Aberrant Presentation of Self-Lipids by Autoimmune B Cells Depletes Peripheral iNKT Cells

• iNKT cells are numerically reduced in mice with B cell-mediated autoimmunity
• Residual iNKT cells in autoimmune mice are hyperactivated
• Autoimmune B cells present CD1d-restricted self-lipids that deplete iNKT cells
• Autoimmune B cells have altered lipidome with aberrant expression of certain lipids

SummaryInvariant natural killer T (iNKT) cells provide cognate help via CD1d to lipid antigen-presenting B cells for antibody production, but whether B cells reciprocally regulate iNKT cells remains largely unexplored. Here, we found peripheral, but not thymic, iNKT cells to be numerically reduced in autoimmune mice lacking Fas specifically in B cells. The residual iNKT cells were antigenically overstimulated, had altered cytokine production, and manifested enhanced proliferation and apoptosis. B cell-specific ablation of CD1d ameliorated these iNKT defects, suggesting that inappropriate presentation of CD1d-restricted self-lipids by autoimmune B cell-depleted peripheral iNKT cells. CD1d+ autoimmune B cells have reduced α-galactosidase A expression and, as revealed by lipidomic profiling, altered lipidome with aberrant accumulation of certain self-lipids and reduction of others. These findings unveil a critical link between autoimmunity, B cell lipidome, and the maintenance of peripheral iNKT cells and highlight an essential homeostatic function of B cells beyond antibody production.

Graphical AbstractFigure optionsDownload as PowerPoint slide