Atherogenic dyslipidemia promotes autoimmune follicular helper T cell responses via IL-27

The incidence of atherosclerosis is higher among patients with systemic lupus erythematosus (SLE); however, the mechanism by which an atherogenic environment affects autoimmunity remains unclear. We found that reconstitution of atherosclerosis-prone Apoe^-/- and Ldlr^-/- mice with bone marrow from lupus-prone BXD2 mice resulted in increased autoantibody production and glomerulonephritis. This enhanced disease was associated with an increase in CXCR3⁺ follicular helper T cells (T_FH cells). T_FH cells isolated from Apoe^-/- mice had higher expression of genes associated with inflammatory responses and SLE and were more potent in inducing production of the immunoglobulin IgG2c. Mechanistically, the atherogenic environment induced the cytokine IL-27 from dendritic cells in a Toll-like receptor 4 (TLR4)-dependent manner, which in turn triggered the differentiation of CXCR3⁺ T_FH cells while inhibiting the differentiation of follicular regulatory T cells. Blockade of IL-27 signals diminished the increased T_FH cell responses in atherogenic mice. Thus, atherogenic dyslipidemia augments autoimmune T_FH cell responses and subsequent IgG2c production in a TLR4- and IL-27-dependent manner.