B cell-intrinsic IL-2 signaling regulates inflammation by promoting IL-10 expression in CD25+ age-associated B cells

Interleukin (IL)-2 can impact both plasma cell (PC) differentiation and the generation of IL-10^pos B cells. We generated mice bearing a B cell-specific deletion of Il2rb (Il2rb^ΔB) to define the B cell-intrinsic role of IL-2. Il2rb^ΔB mice displayed normal B cell development and homeostasis but increased extrafollicular PC responses upon immunization. In vitro, IL-2 sustained both PC differentiation and expression of a regulatory program. In vivo, IL-2 signaling defined a PDCA-1^pos splenic B cell subset exhibiting age-associated B cell (ABC) features. Mechanistically, synergistic IL-2 and IFN-γ signaling induced expression of the transcription factor Maf in these ABC progenitors. MAF promoted IL-10 expression and repression of pro-inflammatory programs. In a preclinical multiple sclerosis model, CD25^pos ABCs contributed to the pool of protective regulatory B cells, and loss of IL-2 signaling reduced IL-10^pos B cells in the central nervous system and exacerbated neuroinflammation. Thus, IL-2 signaling promotes the generation of IL-10^pos ABCs, with implications for autoimmunity and inflammation.