Increased STAT3 phosphorylation on CD27+ B-cells from common variable immunodeficiency disease patients

•IL-21/STAT3 axis influences CD27+ B-cell memory development.•A subgroup of CVID patients (smB −) have low CD27+ B-cell number.•Decreased CD27+ B-cells from smB − patients retain their functional heterogeneity.•smB − CD27+ B-cells show STAT3 hyperphosphorylation in contrast to CD27− B-cells.•IL-21/STAT3 axis defects could contribute to impaired B-cell homeostasis in CVID.

Maturation and differentiation of B-cells are driven by T-cells' help through IL-21/STAT3 axis in GC centers or through extrafollicular pathways, in a T-independent manner. B-cell differentiation is defective in common variable immunodeficiency disease (CVID) patients. We investigated if IL-21/STAT3 axis alterations could influence B-cell fate. We activated purified CVID B-cells with surrogate T-dependent (anti-CD40), T-independent (TLR-9 ligand) stimuli or through B-cell receptor engagement (anti-IgM) with or without IL-21. IL-21 mediated STAT3 activation was greater on CD27− than CD27+ B-cells depending on the stimulus. IL-21 alone induced STAT3 phosphorylation (pSTAT3) only on CD27− B-cells and IL-21 induced higher pSTAT3 levels on CD27− than CD27+ B-cells after anti-IgM or anti-CD40 activation. CVID CD27+ B-cells showed selective STAT3 hyperphosphorylation after activation with anti-IgM or anti-CD40 alone and anti-IgM, anti-CD40 or ODN combined with IL-21. Increased STAT3 activation during immune responses could result in B-cell differentiation defects in CVID.