T Cell and Dendritic Cell Abnormalities Synergize to Expand Pro-Inflammatory T Cell Subsets Leading to Fatal Autoimmunity in B6.NZBc1 Lupus-Prone Mice

Abstract

We have previously shown that B6 congenic mice with a New Zealand Black chromosome 1 (c1) 96-100 cM interval produce anti-nuclear Abs and that at least two additional genetic loci are required to convert this subclinical disease to fatal glomerulonephritis in mice with a c1 70-100 cM interval (c1(70-100)). Here we show that the number of T follicular helper and IL-21-, IFN-γ-, and IL-17-secreting CD4+ T cells parallels disease severity and the number of susceptibility loci in these mice. Immunization of pre-autoimmune mice with OVA recapitulated these differences. Differentiation of naïve T cells in-vitro under polarizing conditions and in-vivo following adoptive transfer of OVA-specific TCR transgenic cells into c1(70-100) or B6 recipient mice, revealed T cell functional defects leading to increased differentiation of IFN-γ- and IL-17-producing cells in the 96-100 cM and 88-96 cM intervals, respectively. However, in-vivo enhanced differentiation of pro-inflammatory T cell subsets was predominantly restricted to c1(70-100) recipient mice, which demonstrated altered dendritic cell function, with increased production of IL-6 and IL-12. The data provide support for the role of pro-inflammatory T cells in the conversion of subclinical disease to fatal autoimmunity and highlight the importance of synergistic interactions between individual susceptibility loci in this process.

Multiple tolerance defects contribute to the breach of B cell tolerance in New Zealand Black chromosome 1 congenic mice

“…Consistent with a potential role for these molecules in c1 congenic mice, we have previously demonstrated the existence of increased germinal center responses in c1(96–100) and c1(70–100) wild type mice [29]. However, the fate of anergic B cells in the context of these altered germinal center responses remains unknown.…”

“…We have previously shown that c1(70–100) congenic mice with a longer NZB chromosome 1 interval encompassing the c1(96–100) interval have T and dendritic cell defects that lead to increased proportions of TH1, TH17, and TFH cells as compared to c1(96–100) mice [29]. To determine the impact of these additional defects on HEL-specific tolerance, we crossed anti-HEL Ig and sHEL transgenes onto the c1(70–100) background.…”

Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling

“…We showed previously that BMDC from congenic mice with an NZB 88-96 cM region demonstrate enhanced secretion of IL-12 and IL-6 when cocultured with OVA 323-339 peptide and naive TCR-Tg OT-II OVA-specific T cells, which was associated with significantly enhanced differentiation of OT-II cells to Th1 and a trend toward increased generation of Th17 and Tfh cells (7). As shown in Fig.…”

“…In contrast, mice with longer NZB intervals demonstrated a progressive increase in the levels of anti-dsDNA Abs and the severity of renal disease that paralleled the size of the NZB interval. Further investigation of the immune mechanisms accompanying this increase in disease severity revealed the presence of intrinsic T cell and dendritic cell (DC) functional abnormalities that led to enhanced expansion of proinflammatory T cell subsets, including Th1, Th17, and T follicular helper (Tfh) cells (7).…”

“…We showed previously that the gene leading to this altered function is localized to the 88-96 cM interval and that it leads to increased production of IL-12 and IL-6 by bone marrow-derived DC (BMDC) in T cell-DC coculture experiments in vitro (7). In this article, we show that there is a promoter polymorphism in NZB mice that leads to reduced levels of the SLAM adapter molecule EWS-activated transcript 2 (EAT-2, also called sh2d1b1) within the 88-96 cM interval and that knockdown of EAT-2 in BMDC of mice that lack this polymorphism reproduces the altered DC phenotype.…”