Low-dose IL-2 enhances the generation of IL-10-producing immunoregulatory B cells
Akimichi Inaba, Zewen Kelvin Tuong, Tian Zhao, Andrew P. Stewart, Rebeccah J. Mathews, Lucy Truman, Rouchelle Sriranjan, Jane Kennet, Kourosh Saeb‐Parsy, Linda S. Wicker, Frank Waldron-Lynch, Joseph Cheriyan, John A. Todd, Ziad Mallat, Menna R. Clatworthy
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.