Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease

The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21) specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn’s disease, ulcerative colitis (UC) and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo. ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL) for the neighboring gene IL18RAP, with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner

The Efficiency of the Human CD8+ T Cell Response: How Should We Quantify It, What Determines It, and Does It Matter?

Multidisciplinary techniques, in particular the combination of theoretical and experimental immunology, can address questions about human immunity that cannot be answered by other means. From the turnover of virus-infected cells in vivo, to rates of thymic production and HLA class I epitope prediction, theoretical techniques provide a unique insight to supplement experimental approaches. Here we present our opinion, with examples, of some of the ways in which mathematics has contributed in our field of interest: the efficiency of the human CD8+ T cell response to persistent viruses

NK cell receptor NKG2D sets activation threshold for the NCR1 receptor early in NK cell development

The activation of natural killer (NK) cells depends on a change in the balance of signals from inhibitory and activating receptors. The activation threshold values of NK cells are thought to be set by engagement of inhibitory receptors during development. Here, we found that the activating receptor NKG2D specifically set the activation threshold for the activating receptor NCR1 through a process that required the adaptor DAP12. As a result, NKGD2-deficient (Klrk1-/-) mice controlled tumors and cytomegalovirus infection better than wild-type controls through the NCR1-induced production of the cytokine IFN-γ. Expression of NKG2D before the immature NK cell stage increased expression of the adaptor CD3ζ. Reduced expression of CD3ζ in Klrk1-/- mice was associated with enhanced signal transduction through NCR1, and CD3ζ deficiency resulted in hyper-responsiveness to stimulation via NCR1. Thus, an activating receptor developmentally set the activity of another activating receptor on NK cells and determined NK cell reactivity to cellular threats

Strategies for Translational Research in the United Kingdom

In the United Kingdom, many foundations and institutions and the government have made substantial investments in translational research. We examine the structures that surround this support and consider some of the results of this prodigious push toward enhancing translational research pursuits and thus improved clinical medicine.The past few years have seen a greatly increased investment in funding for translational research, both in terms of infrastructure and a degree of reorientation of grant awards. Here, we describe key aspects of the UK translational research strategy in the context of recent international developments and, where relevant, draw on specific examples from the Biomedical Research Centre at Guy’s and St. Thomas’ Hospitals and King’s College London, one of the five comprehensive translational institutes funded in 2007 by the UK National Institute for Health Research

Bacterial coinfection restrains antiviral CD8 T-cell response via LPS-induced inhibitory NK cells

Exposure to multiple pathogens is common in nature, yet interactions between the immune components targeting bacterial and viral pathogens during co-infection are poorly understood. Here the authors show that bacteria-derived LPS induces cytotoxic NK cells that suppress antiviral CD8 T cell response