Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by anti-nuclear autoantibodies whose production is promoted by autoreactive T follicular helper (TFH) cells. During SLE pathogenesis, basophils accumulate in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms that remain to be defined. Here, we provide evidence for a direct functional relationship between TFH cells and basophils during lupus pathogenesis, both in humans and mice. PD-L1 upregulation on basophils and IL-4 production are associated with TFH and TFH2 cell expansions and with disease activity. Pathogenic TFH cell accumulation, maintenance, and function in SLO were dependent on PD-L1 and IL-4 in basophils, which induced a transcriptional program allowing TFH2 cell differentiation and function. Our study establishes a direct mechanistic link between basophils and TFH cells in SLE that promotes autoantibody production and lupus nephritis.

In a healthy context (top), unstimulated basophils do not leave the blood stream. In this condition, basophils do not contribute to follicular and extrafollicular responses to a given antigen in secondary lymphoid organs (SLO). In the SLE context (bottom), IL-3 upregulates PD-L1 expression by basophils and prostaglandin D₂ (PGD₂) (through CXCR4 externalization induction) enables basophil accumulation in SLO. There, in a PD-L1- and IL-4-dependent manner, basophils promote CD4+ T cell differentiation into TFH cells mainly of the TFH2 cell subset, germinal center (GC) formation, plasma cell accumulation and autoantibody production. Basophils influence also the maturation of extrafollicular B cells in a PD-L1 dependent way and class switch recombination in an IL-4 dependent manner.