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| Open AccessSecreted IgM modulates IL-10 expression in B cells
Il-10-expressing B cells play a pivotal role in immune homeostasis, but little is known about the factors and pathways that affect the development of this heterologous population of regulatory B cells. Here authors show in a mouse model that in embryonic life, soluble IgM restrains the expansion of Il-10-positive B cells, via utilizing FcµR and other putative receptors.
- Shannon Eileen McGettigan
- , Lazaro Emilio Aira
- & Gudrun F. Debes
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Article
| Open AccessDietary L-Tryptophan consumption determines the number of colonic regulatory T cells and susceptibility to colitis via GPR15
Environmental factors such as diet have been shown to be involved with the development of colitis. Here the authors show that L-tryptophan promotes the development of GPR15+ Treg cells via the host IDO1/2 pathway and that tryptophan consumption in mice reduces severity of colitis in a C. rodentium mouse model.
- Nguyen T. Van
- , Karen Zhang
- & Sangwon V. Kim
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Article
| Open AccessAntigen presentation by B cells enables epitope spreading across an MHC barrier
Increasing evidence suggests that antigen presentation by B cells is critical to the initiation of autoimmunity. Here, the authors demonstrate that tolerance breakdown is initiated outside of germinal centres and that B cells can directly instruct T cells to break tolerance and propagate autoimmune responses.
- Cecilia Fahlquist-Hagert
- , Thomas R. Wittenborn
- & Søren E. Degn
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Article
| Open AccessNBEAL2 deficiency in humans leads to low CTLA-4 expression in activated conventional T cells
NBEAL2 loss of function mutations lead to grey platelet syndrome, a condition characterised by α-granule-deficient platelets and, in a proportion of cases, by autoimmunity. Here authors show that NBEAL2 physically interacts with CTLA-4 in human T cells, and NBEAL2 deficiency leads to reduced CTLA-4 surface expression in effector T cells, but not regulatory T cells, thus tipping the balance towards autoimmunity.
- Laure Delage
- , Francesco Carbone
- & Frédéric Rieux-Laucat
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Article
| Open AccessCostimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity
The blockade of CD28 signalling is known to reduce pathological T cell responses in the context of both autoimmunity and transplantation, but has been associated with impairment of the regulatory T cell compartment. Here the authors show combining costimulation blockade with the administration of interleukin 2 selectively impairs the T effector response whilst maintaining the regulatory T cell pool and suggest functional effect in a murine model of autoimmune diabetes.
- Chun Jing Wang
- , Lina Petersone
- & Lucy S. K. Walker
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Article
| Open AccessPD-L2 controls peripherally induced regulatory T cells by maintaining metabolic activity and Foxp3 stability
Regulatory T (Treg) cells have been implicated in the induction of airway tolerance and amelioration of respiratory duct inflammation. Here the authors show, using PD-L2 deficient mice, that the immune suppression signal from PD-L2 is important for modulating Treg cell metabolism and function for proper induction of respiratory tolerance in mice.
- Benjamin P. Hurrell
- , Doumet Georges Helou
- & Omid Akbari
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Article
| Open AccessTranscriptomic diversity in human medullary thymic epithelial cells
The thymus generates all T cells, including those that underly autoimmune diseases. Here, using deep sequencing, the authors profile human medullary thymic epithelial cells and establish a web portal to query their transcriptome, which may serve as a tool to help identify the drivers of autoimmunity.
- Jason A. Carter
- , Léonie Strömich
- & Hannah V. Meyer
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Article
| Open AccessFollicular T cells are clonally and transcriptionally distinct in B cell-driven mouse autoimmune disease
Follicular T cells regulate germinal centre reactions, but their phenotypes in autoimmune disease are unclear. Using a mouse model of autoantibody disease, the authors show that autoimmune follicular T cells differ by TCR clonotype and transcriptional profile from non-autoimmune follicular T cells.
- Elliot H. Akama-Garren
- , Theo van den Broek
- & Michael C. Carroll
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Article
| Open AccessSpecialized transendothelial dendritic cells mediate thymic T-cell selection against blood-borne macromolecules
T cells are selected in the thymus, through interaction with self-antigens, to remove autoreactive cells. Here the authors show that a specialized thymic dendritic cell subset juxtaposes to microvessels, requires CX3CR1/CX3CL1 for this positioning, and has processes extruding into the blood stream to sample soluble macromolecules and assist in T cell selection.
- Elisabeth H. Vollmann
- , Kristin Rattay
- & Ulrich H. von Andrian
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Article
| Open AccessCD73-mediated adenosine production by CD8 T cell-derived extracellular vesicles constitutes an intrinsic mechanism of immune suppression
Ectonucleotidases associated to regulatory T cells are known modulators in the inflammatory environment. Here the authors describe CD8 T cell-derived extracellular vesicles bearing CD73 and suggest they function as an additional intrinsic modulator of immune responses.
- Enja Schneider
- , Riekje Winzer
- & Eva Tolosa
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Article
| Open AccessInnate-like self-reactive B cells infiltrate human renal allografts during transplant rejection
Intrarenal B cells are indicative of poor prognosis in human renal allografts. Here the authors use single cell RNA sequencing to examine how intrarenal B cells contribute to renal rejection and find a population of innate B cells reactive to renal-specific or inflammation-associated antigens.
- Yuta Asano
- , Joe Daccache
- & Marcus R. Clark
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Article
| Open AccessSingle-cell transcriptional profiling of human thymic stroma uncovers novel cellular heterogeneity in the thymic medulla
The thymus supports T cell immunity by providing the environment for thymocyte differentiation. Here the authors profile human thymic stroma at the single cell level, identifying ionocytes as a new medullary population and defining tissue specific antigen expression in multiple stromal cell types.
- Jhoanne L. Bautista
- , Nathan T. Cramer
- & Audrey V. Parent
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Article
| Open AccessB7-CD28 co-stimulation modulates central tolerance via thymic clonal deletion and Treg generation through distinct mechanisms
B7-CD28 co-stimulation is important for T cell activation and clonal expansion in the periphery. Here the authors show that, in mouse thymus, B7-CD28 differentially controls thymocyte clonal deletion and Treg induction, with distinct CD28 signaling domains and B7-expressing antigen presenting cells mediating these two processes.
- Masashi Watanabe
- , Ying Lu
- & Richard J. Hodes
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Article
| Open AccessDifferential expression of tissue-restricted antigens among mTEC is associated with distinct autoreactive T cell fates
T cell tolerance is established in the thymus via interactions with medullary thymic epithelial cells (mTEC) expressing tissue-restricted self antigens. Here, the authors suggest, using new transgenic mouse lines and single cell transcriptome analyses, that specific mTEC subsets are associated with distinct T cell fates.
- Marie-Ève Lebel
- , Marie Coutelier
- & Heather J. Melichar
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Article
| Open AccessToll-like receptor signaling in thymic epithelium controls monocyte-derived dendritic cell recruitment and Treg generation
Immune tolerance is mediated by the deletion of autoreactive T cells via medullary thymic epithelial cells (mTEC) and dendritic cells (DC), and by the induction of regulatory T cells (Treg). Here the authors show that mTEC receiving toll-like receptor signaling control the recruitment of CD14+Sirpα+ DC population that is capable of inducing Treg for establishing tolerance.
- Matouš Vobořil
- , Tomáš Brabec
- & Dominik Filipp
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Article
| Open AccessDual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance
The transcription factor Aire mediates tissue-specific antigen expression in the thymus for T cell central tolerance induction. Here the authors show that Aire, via its CARD domain, forms multimers that can misdirect Aire to PML bodies leading to the loss of Aire transcriptional activity and induction of autoimmunity.
- Yu-San Huoh
- , Bin Wu
- & Sun Hur
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Article
| Open AccessTIGIT limits immune pathology during viral infections
TIGIT is a lymphocyte co-inhibitory receptor that can limit type 1 and cytotoxic T cell responses and maintain immunological tolerance. Here the authors show that TIGIT also limits immune pathology during LCMV or influenza infections in mice by driving IL-10 expression without negatively affecting the viral load.
- Michelle Schorer
- , Nikolas Rakebrandt
- & Nicole Joller
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Article
| Open AccessImmune checkpoint modulation enhances HIV-1 antibody induction
Elucidation of broadly neutralizing antibodies (bnAb) is a goal in HIV vaccine development. Here, Bradley et al. show that administration of CTLA-4 blocking antibody with vaccine antigens increases HIV-1 envelope antibody responses in macaques and a bnAb precursor mouse model.
- Todd Bradley
- , Masayuki Kuraoka
- & Barton F. Haynes
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Article
| Open AccessTransforming Growth Factor-beta signaling in αβ thymocytes promotes negative selection
. TGFβ is critical for limiting autoreactive responses of peripheral T cells. Here, the authors show that TGFβ signaling in thymocytes mediates elimination of self-reactive T cells and promotes the expression of self-antigens by medullary thymic epithelial cells.
- Mark J. McCarron
- , Magali Irla
- & Julien C. Marie
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Article
| Open AccessmiRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes
miRNA142-3p and Tet2 are separately known to regulate Treg. Here the authors show that miRNA142-3p targets Tet2 and by this opposes Treg differentiation in autoimmune diabetes.
- Martin G. Scherm
- , Isabelle Serr
- & Carolin Daniel
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Article
| Open AccessIn vivo clonal expansion and phenotypes of hypocretin-specific CD4+ T cells in narcolepsy patients and controls
T cells from narcolepsy patients were recently reported to recognize hypocretin, a wakefulness-promoting neurohormone, suggesting autoimmune origin of the disease. Here the authors show that hypocretin-specific T cells expand both in healthy controls and in narcolepsy patients, and identify preliminary features that may distinguish them.
- Wei Jiang
- , James R. Birtley
- & Elizabeth D. Mellins
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Article
| Open AccessB-1a cells acquire their unique characteristics by bypassing the pre-BCR selection stage
B-1a B cells are innate-like cells with biased reactivity to bacteria and self-antigens. Here the authors show that reduced interleukin-7 in developing fetal liver-derived pro-B cells induces premature immunoglobulin κ rearrangement, alleviating the requirement for a pre-BCR selection stage and allowing the generation of autoreactive B1-a B cells.
- Jason B. Wong
- , Susannah L. Hewitt
- & Jane A. Skok
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Article
| Open AccessHuman placental trophoblast cells contribute to maternal–fetal tolerance through expressing IL-35 and mediating iTR35 conversion
Trophoblasts play a critical role in maintaining immunological tolerance at maternal–fetal interface. Here the authors show that IL-35 is made by trophoblasts, converts T cells to immune tolerant iTR35 cells, and is critical to prevent spontaneous abortion.
- Jia Liu
- , Shengnan Hao
- & Haiting Mao
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Article
| Open AccessLong-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes
Injection of donor apoptotic cells induces graft tolerance in mice. Here the authors combine this approach with short immunosuppressive therapy to achieve long-term tolerance to allogeneic islets and restoration of normoglycemia in diabetic nonhuman primates, and delineate cellular and molecular correlates of tolerance induction.
- Amar Singh
- , Sabarinathan Ramachandran
- & Bernhard J. Hering
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Article
| Open AccessIdentification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection
Autoreactive T cells are deleted in the thymus via thymic negative selection and Bim-mediated apoptosis. Here the authors identify a cis-acting enhancer, EBAB, that is essential for proper Bim expression and apoptosis induction, and show that EBAB deficiency specifically impairs thymic negative selection without affecting peripheral T cell homeostasis.
- Miki Arai Hojo
- , Kyoko Masuda
- & Shinpei Kawaoka
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Article
| Open AccessLive-cell imaging reveals the relative contributions of antigen-presenting cell subsets to thymic central tolerance
Both thymic epithelial cells and dendritic cells present self antigens in the thymus to mediate thymic selection and T cell tolerance. Here the authors quantify, using two-photon live imaging of mouse thymic slices, the relative contribution of these two cell types, as well as the effects of antigen cross-presentation by dendritic cells, during tolerance induction.
- J. N. Lancaster
- , H. M. Thyagarajan
- & L. I. R. Ehrlich
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Article
| Open AccessSuppression of a broad spectrum of liver autoimmune pathologies by single peptide-MHC-based nanomedicines
Immune response against tissue-specific antigens is a hallmark of autoimmunity. Here the authors show that a single autoantigen-based nanomedicine can ameliorate pathology in a broad range of liver autoimmunity models without impairing host defenses, suggesting organ-wide tolerization.
- Channakeshava Sokke Umeshappa
- , Santiswarup Singha
- & Pere Santamaria
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Article
| Open AccessFcγRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human
The inhibitory receptor, FcγRIIb, is reported to limit autoimmune B cell response. Here the authors show that FcγRIIb has a dual role in both human and mouse, with reduced FcγRIIb expression or function associated with enhanced pre-immune B cell tolerance, yet defective control of mature autoreactive B cells in the germinal center.
- Marion Espéli
- , Rachael Bashford-Rogers
- & Kenneth G. C. Smith
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Article
| Open AccessCD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens
Autoreactive T cells are suspected to destroy hypocretin-producing neurons in narcolepsy. Here the authors detect CD8 T cells recognizing narcolepsy-related proteins in healthy individuals and in patients with narcolepsy, and show that the frequency of self-reactive CD8 T cells differs between patients and controls sharing the same HLA-II risk allele.
- Natasja Wulff Pedersen
- , Anja Holm
- & Birgitte Rahbek Kornum
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Article
| Open AccessHematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation
Transplantation of allogeneic bone marrow helps establish chimerism that may induce tolerance to tissue grafts. Here the authors show that a CD117-antibody-drug-conjugate helps precondition the recipients for inducing mixed chimerism and allo-tolerance without clear adverse effects or the need for chronic immune suppression.
- Zhanzhuo Li
- , Agnieszka Czechowicz
- & Philip M. Murphy
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Article
| Open AccessThe lineage stability and suppressive program of regulatory T cells require protein O-GlcNAcylation
The transcription factor Foxp3 and Stat5 modulate lineage stability and function of regulatory T (Treg) cells to promote immune homeostasis. Here the authors show that O-GlcNAcylation of Foxp3 and Stat5, mediated by O-GlcNAc transferase (OGT), is essential for Treg-mediate immune balance, with Treg-specific deficiency of OGT leading to severe autoimmunity.
- Bing Liu
- , Oscar C. Salgado
- & Hai-Bin Ruan
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Article
| Open AccessA T-cell receptor escape channel allows broad T-cell response to CD1b and membrane phospholipids
CD1 proteins present lipid antigens to T cells via the T cell receptor. Here the authors describe T cell reactivity to human membrane lipid moieties and provide structural data to define a molecular mechanism of promiscuous recognition of self-derived phospholipids.
- Adam Shahine
- , Peter Reinink
- & Ildiko Van Rhijn
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Article
| Open AccessInterleukin 2 modulates thymic-derived regulatory T cell epigenetic landscape
Regulatory T (Treg) cells are developed in the thymus, and are essential for suppressing detrimental autoimmunity. Here the authors show, using mice with dampened interleukin 2 (IL-2) signaling, that IL-2 helps position the pioneer factor SATB1 to control genome-wide chromatin accessibility to facilitate Treg cell lineage commitment in the thymus.
- Laurent Chorro
- , Masako Suzuki
- & Grégoire Lauvau
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Article
| Open AccessPDL2+ CD11b+ dermal dendritic cells capture topical antigen through hair follicles to prime LAP+ Tregs
Antigen present and presented in the structures of the skin can result in immune responses that elicit tolerance, protective immunity or allergy, depending on the immunological context. Here the authors describe a key role for the hair follicle and CD11b+ dendritic cells in the priming of local antigenic tolerance.
- Leticia Tordesillas
- , Daniel Lozano-Ojalvo
- & M. Cecilia Berin
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Article
| Open AccessNeonatally imprinted stromal cell subsets induce tolerogenic dendritic cells in mesenteric lymph nodes
Induction of tolerance in the gut relies on immunomodulatory functions of mesenteric lymph nodes (mLN). Here the authors show that mLN stromal cells receive early microbiota imprinting in the neonatal phase to exhibit long-term, location-specific transcriptional programs for the induction of regulatory T cells and peripheral tolerance.
- Joern Pezoldt
- , Maria Pasztoi
- & Jochen Huehn
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Article
| Open AccessMarch1-dependent modulation of donor MHC II on CD103+ dendritic cells mitigates alloimmunity
Donor-derived dendritic cells (do-DC) in the graft can contribute to the induction of alloimmunity and tissue rejection, but how do-DC can be targeted for improving graft survival is unclear. Here the authors show that reducing MHC-II expression on do-DCs by DnaK pre-treatment can decrease the priming of alloimmunity and prolong graft survival in mouse models.
- Thiago J. Borges
- , Naoka Murakami
- & Cristina Bonorino
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Article
| Open AccessmTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis
The authors previously showed that mTOR controls the function of regulatory T cells. Here they show how this mTOR signaling orchestrates homeostasis of Treg-cell subsets and prevents fatal autoimmunity.
- Nicole M. Chapman
- , Hu Zeng
- & Hongbo Chi
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Article
| Open AccessLymphotoxin α fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells
Autoreactive T cells are removed during their development in the thymus through the functions of medullary thymic epithelial cells (mTEC) and dendritic cells (DC), a process termed negative selection. Here the authors show that mTEC-T cell crosstalk and lymphotoxin α signalling are essential for the proper recruitment of DCs into the thymus.
- Noëlla Lopes
- , Jonathan Charaix
- & Magali Irla
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Article
| Open AccessDesensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression
Engineered T cells with chimeric antigen receptor (CAR) are emerging as an effective cancer therapy. Here the authors show that CAR T cells recognizing self-MHC can be ‘tuned’ ex vivo via CAR downregulation and CAR T cell death to generate a CAR T pool specifically targeting tumor cells with high MHC expression.
- Chungyong Han
- , Su-Jung Sim
- & Byoung S. Kwon
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Article
| Open AccessT cells specific for post-translational modifications escape intrathymic tolerance induction
Post-translational modifications are associated with autoimmune diseases but definitive evidence of their contribution to escape from central tolerance mechanisms is needed. Here, the authors show that T cells specific for post-translational modifications of type II collagen escape intrathymic tolerance induction in a mouse model of rheumatoid arthritis.
- Bruno Raposo
- , Patrick Merky
- & Johan Bäcklund
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Article
| Open AccessBinding of NUFIP2 to Roquin promotes recognition and regulation of ICOS mRNA
The RNA-binding proteins Roquin-1 and Roquin-2 are essential for immune cell function and postnatal survival in mice. Here, the authors identify NUFIP2 as a cofactor of Roquin; Roquin binds and stabilizes NUFIP2 in cells while NUFIP2 regulates Roquin mRNA target recognition.
- Nina Rehage
- , Elena Davydova
- & Vigo Heissmeyer
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Article
| Open AccessProfiling the lymphoid-resident T cell pool reveals modulation by age and microbiota
Non-circulating, tissue-resident T cells have been reported for non-lymphoid organs, but their characterization and regulation in secondary lymphoid organs (SLO) are still lacking. Here the authors show that age and microbiota both exert SLO-specific effects for the various tissue-resident T cell subsets.
- Aurélie Durand
- , Alexandra Audemard-Verger
- & Bruno Lucas
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Article
| Open AccessInitiation of HIV neutralizing B cell lineages with sequential envelope immunizations
An efficient HIV-1 vaccine will likely depend on eliciting broadly neutralizing antibodies (bnAb). Here the authors analyze the B cell repertoire in macaques and knock-in mice in response to sequential immunization with Env variants that induce a bnAb targeting the CD4-binding site of Env in a HIV-1 infected individual.
- Wilton B. Williams
- , Jinsong Zhang
- & Laurent Verkoczy
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Article
| Open AccessThe mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity
Excessive expansion of the T follicular helper (TFH) cell pool is associated with autoimmune disease and Def6 has been identified as an SLE risk variant. Here the authors show that Def6 limits proliferation of TFH cells in mice via alteration of mTORC1 signaling and inhibition of Bcl6 expression.
- Woelsung Yi
- , Sanjay Gupta
- & Alessandra B. Pernis
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Article
| Open AccessFoxp3+ regulatory T cells maintain the bone marrow microenvironment for B cell lymphopoiesis
Treg cells suppress peripheral immune responses, but their function in haematopoiesis is unclear. Here the authors show they modulate the bone marrow microenvironment to sustain haematopoietic stem cell-driven generation of mature B cells.
- Antonio Pierini
- , Hidekazu Nishikii
- & Robert S. Negrin
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Article
| Open AccessElevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis
Bcl-3 modulates effector T cell responses, but the importance of Bcl-3 in T regulatory cells and autoimmunity is not clear. Here the authors show that Bcl-3 impedes NF-κB DNA binding to alter T regulatory cell development and function, causing spontaneous colitis in mice.
- Sonja Reißig
- , Yilang Tang
- & Nadine Hövelmeyer
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Article
| Open AccessCD40-signalling abrogates induction of RORγt+ Treg cells by intestinal CD103+ DCs and causes fatal colitis
CD103+ dendritic cells induce iTreg cells to maintain immune balance in the gut, but how CD40-signalling regulates this process is unclear. Here the authors show that mice with constitutive CD11c-specific CD40-signalling have altered CD103+dendritic cell migration, reduced iTreg cell induction, and fatal colitis.
- Christian Barthels
- , Ana Ogrinc
- & Thomas Brocker
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Article
| Open AccessIgD attenuates the IgM-induced anergy response in transitional and mature B cells
Self-reactive B cells that are anergic express mainly IgD, yet the function of IgD is not clear. Here the authors analyse primary B cells from mice to show that IgD signalling attenuates self-antigen induced gene expression and promotes survival of anergic B cells that might go on to reactivate to foreign antigens and mutate away from self-reactivity.
- Zahra Sabouri
- , Samuel Perotti
- & Christopher C. Goodnow
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Article
| Open AccessBreaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology
Immunosuppression has been unsuccessful in treatment of Alzheimer’s disease. Here the authors show in a mouse model of the disease that transient inhibition of regulatory T cells mitigates amyloid plaque pathology and reverses cognitive decline, whereas augmenting these cells worsens the pathology.
- Kuti Baruch
- , Neta Rosenzweig
- & Michal Schwartz