Mucosal Immunity

Abstract B cells in germinal centers (GCs) cycle between light zone (LZ) and dark zone (DZ). The cues in the GC microenvironment that regulate the transition from LZ to DZ have not been well characterized. In Peyer’s patches (PPs), transforming growth factor-β (TGFβ) promotes IgA induction in activated B cells that can then differentiate into GC B cells. We show here that TGFβ signaling occurs in B cells in GCs and is distinct from signaling that occurs in activated B cells in PPs. Whereas in activated B cells TGFβ signaling is required for IgA induction, in the GC it was instead required for the transition from LZ to DZ. In the absence of TGFβ signaling, there was an accumulation of LZ GC B cells and reduced antibody affinity maturation likely due to reduced activation of Foxo1. This work identifies TGFβ as a microenvironmental cue that is critical for GC homeostasis and function. Submitted: 1 November 2018 Revision received 18 June 2019 Accepted: 1 August 2019 http://www.rupress.org/terms/ https://creativecommons.org/licenses/by-nc-sa/4.0/ This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

In lymph nodes, fibroblastic reticular cells (FRCs) and associated collagen fibers assemble into a network of “conduits.” The network is believed to allow the swift and efficient uptake of lymph-borne antigens. The role of these networks in other lymphoid tissues is less well described. Chang et al. characterized a similar conduit system in Peyer's patches (PPs) in the intestine. In this case, the conduits regulate the flow of absorbed luminal fluid. The maintenance of this system by FRCs depends on luminal flow and is needed to sustain lymphocyte recruitment to PPs and for effective humoral immune responses. Intriguingly, FRCs perceive luminal flow by means of the mechanosensitive ion channel Piezo1. Nat. Immunol. 20, 1506 (2019).

KEY POINTS Inhibitory receptors are upregulated on peripheral Tregs of DC-deficient mice. Tregs from DC-deficient mice are functionally impaired. Tregs require DCs for inhibition of T cell transfer-induced colitis. Abstract Dendritic cells (DCs) together with regulatory T cells (Tregs) are essential mediators of immune homeostasis. Disruption of function or frequency of either cell type can lead to fatal autoimmunity. We previously described that mice constitutively lacking DCs (∆DC) develop autoimmunity characterized by reduced body weight, autoantibodies, and pronounced intestinal inflammation. In this study, we show that lack of DCs leads to an altered gene expression profile in peripheral but not thymic Tregs with increased expression of inhibitory receptors. The suppressive function of Tregs from ΔDC mice was impaired in T cell cocultures. In a model of transfer colitis, Tregs from ∆DC mice were only functional in the presence of DCs in recipient mice. Lack of MHC class II on DCs also resulted in upregulation of inhibitory receptors on Tregs, reduced body weight, and elevated serum IgA levels. Further analysis of the IgA response revealed an expansion of IgA+ germinal center B cells and plasma cells in mesenteric lymph nodes and more IgA-coated commensal bacteria in feces of ∆DC mice. Thus, we show a critical role for DCs to establish intestinal homeostasis by regulating Treg function for prevention of spontaneous inflammation. Footnotes This work was supported by Deutsche Forschungsgemeinschaft Grants CRC643_B15 (to D.V.), CRC1181_A02 (to D.V.), CRC1181_C04 (to J.M.), and CRC1181_A07 (to D.D.), the Staedler Stiftung (to J.M.), and an Interdisciplinary Center for Clinical Research intramural Grant IZKF_J54 (to C.H.K.L.). The dataset presented in this article has been submitted to the Gene Expression Omnibus database under accession number GSE120690. The online version of this article contains supplemental material. Received March 18, 2019. Accepted September 25, 2019. Copyright © 2019 by The American Association of Immunologists, Inc.

Abstract Secretory IgA (SIgA) is a well‐known mucosal‐surface molecule in first‐line defense against extrinsic pathogens and antigens. Its immunomodulatory and pathological roles have also been emp...

PostScript Letter HLA-DQ2/DQ8 typing for non-biopsy diagnosis of coeliac disease: is it necessary? Siba Prosad Paul1,2, Jagrati Chopra2,3, Camelia Laura Vaina4, Akshatha Mallikarjuna2, Dharamveer Basude2,3 Paediatrics, Torbay Hospital, Torquay, UK Paediatric Gastroenterology, Bristol Royal Hospital for Children, Bristol, UK Medical School, University of Bristol Faculty of Health Sciences, Bristol, UK Paediatrics, Yeovil District Hospital, Yeovil, UK Correspondence to Dr Siba Prosad Paul; siba.paul{at}nhs.net View Full Text Statistics from Altmetric.com In 2012, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) revised diagnostic guidance for paediatric coeliac disease (CD).1 It recommended a no-biopsy pathway (NBP) for symptomatic children if so-called ‘triple test’ criteria are satisfied1: IgA anti-tissue transglutaminase antibodies (anti-tTGA) titre >10 times upper-limit-of-normal (10×ULN) and are IgA sufficient. Positive IgA anti-endomysial antibodies (EMA). Positive HLA-DQ2/DQ8 haplotype. The British Society of Paediatric Gastroenterology, Hepatology and Nutrition adopted the guidelines in 2013. ESPGHAN suggested that CD can only be diagnosed by paediatric gastroenterologists or consultant paediatricians with special interest (SPIN) in gastroenterology.1 Many secondary care centres (SCC) in the UK have no SPIN consultant, therefore CD diagnosis is often made by (non-SPIN) general paediatricians. The NBP was implemented in Southwest England (SWE) in May 2013.2 An electronic register is maintained in … View Full Text Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. Copyright information: © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ. Read the full text or download the PDF: Subscribe Log in

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation with accumulation of activated group 2 innate lymphoid cells (ILC2s) and elevation of thymic stromal lymphopoietin (TSLP).

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Professor Alan SalamaProfessor of Nephrology and Honorary Consultant NephrologistRoyal Free Hospital LondonJune 2016 What is Henoch-Schönlein Purpura? Henoch-Schönlein Purpura (HSP) is a systemic vasculitis which can affect the skin, joints, ...

KEY POINTS A fix/permeabilization approach allows isolation of Ag- and isotype-specific ASC. IgM, IgG, and IgA ASC have shared and distinct transcriptome components. Each ASC isotype displays distinct, expanded CDR3 regions. Visual Abstract Abstract Ab-secreting cells (ASC) or plasma cells are essential components of the humoral immune system. Although Abs of different isotypes have distinct functions, it is not known if the ASC that secrete each isotype are also distinct. ASC downregulate their surface BCR upon differentiation, hindering analyses that couple BCR information to other molecular characteristics. In this study, we developed a methodology using fixation, permeabilization, and intracellular staining coupled with cell sorting and reversal of the cross-links to allow RNA sequencing of isolated cell subsets. Using hemagglutinin and nucleoprotein Ag-specific B cell tetramers and intracellular staining for IgM, IgG, and IgA isotypes, we were able to derive and compare the gene expression programs of ASC subsets that were responding to the same Ags following influenza infection in mice. Intriguingly, whereas a shared ASC signature was identified, each ASC isotype-specific population expressed distinct transcriptional programs controlling cellular homing, metabolism, and potential effector functions. Additionally, we extracted and compared BCR clonotypes and found that each ASC isotype contained a unique, clonally related CDR3 repertoire. In summary, these data reveal specific complexities in the transcriptional programming of Ag-specific ASC populations. This article is featured in In This Issue, p.2027 Footnotes This work was supported by National Institutes of Health (NIH) Grants 5R01 CA095318 (to C.D.S.), 1R01 AI123733 and P01 AI125180 (to J.M.B.), and NIH F31 AI138391 (to M.J.P.). The RNA sequence data presented in this article have been submitted to the National Center for Biotechnology Information's Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE124578. The online version of this article contains supplemental material. Abbreviations used in this article: ASC Ab-secreting cell DEG differentially expressed gene dLN draining lymph node HA hemagglutinin NP nucleoprotein PCA principal component analysis RNA-seq RNA sequencing. Received March 8, 2019. Accepted August 13, 2019. Copyright © 2019 by The American Association of Immunologists, Inc.

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Abstract Mucosal-associated invariant T (MAIT) cells are semi-invariant T cells specifically recognizing riboflavin derivatives that are synthesized by many bacteria and fungi presented by MHC class I–related MR1 molecules. Accumulating evidence, however, indicates that MAIT cell functions are inducible by cytokine stimuli in the absence of TCR ligation, identifying MAIT cells as innate sentinels in inflammatory environments. In this study, we demonstrate that death receptor 3 (DR3), a member of the TNFR superfamily, is ex vivo expressed and predominantly upregulated on the surface of human MAIT cells by innate cytokine stimulation. In turn, the DR3 ligand TNF-like protein 1A (TL1A) licenses innate TNF-α production in the absence of cognate triggers, being sufficient to promote activation of primary endothelial cells in vitro. TL1A further amplifies synthesis of IFN-γ and granzyme B in the presence of otherwise weak innate stimuli and strongly augments polyfunctionality. Mechanistically, TL1A potentiates T-bet expression, early NF-κB, and late p38 MAP kinase phosphorylation, with the latter being indispensable for TNF-α production by MAIT cells. Of note, endogenous TL1A is also rapidly released from PBMC cultures in response to bacterial triggering, thereby equally augmenting Ag-specific MAIT cell effector functions. In summary, to our knowledge, we identify a new inflammatory mechanism in MAIT cells linking the DR3/TL1A axis with amplification of TCR-dependent and -independent effector functions, particularly inducing excessive innate TNF-α production. Given that both TL1A and TNF-α are abundantly present at sites of chronic inflammation, the contribution of MAIT cells in such scenarios needs to be determined.

KEY POINTS VLP enhances antinorovirus IgA recall responses in humanized mice. Particulate structure is required for IgA enhancement. VLP-driven IgA responses are functionally superior to IgG responses. Abstract Virus-like particles (VLPs) provide a well-established vaccine platform; however, the immunogenic properties acquired by VLP structure remain poorly understood. In this study, we showed that systemic vaccination with norovirus VLP recalls human IgA responses at higher magnitudes than IgG responses under a humanized mouse model that was established by introducing human PBMCs in severely immunodeficient mice. The recall responses elicited by VLP vaccines depended on VLP structure and the disruption of VLP attenuated recall responses, with a more profound reduction being observed in IgA responses. The IgA-focusing property was also conserved in a murine norovirus-primed model under which murine IgA responses were recalled in a manner dependent on VLP structure. Importantly, the VLP-driven IgA response preferentially targeted virus-neutralizing epitopes located in the receptor-binding domain. Consequently, VLP-driven IgA responses were qualitatively superior to IgG responses in terms of the virus-neutralizing activity in vitro. Furthermore, the IgA in mucosa obtained remarkable protective function toward orally administrated virus in vivo. Thus, our results indicate the immune-focusing properties of the VLP vaccine that improve the quality/quantity of mucosal IgA responses, a finding with important implications for developing mucosal vaccines. Footnotes This work was partly supported by Grants-in-Aid for Scientific Research (C) 17K08895 and 25860377 from the Japan Society for the Promotion of Science and by the Research Program on Emerging and Re-emerging Infectious Disease from the Japan Agency for Medical Research and Development (Grant JP18fk0108051). The online version of this article contains supplemental material. Received April 29, 2019. Accepted October 8, 2019. Copyright © 2019 by The American Association of Immunologists, Inc. This article is distributed under The American Association of Immunologists, Inc., Reuse Terms and Conditions for Author Choice articles.

Abstract Lymph flow through Peyer’s patches enhances mucosal antibody production. After infection, lymph fluid flows from peripheral tissues to the draining lymph node, carrying along tissue antigens including bacteria and viruses. Lymph reaching the node passes through a series of sinuses, where antigen presenting cells can access lymph-borne particulates and display them to naïve lymphocytes. Lymph first encounters a subcapsular sinus lined with macrophages that relay captured antigen to underlying B cell follicles. In between follicles, a series of small channels formed by stromal cells connect the subcapsular sinus to the node’s interior paracortex, also referred to as the T cell zone. Small molecules carried in lymph can enter these channels, called conduits, and are conveyed through the T cell zone to the high endothelial venules that are the sites of lymphocyte entry from the blood. Until now, the importance of the conduits during immune responses has been unclear because experimentally perturbing lymph flow specifically through nodal conduits has proven difficult. To examine the impact of conduits on adaptive immunity, Chang et al. investigated Peyer’s patches, organized lymphoid structures in the intestine. Like lymph nodes, Peyer’s patches have B cell follicles and T cell zones; however, they lack several key features of lymph nodes, including subcapsular sinuses. Therefore, Chang et al. first demonstrated that, like lymph nodes, Peyer’s patches contain a conduit system formed by stromal cells that transports small, ingested proteins directly from the intestines. Similar to lymph nodes, Peyer’s patch conduits connect directly to the blood vessels through which lymphocytes enter. The authors then used two clever approaches to manipulate lymph flow through Peyer’s patch conduits: increasing the osmolarity in the intestines and ablating the mechanosensory molecule Piezo1 in Peyer’s patch stromal cells. Both approaches dramatically altered the structure of conduit-connected blood vessels, which could no longer fully recruit lymphocytes. This reduction in lymphocyte entry impacted mucosal antibody responses to vaccination. Although this study sheds important light on conduit function, the altered Peyer’s cellularity makes it difficult to assess the importance of conduit-antigen delivery during adaptive immune responses. Regardless, these findings reveal that there are still unappreciated factors, including solutes in the intestine, poised to shape mucosal antibody responses. Highlighted Article J. E. Chang, M. B. Buechler, E. Gressier, S. J. Turley, M. C. Carroll, Mechanosensing by Peyer’s patch stroma regulates lymphocyte migration and mucosal antibody responses. Nat. Immunol. 20, 1506–1516 (2019).OpenUrl Copyright © 2019, American Association for the Advancement of Science

Journal of Immunology Research is a peer-reviewed, Open Access journal that provides a platform for scientists and clinicians working in different areas of immunology and therapy. The journal publishes research articles, review articles, as well as clinical studies related to classical immunology,...

The generation of tissue-resident memory T cells (TRM) is an essential aspect of immunity at mucosal surfaces, and it has been suggested that preferential generation of TRM is one of the principal advantages of mucosally administered vaccines.

European badgers are a wildlife reservoir of bovine tuberculosis in parts of Great Britain. Accurate diagnosis of tuberculosis in badgers is important for the development of strategies for the control of the disease.

There are three times as many people with the chronic and debilitating bowel disorder called inflammatory bowel disease (IBD) as ever thought before, according to a new study presented today at UEG Week 2019, at Barcelona.

KEY POINTS A mucosally associated lymphoid tissue is identified in teleost pharyngeal cavity. Trout pharyngeal bacteria are mainly coated with secretory IgT. Teleost IgT plays a vital role in protecting the PC from invading pathogens. Abstract The pharyngeal organ is located at the crossroad of the respiratory and digestive tracts in vertebrate, and it is continuously challenged by varying Ags during breathing and feeding. In mammals, the pharyngeal mucosa (PM) is a critical first line of defense. However, the evolutionary origins and ancient roles of immune defense and microbiota homeostasis of PM are still unknown. In this study, to our knowledge, we are the first to find that diffuse MALT is present in PM of rainbow trout, an early vertebrate. Importantly, following parasitic infection, we detect that strong parasite-specific mucosal IgT and dominant proliferation of IgT+ B cell immune responses occurs in trout PM, providing, to our knowledge, the first demonstration of local mucosal Ig responses against pathogens in pharyngeal organ of a nonmammal species. Moreover, we show that the trout PM microbiota is prevalently coated with secretory IgT and, to a much lesser degree, by IgM and IgD, suggesting the key role of mucosal Igs in the immune exclusion of teleost pharyngeal bacteria. Overall, to our knowledge, our findings provide the first evidence that pharyngeal mucosal immunity appear earlier than tetrapods. Footnotes This work was supported by grants from the National Key Research and Development Program of China (2018YFD0900503 and 2018YFD0900400) (to Z.X.) and the National Natural Science Foundation of China (31873045) (to Z.X.). The data presented in this article have been submitted to the National Center for Biotechnology Information Sequence Read Archive (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA560631/) under accession number PRJNA560631. The online version of this article contains supplemental material. Received July 31, 2019. Accepted September 25, 2019. Copyright © 2019 by The American Association of Immunologists, Inc. This article is distributed under The American Association of Immunologists, Inc., Reuse Terms and Conditions for Author Choice articles.

Helicobacter pylori colonizes human gastric epithelial cells and contributes to the development of several gastrointestinal disorders. Interleukin (IL)-33 is involved in various immune responses, with reported proinflammatory and anti-inflammatory effects, which may be associated with colitis and...

Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1β (IL-1β) in t…...

KEY POINTS We report (to our knowledge) novel CMV-specific KLRG1+CD27+ CD57+/− CD8+ TAEFF in primary infection. KLRG1+ TAEFF correlates with CMV function and control in lung transplant patients. Abstract CMV remains an important opportunistic pathogen in high-risk lung transplant recipients. We characterized the phenotype and function of CD8+ T cells from acute/primary into chronic CMV infection in 23 (donor+/recipient−; D+R−) lung transplant recipients and found rapid induction of both KLRG1+ and/or CD57+ CMV-specific CD8+ T cells with unexpected coexpression of CD27. These cells demonstrated maturation from an acute effector T cell (TAEFF) to an effector memory T cell (TEM) phenotype with progressive enrichment of KLRG1+CD57+CD27− cells into memory. CMV-specific KLRG1+ TAEFF were capable of in vitro proliferation that diminished upon acquisition of CD57, whereas only KLRG1+ expression correlated with T-bet expression and effector function. In contrast to blood TAEFF, lung mucosal TAEFF demonstrated reduced KLRG1/T-bet expression but similar CD57 levels. Additionally, increased KLRG1+TAEFF were associated with early immune viral control following primary infection. To our knowledge, our findings provide new insights into the roles of KLRG1 and CD57 expression in human T cells, forming the basis for a refined model of CD8+ T cell differentiation during CMV infection. Footnotes This work was supported by National Institutes of Health Grants R01 AI079175 and R01HL133184 (to J.F.M.) and funding from the Immune Transplant and Therapy Center of UPMC. The online version of this article contains supplemental material. Abbreviations used in this article: BAL bronchoalveolar lavage ChIP chromatin immunoprecipitation D+R− donor+/recipient− KLRG1 killer cell lectin-like receptor subfamily G member 1 LMNC lung mucosal mononuclear cell LTR lung transplant recipient TAEFF acute effector T cell TEM effector memory T cell. Received April 5, 2019. Accepted July 31, 2019. Copyright © 2019 by The American Association of Immunologists, Inc.

Parkinson’s disease (PD) has long been considered a brain disease, but studies now point to the gastrointestinal (GI) tract as a potential starting point for PD. In particular, the human vermiform appendix has been implicated in PD.

Immune dysregulation is one of the mechanisms to promote endometriosis (EMS). Various T cell subpopulations have been reported to play different roles in the development of EMS. The mucosa-associated invariant T cell (MAIT) is an important T cell subset in the pathogenesis of various autoimmune...