Genome-wide association studies have uncovered thousands of common variants associated with human disease, but the contribution of rare variation to common disease remains relatively unexplored. The UK Biobank (UKB) contains detailed phenotypic data linked to medical records for approximately 500,000 participants, offering an unprecedented opportunity to evaluate the impact of rare variation on a broad collection of traits1,2. Here, we studied the relationships between rare protein-coding variants and 17,361 binary and 1,419 quantitative phenotypes using exome sequencing data from 269,171 UKB participants of European ancestry. Gene-based collapsing analyses revealed 1,703 statistically significant gene-phenotype associations for binary traits, with a median odds ratio of 12.4. Furthermore, 83% of these associations were undetectable via single variant association tests, emphasizing the power of gene-based collapsing analysis in the setting of high allelic heterogeneity. Gene-phenotype associations were also significantly enriched for loss-of-function-mediated traits and approved drug targets. Finally, we performed ancestry-specific and pan-ancestry collapsing analyses using exome sequencing data from 11,933 UKB participants of African, East Asian, or South Asian ancestry. Together, our results highlight a significant contribution of rare variants to common disease. Summary statistics are publicly available through an interactive portal (http://azphewas.com/).

Key Points• The frequency of CD161 ϩϩ MAIT cells is dramatically decreased in the blood of HIVinfected patients, and they are nonrecoverable with HAART.• Gut sequestration and apoptosis in response to bacterial signals may, amongst others, be mechanisms that contribute to this. IntroductionThe natural course of human immunodeficiency virus type 1 (HIV-1) infection is associated with progressive immune dysfunction, perturbation of immune-cell subsets and increased opportunistic infections. In early disease, there is a dramatic loss of CD4 ϩ T cells from the gastrointestinal tract resulting in impaired mucosal immunity, reduced peripheral CD4 ϩ T-cell count, and increased systemic T-cell activation. [1][2][3][4] These factors contribute to an increased susceptibility to infection with specific organisms such as Mycobacterium tuberculosis and Candida albicans. [5][6][7] In addition, more recent evidence suggests an important role for the loss of CD8 ϩ T cells in susceptibility to bacterial pneumonia and all-cause mortality in HIV infection. 8 MAIT cells are a distinct subset of tissue-infiltrating lymphocytes with antibacterial functions that account for up to one-third of the CD8 ϩ T-cell population in the blood of healthy individuals. [9][10][11] MAIT cells are identified by expression of a semi-invariant T-cell receptor (TCR), iV␣7.2, 10,12,13 which recognizes ligands presented by MHC class I related (MR1) protein. 14 MR1 presentation occurs on dendritic cells, monocytes, and lung epithelial cells in response to bacterial pathogens. 9,10,12 MAIT cells are activated in vitro in an MR1-dependent fashion by a range of bacterial and fungal pathogens, including Escherichia coli, M tuberculosis, and C albicans, 9,10 and in mouse models have been shown to provide protection against bacterial infection. 10,15 In addition, MAIT cells have been shown to be lost from the blood and present in the lungs of patients with active tuberculosis, suggesting they may play an important role in host immunity to M tuberculosis. 9,10 Specific subsets of CD4 ϩ and CD8 ϩ T cells, termed Th17 and Tc17, are defined by their ability to produce IL17A and are important in the regulation of mucosal integrity and antibacterial immunity. [16][17][18][19][20] Early in HIV infection, Th17 cells are lost from the gastrointestinal tract, but may be restored through long-term highly active antiretroviral therapy (HAART) concurrent with a reduction in immune activation levels. 21 The loss of this IL17A and Submitted June 12, 2012; accepted November 26, 2012. Prepublished online as Blood First Edition paper, December 18, 2012; DOI 10.1182 DOI 10. /blood-2012 *C.C. and J.E.U. contributed equally to this work.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 7, 2018. by guest www.bloodjournal.org...

The C-type lectin-like receptor CD161 is expressed on lymphocytes found in human gut and liver, as well as blood, especially Natural Killer cells, T helper 17 cells and a population of unconventional T cells known as Mucosal Associated Invariant T (MAIT) cells. The association of high CD161 expression with innate T cell populations including MAIT cells is established. Here we show that CD161 is also expressed, at intermediate levels, on a prominent subset of polyclonal CD8+ T cells, including anti-viral populations, which display a memory phenotype. These memory CD161int CD8+ T cells are enriched within the colon and express both CD103 and CD69, markers associated with tissue residence. Furthermore, this population was characterised by enhanced polyfunctionality, increased levels of cytotoxic mediators and high expression of the transcription factors T-bet and Eomesodermin. Such populations were induced by novel vaccine strategies based on adenoviral vectors, currently in trial against Hepatitis C virus. Thus, intermediate CD161 expression marks potent polyclonal, polyfunctional tissue-homing CD8+ T cell populations in humans. Since induction of such responses represents a major aim of T cell prophylactic and therapeutic vaccines in viral disease and cancer, analysis of these populations could be of value in the future.

Enterovirus infections, in particular those with Coxsackieviruses, have been linked to the development of type 1 diabetes (T1D). Although animal models have demonstrated that interferons (IFNs) regulate virus-induced T1D by acting directly on the beta cell, little is known on the human pancreatic islet response to IFNs. Here we show that human islet cells respond to IFNs by expressing signature genes of antiviral defense. We also demonstrate that they express three intracellular sensors for viral RNA, the toll like receptor 3 (TLR3) gene, the retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene-5 (MDA-5), which induce type I IFN production in infected cells. Finally, we show for the first time that the IFN-induced antiviral state provides human islets with a powerful protection from the replication of Coxsackievirus. This may be critical for beta cell survival and protection from virus-induced T1D in humans.