Type 1 diabetes (T1D) is a chronic multi-factorial disorder characterized by the immune-mediated destruction of insulin-producing pancreatic beta cells. Variations at a large number of genes ...influence susceptibility to spontaneous autoimmune T1D in non-obese diabetic (NOD) mice, one of the most frequently studied animal models for human disease. The genetic analysis of these mice allowed the identification of many insulin-dependent diabetes (Idd) loci and candidate genes, one of them being Cd101. CD101 is a heavily glycosylated transmembrane molecule which exhibits negative-costimulatory functions and promotes regulatory T (Treg) function. It is abundantly expressed on subsets of lymphoid and myeloid cells, particularly within the gastrointestinal tract. We have recently reported that the genotype-dependent expression of CD101 correlates with a decreased susceptibility to T1D in NOD.B6 Idd10 congenic mice compared to parental NOD controls. Here we show that the knockout of CD101 within the introgressed B6-derived Idd10 region increased T1D frequency to that of the NOD strain. This loss of protection from T1D was paralleled by decreased Gr1-expressing myeloid cells and FoxP3.sup.+ Tregs and an enhanced accumulation of CD4-positive over CD8-positive T lymphocytes in pancreatic tissues. As compared to CD101.sup.+/+ NOD.B6 Idd10 donors, adoptive T cell transfers from CD101.sup.-/- NOD.B6 Idd10 mice increased T1D frequency in lymphopenic NOD scid and NOD.B6 Idd10 scid recipients. Increased T1D frequency correlated with a more rapid expansion of the transferred CD101.sup.-/- T cells and a lower proportion of recipient Gr1-expressing myeloid cells in the pancreatic lymph nodes. Fewer of the Gr1.sup.+ cells in the recipients receiving CD101.sup.-/- T cells expressed CD101 and the cells had lower levels of IL-10 and TGF-beta mRNA. Thus, our results connect the Cd101 haplotype-dependent protection from T1D to an anti-diabetogenic function of CD101-expressing Tregs and Gr1-positive myeloid cells and confirm the identity of Cd101 as Idd10.
Background
: Angiotensin I converting enzyme 2 (ACE2) is a receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and differences in its expression may affect susceptibility to ...infection.
Methods
: We performed a genome-wide expression quantitative trait loci (eQTL) analysis using hepatitis C virus-infected liver tissue from 190 individuals.
Results
: We discovered that polymorphism in a type III interferon gene (
IFNL4
), which eliminates IFN-λ4 production, is associated with a two-fold increase in ACE2 RNA expression. Conversely, among genes negatively correlated with
ACE2
expression, IFN-signalling pathways were highly enriched and
ACE2
was downregulated after IFN-α treatment. Negative correlation was also found in the gastrointestinal tract where inflammation driven IFN-stimulated genes were negatively correlated with
ACE2
expression and in lung tissue from a murine model of SARS-CoV-1 infection suggesting conserved regulation of
ACE2
across tissue and species.
Conclusions
: We conclude that
ACE2
is likely a negatively-regulated interferon-stimulated gene (ISG) and carriage of
IFNL4
gene alleles which modulates ISGs expression in viral infection may play a role in SARS-CoV-2 pathogenesis with implications for therapeutic interventions.
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