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| Open AccessThe transcription factor Foxp1 preserves integrity of an active Foxp3 locus in extrathymic Treg cells
Regulatory T (Treg) cells suppress immune cell activation to maintain immune homeostasis, and have their lineage enforced by the master transcription factor Foxp3. Here the authors show that Foxp3 expression is promoted and maintained by a related family member, Foxp1, specifically in peripherally induced Treg but not in Treg cells of thymic origin.
- Sayantani Ghosh
- , Sinchita Roy-Chowdhuri
- & Dipayan Rudra
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Article
| Open AccessPOH1 deubiquitinates pro-interleukin-1β and restricts inflammasome activity
The inflammasomes are important for activating the pro-inflammatory cytokine interleukin-β (IL-1β) for protection against pathogens. Here the authors show that a deubiquitinase, POH1, reduces the conversion of pro-IL-1β into its active form, with in vivo data further implicating a role of POH1 for maintaining immune homeostasis.
- Li Zhang
- , Yun Liu
- & Yongzhong Liu
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Article
| Open AccessHallmarks of primate lentiviral immunodeficiency infection recapitulate loss of innate lymphoid cells
Innate lymphoid cells (ILCs) have been shown to be depleted during HIV-1 infection. Here the authors show that ILC loss is associated with CD4 depletion and gastrointestinal damage in a primate model of SIV infection.
- Joseph C. Mudd
- , Kathleen Busman-Sahay
- & Jason M. Brenchley
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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 AccessEosinophil recruitment is dynamically regulated by interplay among lung dendritic cell subsets after allergen challenge
Eosinophils are important mediators of allergic responses, but how they are recruited to the inflamed site is still unclear. Here the authors show that CD103+ cDC1 cells secrete CCL17 and CCL22 for eosinophil recruitment, with this process promoted by CD24−CD11b+ DC2s in the early phase but suppressed by CD24+ cDC2s in the late phase.
- Shuying Yi
- , Jing Zhai
- & Hua Tang
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Article
| Open AccessAlpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis
The Hiccs locus has been associated with susceptibility to colitis in mice. Here the authors identify a Hiccs locus gene encoding Alpha kinase 1 as a potent regulator of intestinal inflammation via modulation of the IL-12/Th1 axis.
- Grigory Ryzhakov
- , Nathaniel R. West
- & Fiona Powrie
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Article
| Open AccessMicrobiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis
T cells play a critical role in intestinal homeostasis, with increasing evidence suggesting a role for the microbiome metabolome in modulating this response. Here the authors show short-chain fatty acids promote IL-10 production in Th1 cells.
- Mingming Sun
- , Wei Wu
- & Yingzi Cong
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Article
| Open AccessChitin-based barrier immunity and its loss predated mucus-colonization by indigenous gut microbiota
The coevolution of the animal gut mucosa and the gut microbiota is poorly understood. Here, Nakashima et al. identify intestinal chitinous membranes in basal chordates and ray-finned fish, and propose that the loss of this chitin barrier allowed mucus layers to become colonized by microbes in mammals.
- Keisuke Nakashima
- , Satoshi Kimura
- & Noriyuki Satoh
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Article
| Open AccessMAIT cells protect against pulmonary Legionella longbeachae infection
Mucosal associated invariant T (MAIT) cells have been implicated in antibacterial responses. Here the authors show MAIT cells confer IFN-γ-mediated protection from lethal infection in a mouse model of Legionella infection, which can be enhanced by synthetic MR1 ligands.
- Huimeng Wang
- , Criselle D’Souza
- & Zhenjun Chen
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Review Article
| Open AccessMicrobial tryptophan catabolites in health and disease
Gut microbial metabolites are known to impact many physiological processes of the host and play a critical role in immune-homeostasis. Here the authors review our current understanding and appreciation of the importance of microbially derived tryptophan catabolites during both health and disease.
- Henrik M. Roager
- & Tine R. Licht
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Article
| Open AccessCommensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma
Glaucoma is a neurodegenerative disease of which the etiology is still unclear. Here the authors show that elevation of intraocular pressure induces T cell infiltration in the eyes. Furthermore, they show that T cell cross-reactivity between endogenous and commensal antigens contributes to disease onset in mice.
- Huihui Chen
- , Kin-Sang Cho
- & Dong F. Chen
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Article
| Open AccessWASP-mediated regulation of anti-inflammatory macrophages is IL-10 dependent and is critical for intestinal homeostasis
Deficiency in Wiskott-Aldrich syndrome protein (WASP) has been associated with autoimmune colitis, but the underlying mechanism is still unclear. Here the authors show that WASP deficiency is associated with defective WASP/DOCK8 complex formation, altered IL-10 signalling, and impaired anti-inflammatory macrophage functions.
- Amlan Biswas
- , Dror S. Shouval
- & Scott B. Snapper
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Article
| Open AccessThe role of CSF1R-dependent macrophages in control of the intestinal stem-cell niche
Colony stimulating factor 1 controls the growth and differentiation of macrophages. Here the authors demonstrate that its blockade depletes gut macrophages and indirectly affects gut epithelial cell differentiation as the macrophages help maintain the Paneth and stem cells in intestinal crypts.
- Anuj Sehgal
- , David S. Donaldson
- & Neil A. Mabbott
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Article
| Open AccessCalcineurin-mediated IL-2 production by CD11chighMHCII+ myeloid cells is crucial for intestinal immune homeostasis
Treg cells can maintain intestinal homeostasis and limit intestinal bowel disease. Here the authors use a mouse model of spontaneous colitis to show that calcineurin-NFAT-induced IL-2 production by dendritic cells regulates the balance between Treg and effector T cells in the gut lamina propria.
- Andrea Mencarelli
- , Hanif Javanmard Khameneh
- & Alessandra Mortellaro
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Article
| Open AccessFcαRI co-stimulation converts human intestinal CD103+ dendritic cells into pro-inflammatory cells through glycolytic reprogramming
Dendritic cells (DC) are important for maintaining immune homeostasis in the gut, but how they promote intestinal inflammation upon bacterial infection is still unclear. Here the authors show that IgA immune complexes induce proinflammatory cytokine production by metabolic reprogramming of otherwise tolerogenic human CD103+ DCs.
- Ivo S. Hansen
- , Lisette Krabbendam
- & Jeroen den Dunnen
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Article
| Open AccessHost defense against oral microbiota by bone-damaging T cells
IL-17-producing T cells are protective against infection, but the authors of this article previously showed that these cells also contribute to inflammatory bone destruction. Here they show in the context of periodontitis that microbiota-driven Th17-mediated bone destruction may actually be a physiological rather than a pathological process, as associated tooth loss prevents dissemination of oral bacteria.
- Masayuki Tsukasaki
- , Noriko Komatsu
- & Hiroshi Takayanagi
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Article
| Open AccessThe tumour microenvironment creates a niche for the self-renewal of tumour-promoting macrophages in colon adenoma
Tissue-resident F4/80hi macrophages can be found both in normal gut as well as in intestinal tumours. Here the authors show that in the colon these macrophages are CCR2-dependent, while in tumours they gain the ability to self-renew, relying on CSF1 and promoting cancer progression.
- Irene Soncin
- , Jianpeng Sheng
- & Christiane Ruedl
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Article
| Open AccessTRPM7 kinase activity is essential for T cell colonization and alloreactivity in the gut
Gut-homing and colonization of T cells are important for maintaining local immune homoeostasis and protective immunity. Here the authors show that the kinase activity of TRPM7 regulates Th17 differentiation and T cell alloreactivity in the gut by modulating SMAD2 activation and CD103 expression in T cells
- Andrea Romagnani
- , Valentina Vettore
- & Susanna Zierler
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Article
| Open AccessCCDC88B is required for pathogenesis of inflammatory bowel disease
Hook-related protein family member CCDC88b is encoded by a locus that has been associated with inflammatory bowel disease. Here the authors show that Ccdc88b inactivation in T cells prevents colitis in a transfer model, and detect high colonic levels of CCDC88b in patients with Crohn disease or ulcerative colitis, identifying that expression correlates with disease risk.
- Nassima Fodil
- , Neda Moradin
- & Philippe Gros
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Article
| Open AccessTGFβR signalling controls CD103+CD11b+ dendritic cell development in the intestine
Developmental cues for the different dendritic cell (DC) subsets in the intestine are yet to be defined. Here the authors show that TGFβR1 signalling is needed for development of CD103+CD11b+ intestinal DCs from CD103−CD11b+ cells and that they contribute to the generation of Th17 and regulatory T cells
- C. C. Bain
- , J. Montgomery
- & A. McI. Mowat
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Article
| Open AccessDifferent populations of CD11b+ dendritic cells drive Th2 responses in the small intestine and colon
T helper 2 (Th2) cell responses are essential for immunity against parasites, but how Th2 response is modulated in the gut is still unclear. Here the authors show that distinct dendritic cell subsets distinguishable by CD11b, CD103 and IRF4 function in the small intestine or colon to promote Th2 responses.
- Johannes U. Mayer
- , Mimoza Demiri
- & Simon W. Milling
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Article
| Open AccessAllograft inflammatory factor 1 is a regulator of transcytosis in M cells
M cells are intestinal epithelial cells that are specialized to transcytose antigens and bacteria from the intestinal lumen to antigen presenting cells on the other side. Here the authors show that the actin-binding protein Aif1 is highly expressed by intestinal M cells and regulates this transcytosis.
- Sari Kishikawa
- , Shintaro Sato
- & Hiroshi Kiyono
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Article
| Open AccessThe microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner
γδ T cells are major producers of IL-17A in response to microbial infection. Here the authors show that a high load of commensal microbes can maintain homeostasis of IL-17A+γδ T cells in the liver via CD1d antigen presentation, with implications for liver diseases.
- Fenglei Li
- , Xiaolei Hao
- & Zhigang Tian
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Article
| Open AccessA TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice
TNFSF14 (LIGHT) contributes to airway inflammation and remodelling. Here the authors show that TNFSF14 acting on its receptor TNFRSF14 on mast cells enhances their IgE-dependent activation and that interference with this pathway attenuates features of asthma pathology in mice.
- Riccardo Sibilano
- , Nicolas Gaudenzio
- & Stephen J. Galli
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Article
| Open AccessAkkermansia muciniphila mediates negative effects of IFNγ on glucose metabolism
Mice deficient in the pro-inflammatory cytokine IFNγ have improved glucose tolerance. Here, the authors show that this effect depends on the gut microbeAkkermansia muciniphila, whose abundance increases in the absence IFNγ, and which is known to have beneficial effects on host metabolism.
- Renee L. Greer
- , Xiaoxi Dong
- & Natalia Shulzhenko
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Article
| Open AccessLimited clonal relatedness between gut IgA plasma cells and memory B cells after oral immunization
The presence of long-lived memory IgA-producing B cells in the intestine has been difficult to document. Here the authors show that these cells can be induced by oral but not systemic immunization in mice, and characterize unique features that distinguish them from IgA plasma cells.
- Mats Bemark
- , Helena Hazanov
- & Nils Y. Lycke
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Article
| Open AccessGut immunity in a protochordate involves a secreted immunoglobulin-type mediator binding host chitin and bacteria
Protochordates, including Ciona intestinalis, lack an adaptive immune system but possess innate immune receptors, including the secreted immunoglobulin V-region-containing VCBPs. Here the authors show that VCBP-C of Cionabinds gut bacteria and chitin-rich gut mucosa, influences biofilm formation and likely plays a role in gut homeostasis.
- Larry J. Dishaw
- , Brittany Leigh
- & Gary W. Litman
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Article
| Open AccessMucosal immunoglobulins at respiratory surfaces mark an ancient association that predates the emergence of tetrapods
In teleost fish the gills perform—in addition to respiration—functions such as immune defence. Here the authors show that IgT, a teleost specific Ig previously shown to be involved in gut and skin mucosal immunity, is locally induced in the gill, where it plays a key role in immunity in rainbow trout.
- Zhen Xu
- , Fumio Takizawa
- & J. Oriol Sunyer
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Article
| Open AccessIntestinal CD169+ macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes
Macrophages and dendritic cells residing in the lamina propria are involved in controlling mucosal immune balance. Here, the authors identify CD169+macrophages as contributors to the inflammation of DSS colitis through their role in mediating the recruitment of monocytes by secreting the cytokine CCL8.
- Kenichi Asano
- , Naomichi Takahashi
- & Masato Tanaka
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Article
| Open AccessNeutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis
Autoimmune pulmonary alveolar proteinosis is caused by autoantibodies to GM-CSF. Here the authors show that the individual autoantibodies only partially neutralize GM-CSF and that antibodies to at least three different epitopes are required to block GM-CSF bioavailability.
- Luca Piccoli
- , Ilaria Campo
- & Antonio Lanzavecchia
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Article
| Open AccessIntestinal intraepithelial lymphocyte activation promotes innate antiviral resistance
Intraepithelial lymphocytes in the gut eliminate dysfunctional epithelial cells and promote regrowth of healthy cells. Here the authors show that, in addition, these lymphocytes protect cells against viral infections by rapidly activating interferon-dependent pathways in intestinal epithelial cells.
- Mahima Swamy
- , Lucie Abeler-Dörner
- & Adrian C. Hayday
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IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis
Innate immune responses are regulated in the intestine to prevent excessive inflammation. Here the authors demonstrate a pivotal role for intestinal macrophages that constitutively produce IL-10 in controlling excessive innate immune activation and preventing tissue damage after an acute bacterial infection.
- Petra Krause
- , Venetia Morris
- & Masako Murai
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Article
| Open AccessMulti-spectral fluorescent reporter influenza viruses (Color-flu) as powerful tools for in vivo studies
Animal models are important to study organismal immune responses to infection with influenza viruses. Here, Fukuyama et al.report a new generation of fluorescently labelled influenza viruses that facilitate the study of viral infections in animal models at cellular level.
- Satoshi Fukuyama
- , Hiroaki Katsura
- & Yoshihiro Kawaoka
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Vaginal type-II mucosa is an inductive site for primary CD8+ T-cell mucosal immunity
Priming of naïve T cells is thought to occur in tissue-draining lymph nodes. Here Wang et al. show that vaginal mucosa, despite lacking structured lymphoid organs, can support priming of naïve CD8 T-cell responses and activation of memory CD8 T cells.
- Yichuan Wang
- , Yongjun Sui
- & Jay A. Berzofsky
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Article
| Open AccessCCR7-dependent trafficking of RORγ+ ILCs creates a unique microenvironment within mucosal draining lymph nodes
Innate lymphoid cells have an important role in mucosal immunity and present peptide:MHCII to CD4 T cells. Here the authors show that innate lymphoid cell subsets migrate from the gut mucosa to the draining lymph nodes via different mechanisms, where they form distinct microenvironments.
- Emma C. Mackley
- , Stephanie Houston
- & David R. Withers
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Nasal immunity is an ancient arm of the mucosal immune system of vertebrates
The nasopharynx-associated lymphoid tissue (NALT) of terrestrial mammals serves as a first line of defence against pathogens. Here the authors show that fish also have NALT, characterized by the presence of diffuse lymphoid cells including IgT+B cells, and demonstrate successful intranasal immunization.
- Luca Tacchi
- , Rami Musharrafieh
- & Irene Salinas
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The parasite Entamoeba histolytica exploits the activities of human matrix metalloproteinases to invade colonic tissue
The protozoan parasite Entamoeba histolyticainvades the colon and remodels the extracellular matrix, and the parasite-derived proteinase A5 (CP-A5) is known to be involved. Here, the authors show that CP-A5 activates metalloproteinases in the host, changing colon architecture and aiding tissue invasion.
- Roman Thibeaux
- , Patrick Avé
- & Elisabeth Labruyère
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A20 controls intestinal homeostasis through cell-specific activities
Aetiology of colitis is highly complex and incompletely understood. Here the authors show in mouse models that A20 deubiquitinase limits pro-inflammatory cytokine production in myeloid cells while inhibiting proapoptotic response to these cytokines in enterocytes, and that only upon losing both functions intestinal pathologies develop.
- Lars Vereecke
- , Sara Vieira-Silva
- & Geert van Loo
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Resident CD4+ T cells accumulate in lymphoid organs after prolonged antigen exposure
T follicular helper cells are lymph node residents, but whether other CD4+ T cells also reside in lymph nodes is not clear. Here, the authors use photoconversion to examine T cell migration in lymph nodes and Peyer’s patches and identify a population of antigen-experienced CD4+T cells retained in lymphoid tissue.
- Milas Ugur
- , Olga Schulz
- & Oliver Pabst
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Article
| Open AccessRestricted VH/VL usage and limited mutations in gluten-specific IgA of coeliac disease lesion plasma cells
Coeliac disease is characterized by an inappropriate immune response to dietary gluten proteins, involving the production of antibodies reactive to gluten. Here, the authors study the intestinal antibody response against gluten and show that gluten-specific antibodies have a low degree of somatic hypermutations.
- Øyvind Steinsbø
- , Carole J. Henry Dunand
- & Ludvig M. Sollid
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Article |
Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire
Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells, abundant in mucosal tissues, blood and liver. Here, using T-cell cloning and deep sequencing, Lepore et al. analyse the T-cell receptorβ repertoire of MAIT cells and further characterize function and tissue distribution of two semi-invariant subsets of these cells.
- Marco Lepore
- , Artem Kalinichenko
- & Lucia Mori
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Generation of colonic IgA-secreting cells in the caecal patch
Gut-associated Peyer’s patches are lymphoid tissues that generate IgA-secreting cells, however less is known about related caecal patches. Here, Masahata et al.show that caecal patches produce IgA-positive B cells that migrate to the intestines to maintain faecal microbiota homeostasis.
- Kazunori Masahata
- , Eiji Umemoto
- & Kiyoshi Takeda
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Article
| Open AccessAcquisition of innate-like microbial reactivity in mucosal tissues during human fetal MAIT-cell development
Mucosa-associated invariant T (MAIT) cells are a recently described subset of unconventional, innate-like T cells and their development is not well understood. Here, the authors analyse MAIT cells in fetal human tissues and show that, unlike in mice, the commensal microflora is not necessary for their maturation in humans.
- Edwin Leeansyah
- , Liyen Loh
- & Johan K. Sandberg
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Recognition of vitamin B metabolites by mucosal-associated invariant T cells
T-cell receptors expressed on mucosal-associated invariant T cells function in a similar manner to innate immune receptors by recognizing small molecules such as microbial metabolites. Here, the authors report structures of this receptor in complex with vitamin B metabolites presented by the MHC-like protein MR1.
- Onisha Patel
- , Lars Kjer-Nielsen
- & Jamie Rossjohn
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The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells
Intraepithelial lymphocytes (IELs) defend against pathogens in the gut, and their differentiation depends on both diet and microbiota-derived factors. Nakajima et al. show that signalling through the aryl hydrocarbon receptor nuclear translocator and STAT3 is required for the development of a subset of IELs.
- Kohei Nakajima
- , Yoichi Maekawa
- & Koji Yasutomo
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Article
| Open AccessMicrobe-dependent CD11b+ IgA+ plasma cells mediate robust early-phase intestinal IgA responses in mice
Intestinal plasma cells contribute to the delicate balance between immunity against pathogens and tolerance of intestinal microflora. Kunisawa et al. identify a subpopulation of plasma cells whose proliferation depends on stimulation by microbes and IL-10, and which mediate early-phase responses to oral antigens.
- Jun Kunisawa
- , Masashi Gohda
- & Hiroshi Kiyono