Elizabeth E. Gray

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10−8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10−6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27–positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation

Subcapsular sinus (SCS) macrophages capture antigens from lymph and present them intact for B cell encounter and follicular delivery. However, the properties of SCS macrophages are poorly defined. Here we show SCS macrophage development depended on lymphotoxin-α1β2, and the cells had low lysosomal enzyme expression and retained opsonized antigens on their surface. Intravital imaging revealed immune complexes moving along macrophage processes into the follicle. Moreover, noncognate B cells relayed antigen opsonized by newly produced antibodies from the subcapsular region to the germinal center, and affinity maturation was impaired when this transport process was disrupted. Thus, we characterize SCS macrophages as specialized antigen-presenting cells functioning at the apex of an antigen transport chain that promotes humoral immunity.

A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk

Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein–Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)—a macrophage-associated autoimmune disease—than randomly selected immune response genes (P = 8.85 × 10−6). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 × 10−10; odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.

Cutting edge: Identification of a motile IL-17-producing gammadelta T cell population in the dermis.

Dendritic epidermal T cells (DETCs) are a well-studied population of γδ T cells that play important roles in wound repair. In this study, we characterize a second major population of γδ T cells in the skin that is present in the dermis. In contrast to DETCs, these Vγ5-negative cells are IL-7RhiCCR6hi retinoic acid-related orphan receptor γt+ and are precommitted to IL-17 production. Dermal γδ T cells fail to reconstitute following irradiation and bone marrow transplantation unless the mice also receive a transfer of neonatal thymocytes. Real-time intravital imaging of CXCR6GFP/+ mouse skin reveals dermal γδ T cells migrate at ∼4 μm/min, whereas DETCs are immobile. Like their counterparts in peripheral lymph nodes, dermal γδ T cells rapidly produce IL-17 following exposure to IL-1β plus IL-23. We have characterized a major population of skin γδ T cells and propose that these cells are a key source of IL-17 in the early hours after skin infection.

Cutting Edge: Identification of a Motile IL-17–Producing γδ T Cell Population in the Dermis

Dendritic epidermal T cells (DETCs) are a well-studied population of γδ T cells that play important roles in wound repair. In this study, we characterize a second major population of γδ T cells in the skin that is present in the dermis. In contrast to DETCs, these Vγ5-negative cells are IL-7RhiCCR6hi retinoic acid-related orphan receptor γt+ and are precommitted to IL-17 production. Dermal γδ T cells fail to reconstitute following irradiation and bone marrow transplantation unless the mice also receive a transfer of neonatal thymocytes. Real-time intravital imaging of CXCR6GFP/+ mouse skin reveals dermal γδ T cells migrate at ∼4 μm/min, whereas DETCs are immobile. Like their counterparts in peripheral lymph nodes, dermal γδ T cells rapidly produce IL-17 following exposure to IL-1β plus IL-23. We have characterized a major population of skin γδ T cells and propose that these cells are a key source of IL-17 in the early hours after skin infection.

DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway.

Viral oncogenes remove the hosts STING Cancer-causing viruses, such as the human papilloma virus (HPV) that causes cervical cancer, account for 12% of human cancers. One way they can cause cancer is by targeting tumor suppressor proteins in the host. Now Lau et al. report that DNA tumor viruses can also thwart the hosts immune system. Oncogenes from HPV and human adenovirus bound to the protein STING, a key component of the cGAS-STING pathway that senses and defends against intracellular DNA. In this way, the viruses subvert the hosts antiviral immunity and set up shop, which, for an unlucky few, eventually causes cancer. Science, this issue p. 568 Oncogenes encoded by DNA tumor viruses subvert antiviral immunity. Cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) detects intracellular DNA and signals through the adapter protein STING to initiate the antiviral response to DNA viruses. Whether DNA viruses can prevent activation of the cGAS-STING pathway remains largely unknown. Here, we identify the oncogenes of the DNA tumor viruses, including E7 from human papillomavirus (HPV) and E1A from adenovirus, as potent and specific inhibitors of the cGAS-STING pathway. We show that the LXCXE motif of these oncoproteins, which is essential for blockade of the retinoblastoma tumor suppressor, is also important for antagonizing DNA sensing. E1A and E7 bind to STING, and silencing of these oncogenes in human tumor cells restores the cGAS-STING pathway. Our findings reveal a host-virus conflict that may have shaped the evolution of viral oncogenes.

Lymph node macrophages

Lymph node (LN) macrophages have long been known for their efficient uptake of lymph-borne antigens. A convergence of studies on innate and adaptive immune responses has led to exciting recent advances in understanding their more specialized properties: presenting antigens to B cells, dendritic cells and T cells, producing trophic factors and cytokines, and, remarkably, being permissive for viral infection, a property critical for mounting anti-viral responses. LN macrophages have been traditionally divided into subsets based on their subcapsular sinus and medullary locations. Here, we classify LN macrophages into three subsets: subcapsular sinus macrophages, medullary sinus macrophages and medullary cord macrophages. We review the literature regarding the roles of these cells in innate and adaptive immune responses and requirements for their development. We also discuss challenges associated with their purification as well as the existence of additional heterogeneity among LN macrophages.

Deficiency in IL-17-committed V[gamma]4+ [gamma][delta] T cells in a spontaneous Sox13-mutant CD45.1+ congenic mouse substrain provides protection from dermatitis

Interleukin 17 (IL-17)-committed γδ T cells (γδT17 cells) participate in many immune responses, but their developmental requirements and subset specific functions remain poorly understood. Here we report that a commonly used CD45.1+ congenic C57BL/6 mouse substrain is characterized by selective deficiency in Vγ4+ γδT17 cells. This trait was due to a spontaneous mutation in the gene encoding the transcription factor Sox13 that caused an intrinsic defect in development of those cells in the neonatal thymus. The γδT17 cells migrated from skin to lymph nodes at low rates. In a model of psoriasis-like dermatitis, the Vγ4+ γδT17 cell subset expanded considerably in lymph nodes and homed to inflamed skin. Sox13-mutant mice were protected from psoriasis-like skin changes, which identified a role for Sox13-dependent γδT17 cells in this inflammatory condition.

Cutting Edge: cGAS Is Required for Lethal Autoimmune Disease in the Trex1-Deficient Mouse Model of Aicardi–Goutières Syndrome

Detection of intracellular DNA triggers activation of the stimulator of IFN genes–dependent IFN-stimulatory DNA (ISD) pathway, which is essential for antiviral immune responses. However, chronic activation of this pathway is implicated in autoimmunity. Mutations in TREX1, a 3′ repair exonuclease that degrades cytosolic DNA, cause Aicardi–Goutières syndrome and chilblain lupus. Trex1−/− mice develop lethal, IFN-driven autoimmune disease that is dependent on activation of the ISD pathway, but the DNA sensors that detect the endogenous DNA that accumulates in Trex1−/− mice have not been defined. Multiple DNA sensors have been proposed to activate the ISD pathway, including cyclic GMP–AMP synthase (cGAS). In this study, we show that Trex1−/− mice lacking cGAS are completely protected from lethality, exhibit dramatically reduced tissue inflammation, and fail to develop autoantibodies. These findings implicate cGAS as a key driver of autoimmune disease and suggest that cGAS inhibitors may be useful therapeutics for Aicardi–Goutières syndrome and related autoimmune diseases.

The SKIV2L RNA exosome limits activation of the RIG-I-like receptors

Sensors of the innate immune system that detect intracellular nucleic acids must be regulated to prevent inappropriate activation by endogenous DNA and RNA. The exonuclease Trex1 regulates the DNA-sensing pathway by metabolizing potential DNA ligands that trigger it. However, an analogous mechanism for regulating the RIG-I-like receptors (RLRs) that detect RNA remains unknown. We found here that the SKIV2L RNA exosome potently limited the activation of RLRs. The unfolded protein response (UPR), which generated endogenous RLR ligands through the cleavage of cellular RNA by the endonuclease IRE-1, triggered the production of type I interferons in cells depleted of SKIV2L. Humans with deficiency in SKIV2L had a type I interferon signature in their peripheral blood. Our findings reveal a mechanism for the intracellular metabolism of immunostimulatory RNA, with implications for specific autoimmune disorders.