Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD.

Coeliac disease (CeD) is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that selectively occurs in a subset of genetically susceptible HLA-DQ8 and HLA-DQ2 individuals 1 , 2 . The need to develop non-dietary treatments is now widely recognized 3 , but it is hampered by the lack of a pathophysiologically relevant gluten- and HLA-dependent preclinical model. Furthermore, while human studies have led to major advances in our understanding of CeD pathogenesis 4 , direct demonstration of the respective roles of disease-predisposing HLA molecules, and adaptive and innate immunity in the development of tissue damage is missing. To address these unmet needs, we engineered a mouse model that reproduces the dual overexpression of IL-15 in the gut epithelium and the lamina propria (LP) characteristic of active CeD, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy (VA) upon gluten ingestion. We show that overexpression of IL-15 in both the epithelium and LP is required for the development of VA, demonstrating the location-dependent central role of IL-15 in CeD pathogenesis. Furthermore, our study reveals that CD4 + T cells and HLA-DQ8 are required for VA development, because of their critical role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell (IEC) lysis. Finally, it establishes that IFN-γ and transglutaminase 2 (TG2) are central for tissue destruction. This mouse model, by reflecting the complex interplay between gluten, genetics and the IL-15-driven tissue inflammation, represents a powerful preclinical model for the characterization of cellular circuits critically involved in intestinal tissue damage in CeD, and the identification and testing of new therapeutic strategies.

Here we find that CD8 + T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49 + CD8 + regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8 + T cells efficiently eliminated pathogenic gliadin-specific CD4 + T cells from celiac disease patients’ leukocytes in vitro. We also find elevated levels of KIR + CD8 + T cells, but not CD4 + regulatory T cells, in COVID-19 patients, which correlated with disease severity and vasculitis. Selective ablation of Ly49 + CD8 + T cells in virus-infected mice led to autoimmunity post infection. Our results indicate that in both species, these regulatory CD8 + T cells act uniquely to suppress pathogenic T cells in autoimmune and infectious diseases.

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Edited by Ruma BanerjeeTransglutaminase 2 (TG2) catalyzes transamidation or deamidation of its substrates and is ordinarily maintained in a catalytically inactive state in the intestine and other organs. Aberrant TG2 activity is thought to play a role in celiac disease, suggesting that a better understanding of TG2 regulation could help to elucidate the mechanistic basis of this malady. Structural and biochemical analysis has led to the hypothesis that extracellular TG2 activation involves reduction of an allosteric disulfide bond by thioredoxin-1 (TRX), but cellular and in vivo evidence for this proposal is lacking. To test the physiological relevance of this hypothesis, we first showed that macrophages exposed to pro-inflammatory stimuli released TRX in sufficient quantities to activate their extracellular pools of TG2. By using the C35S mutant of TRX, which formed a metastable mixed disulfide bond with TG2, we demonstrated that these proteins specifically recognized each other in the extracellular matrix of fibroblasts. When injected into mice and visualized with antibodies, we observed the C35S TRX mutant bound to endogenous TG2 as its principal protein partner in the small intestine. Control experiments showed no labeling of TG2 knock-out mice. Intravenous administration of recombinant TRX in wild-type mice, but not TG2 knock-out mice, led to a rapid rise in intestinal transglutaminase activity in a manner that could be inhibited by small molecules targeting TG2 or TRX. Our findings support the potential pathophysiological relevance of TRX in celiac disease and establish the Cys 370 -Cys 371 disulfide bond of TG2 as one of clearest examples of an allosteric disulfide bond in mammals. Transglutaminase 2 (TG2)2 is a ubiquitous member of the mammalian transglutaminase family that catalyzes transamidation or deamidation of its protein or peptide substrates. It is expressed in many cell types (1), and a considerable fraction of the expressed protein is released into the extracellular environment through an unconventional secretory mechanism whose details have not yet been elucidated (2, 3). Aberrant activity of extracellular TG2 has been implicated in several human diseases, including celiac disease, various cancers, and certain fibrotic disorders (4 -6), yet the enzyme is dormant in the extracellular matrix (ECM) of virtually all organs under normal physiological conditions (7,8). Whereas the enzymatic chemistry of TG2 has been extensively studied, our understanding of its function and regulation is still in its infancy.The post-translational regulatory mechanisms of TG2 have been reviewed elsewhere (9). Here, we focus on the redox regulation of TG2, because it is believed to be a principal mechanism for controlling the activity of extracellular TG2. It has long been known that exposure to an oxidizing environment abolishes the enzymatic activity of TG2 (10, 11). The discovery of an unusual disulfide bond (between Cys 370 and Cys 371 ) located distal to the active site of human TG2 (12) was followed by extensiv...