Type I IFN Contributes to the Phenotype of Unc93b1D34A/D34A Mice by Regulating TLR7 Expression in B Cells and Dendritic Cells.

Abstract

TLR7 recognizes pathogen-derived and self-derived RNA, and thus a regulatory system for control of the TLR7 response is required to avoid excessive activation. Unc93 homolog B1 (Unc93B1) is a regulator of TLR7 that controls the TLR7 response by transporting TLR7 from the endoplasmic reticulum to endolysosomes. We have previously shown that a D34A mutation in Unc93B1 induces hyperactivation of TLR7, and that Unc93b1(D34A/D34A) mice (D34A mice) have systemic inflammation spontaneously. In this study, we examined the roles of inflammatory cytokines such as IFN-γ, IL-17A, and type I IFNs to understand the mechanism underlying the phenotype in D34A mice. mRNAs for IFN-γ and IL-I7A in CD4(+) T cells increased, but inflammatory phenotype manifesting as thrombocytopenia and splenomegaly was still observed in Ifng(-/-) or Il17a(-/-) D34A mice. In contrast to T cell-derived cytokines, Ifnar1(-/-) D34A mice showed an ameliorated phenotype with lower expression of TLR7 in B cells and conventional dendritic cells (cDCs). The amount of TLR7 decreased in B cells from Ifnar1(-/-) D34A mice, but the percentage of TLR7(+) cells decreased among CD8α(-) cDCs. In conclusion, type I IFNs maintain expression of TLR7 in B cells and cDCs in different ways; total amount of TLR7 is kept in B cells and TLR7(+) population is retained among cDCs. Our results suggested that these TLR7-expressing cells are activated initially and influence TLR7-dependent systemic inflammation.