Elevated IL-10 is Linked With the Expansion of T-bethighCD21low B Cells in Patients With Common Variable Immunodeficiency

Abstract Common variable immunodeficiency (CVID) is frequently complicated by autoimmune and inflammatory manifestations associated with profound immune dysregulation (CVIDc), including expansion of T-bet high CD21 low B cells (CD21 low B cells). Elevated serum IL-10 levels have repeatedly been reported in CVIDc, yet their relationship to CD21 low B-cell differentiation remains unclear. In this study, we determined a significant correlation between increased serum IL-10 levels and frequency of circulating CD21 low B cells, particularly marked in CVIDc patients. Transcriptomic and protein analyses identified multiple cellular sources of IL-10 in CVID, including monocytes, T cells, and a subset of CD21 low B cells in peripheral blood and inflamed tissues. CD21 low B cells expressed elevated levels of IL-10 receptor subunits and displayed intact IL-10–induced STAT3 signaling, indicating preserved responsiveness to IL-10. Functionally, IL-10 alone neither induced CD21 low B-cell differentiation nor inhibited IFN-γ–driven polarization. However, in vitro differentiation assays showed that IL-10 can substitute for IL-21 during CD40L/T cell–dependent differentiation of CD21 low -like B cells and promote their survival in vitro. These findings suggest that IL-10 may support the expansion and persistence of CD21 low B cells at inflammatory sites. Collectively, our data identify IL-10 as a component of the inflammatory environment associated with CD21 low B-cell expansion and suggest that IL-10 can functionally replace IL-21 during their differentiation and promote their survival in CVID-associated immune dysregulation.