LAUSR

Interleukin (IL)-21-producing T peripheral helper (Tph) cells are thought to contribute to extra-follicular B cell activation and play a pathogenic role in autoimmune diseases. In this study, we investigated relationship between Tph cells and interferons (IFNs) in several autoimmune diseases because our previous study demonstrated that type I IFNs promote differentiation of IL-21-producing Tph-like cells. Frequency of Tph cells in the blood as well as serum IFN-α2a and IFN-λ1 were markedly elevated in patients with active systemic lupus erythematosus (SLE) compared to other autoimmune diseases or healthy controls. Notably, frequency of Tph cells were positively correlated with SLE disease activity index, serum IFN-α, and serum IFN-λ1 in SLE patients. Additionally, we found that type III IFNs (IFN-λ1, IFN-λ2, and IFN-λ3) promote differentiation of programmed cell death-1 (PD-1)-positive CXCR5 -CD4 + T cells and enhance secretion of IL-21, IFN-γ, and CXCL13. IFN-λ1, like IFN-α, up-regulated the mRNA expression of IL21, IFNG, CXCL13, CD244, SLAMF7, GZMB, PRF1, CCR5, and PRDM1, whereas down-regulated that of CXCR5 and BCL6, reflecting a Tph-related gene expression pattern. IFN-α in combination with IFN-λ1, IFN-λ2, or IFN-λ3 significantly increased differentiation of PD-1 +CXCR5 - Tph-like cells and secretion of Tph-related cytokines as compared with each IFN alone, suggesting a cooperative interaction. From these findings, it is highly probable that type III IFNs in addition to type I IFNs play a key role in differentiation of Tph cells and that high levels of IFN-α and IFN-λ1 trigger differentiation and expansion of Tph cells in SLE. (242 words).