hipp N, Symington H, Pastoret C, Caron G, Monvoisin C, Tarte K . IL-2 imprints human naive B cell fate towards plasma cell through ERK/ELK1-mediated BACH2 repression. Nat Commun. 2017; 8(1):1443. PMC: 5682283. DOI: 10.1038/s41467-017-01475-7. View

Hartemann A, Bensimon G, Payan C, Jacqueminet S, Bourron O, Nicolas N . Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014; 1(4):295-305. DOI: 10.1016/S2213-8587(13)70113-X. View

Wallin E, Jolly E, Suchanek O, Bradley J, Espeli M, Jayne D . Human T-follicular helper and T-follicular regulatory cell maintenance is independent of germinal centers. Blood. 2014; 124(17):2666-74. PMC: 4208282. DOI: 10.1182/blood-2014-07-585976. View

Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V . Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011; 365(22):2067-77. DOI: 10.1056/NEJMoa1105143. View

Igarashi K, Ochiai K, Itoh-Nakadai A, Muto A . Orchestration of plasma cell differentiation by Bach2 and its gene regulatory network. Immunol Rev. 2014; 261(1):116-25. DOI: 10.1111/imr.12201. View

Mauri C, Gray D, Mushtaq N, Londei M . Prevention of arthritis by interleukin 10-producing B cells. J Exp Med. 2003; 197(4):489-501. PMC: 2193864. DOI: 10.1084/jem.20021293. View

Tanaka H, Muto A, Shima H, Katoh Y, Sax N, Tajima S . Epigenetic Regulation of the Blimp-1 Gene (Prdm1) in B Cells Involves Bach2 and Histone Deacetylase 3. J Biol Chem. 2016; 291(12):6316-30. PMC: 4813568. DOI: 10.1074/jbc.M116.713842. View

Wolock S, Lopez R, Klein A . Scrublet: Computational Identification of Cell Doublets in Single-Cell Transcriptomic Data. Cell Syst. 2019; 8(4):281-291.e9. PMC: 6625319. DOI: 10.1016/j.cels.2018.11.005. View

10.

Li J, Luo Y, Wang X, Feng G . Regulatory B cells and advances in transplantation. J Leukoc Biol. 2018; 105(4):657-668. DOI: 10.1002/JLB.5RU0518-199R. View

11.

Han H, Cho J, Lee S, Yun A, Kim H, Bae D . TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions. Nucleic Acids Res. 2017; 46(D1):D380-D386. PMC: 5753191. DOI: 10.1093/nar/gkx1013. View

12.

Koreth J, Matsuoka K, Kim H, McDonough S, Bindra B, Alyea 3rd E . Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011; 365(22):2055-66. PMC: 3727432. DOI: 10.1056/NEJMoa1108188. View

13.

Baba Y, Matsumoto M, Kurosaki T . Signals controlling the development and activity of regulatory B-lineage cells. Int Immunol. 2015; 27(10):487-93. DOI: 10.1093/intimm/dxv027. View

14.

Malvaez M, McQuown S, Rogge G, Astarabadi M, Jacques V, Carreiro S . HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc Natl Acad Sci U S A. 2013; 110(7):2647-52. PMC: 3574934. DOI: 10.1073/pnas.1213364110. View

15.

Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P, Bahadoran P . Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol. 2014; 150(7):748-51. DOI: 10.1001/jamadermatol.2014.504. View

16.

He J, Zhang X, Wei Y, Sun X, Chen Y, Deng J . Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat Med. 2016; 22(9):991-3. DOI: 10.1038/nm.4148. View

17.

Aran D, Looney A, Liu L, Wu E, Fong V, Hsu A . Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019; 20(2):163-172. PMC: 6340744. DOI: 10.1038/s41590-018-0276-y. View

18.

Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg R, Bhan A . Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity. 2002; 16(2):219-30. DOI: 10.1016/s1074-7613(02)00274-1. View

19.

Menon M, Blair P, Isenberg D, Mauri C . A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus. Immunity. 2016; 44(3):683-697. PMC: 4803914. DOI: 10.1016/j.immuni.2016.02.012. View

20.

Miura Y, Morooka M, Sax N, Roychoudhuri R, Itoh-Nakadai A, Brydun A . Bach2 Promotes B Cell Receptor-Induced Proliferation of B Lymphocytes and Represses Cyclin-Dependent Kinase Inhibitors. J Immunol. 2018; 200(8):2882-2893. DOI: 10.4049/jimmunol.1601863. View