Altered CD4+ T cell differentiation with preferential expansion of Th1 cells in TLR7-driven autoimmunity (171.45)

Abstract

Abstract TLR7 is a single-stranded RNA-recognizing innate immune receptor with roles in anti-viral immunity and systemic lupus erythematosus (SLE) in humans and SLE-like autoimmunity in mice. TLR7 gene duplication drives inflammation and autoimmunity in the BXSB mouse model and other Y autoimmune accelerator (Yaa)-derived models of murine lupus. Additionally, TLR7 SNPs associate with SLE in Eastern Asian populations. In this study, we investigated effects of TLR7 overexpression on CD4+ T cell subsets. In unmanipulated, 5-6 month old TLR7 BAC transgenic mice, we observed amplified activated:naïve T cell ratios and preferential expansion of the Th1 subset compared to wild type controls. We also evaluated the phenotype of TCR transgenic T cells specific for the RNA-binding autoantigen, human La, following adoptive transfer into TLR7 BAC transgenic mice. These human La-specific T cells demonstrated enhanced differentiation to Th1 and PSGL1lowCXCR4+ extrafollicular helper phenotypes after recovery from TLR7-overexpressing human La transgenic mice compared to wild type human La transgenic controls seven days after transfer. Moreover, TLR7 overexpression in recipient mice resulted in significantly reduced expansion of the CD4+ Foxp3+ phenotype among transferred, human La-specific cells. These data indicate that TLR7 overexpression alters CD4+ T cell populations in a manner that potentially contributes to autoinflammatory disease in these animals.