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1.
Nat Commun ; 13(1): 6915, 2022 11 28.
Article in English | MEDLINE | ID: mdl-36443301

ABSTRACT

Still's disease is a severe inflammatory syndrome characterized by fever, skin rash and arthritis affecting children and adults. Patients with Still's disease may also develop macrophage activation syndrome, a potentially fatal complication of immune dysregulation resulting in cytokine storm. Here we show that mTORC1 (mechanistic target of rapamycin complex 1) underpins the pathology of Still's disease and macrophage activation syndrome. Single-cell RNA sequencing in a murine model of Still's disease shows preferential activation of mTORC1 in monocytes; both mTOR inhibition and monocyte depletion attenuate disease severity. Transcriptomic data from patients with Still's disease suggest decreased expression of the mTORC1 inhibitors TSC1/TSC2 and an mTORC1 gene signature that strongly correlates with disease activity and treatment response. Unrestricted activation of mTORC1 by Tsc2 deletion in mice is sufficient to trigger a Still's disease-like syndrome, including both inflammatory arthritis and macrophage activation syndrome with hemophagocytosis, a cellular manifestation that is reproduced in human monocytes by CRISPR/Cas-mediated deletion of TSC2. Consistent with this observation, hemophagocytic histiocytes from patients with macrophage activation syndrome display prominent mTORC1 activity. Our study suggests a mechanistic link of mTORC1 to inflammation that connects the pathogenesis of Still's disease and macrophage activation syndrome.


Subject(s)
Arthritis, Juvenile , Lymphohistiocytosis, Hemophagocytic , Macrophage Activation Syndrome , Adult , Child , Humans , Mice , Animals , Macrophage Activation Syndrome/genetics , Mechanistic Target of Rapamycin Complex 1/genetics , Lymphohistiocytosis, Hemophagocytic/genetics , Models, Theoretical
2.
Gut ; 2022 Jul 25.
Article in English | MEDLINE | ID: mdl-35879049

ABSTRACT

Coeliac disease (CD) is a frequent immune enteropathy induced by gluten in genetically predisposed individuals. Its pathogenesis has been extensively studied and CD has emerged as a model disease to decipher how the interplay between environmental and genetic factors can predispose to autoimmunity and promote lymphomagenesis. The keystone event is the activation of a gluten-specific immune response that is driven by molecular interactions between gluten, the indispensable environmental factor, HLA-DQ2/8, the main predisposing genetic factor and transglutaminase 2, the CD-specific autoantigen. The antigluten response is however not sufficient to induce epithelial damage which requires the activation of cytotoxic CD8+ intraepithelial lymphocytes (IEL). In a plausible scenario, cooperation between cytokines released by gluten-specific CD4+ T cells and interleukin-15 produced in excess in the coeliac gut, licenses the autoimmune-like attack of the gut epithelium, likely via sustained activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway in IEL. Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication. If our understanding of CD pathogenesis has considerably progressed, several questions and challenges remain. One unsolved question concerns the considerable variability in disease penetrance, severity and presentation, pointing to the role of additional genetic and environmental factors that remain however uneasy to untangle and hierarchize. A current challenge is to transfer the considerable mechanistic insight gained into CD pathogenesis into benefits for the patients, notably to alleviate the gluten-free diet, a burden for many patients.

3.
Science ; 376(6590): 243-244, 2022 04 15.
Article in English | MEDLINE | ID: mdl-35420956

ABSTRACT

A subset of CD8+ T cells regulate chronic inflammation by killing pathogenic CD4+ T cells.


Subject(s)
CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , T-Lymphocytes, Regulatory
4.
Cell Rep ; 37(4): 109902, 2021 10 26.
Article in English | MEDLINE | ID: mdl-34706228

ABSTRACT

Rheumatoid arthritis is a systemic autoimmune disease, but disease flares typically affect only a subset of joints, distributed in a distinctive pattern for each patient. Pursuing this intriguing pattern, we show that arthritis recurrence is mediated by long-lived synovial resident memory T cells (TRM). In three murine models, CD8+ cells bearing TRM markers remain in previously inflamed joints during remission. These cells are bona fide TRM, exhibiting a failure to migrate between joints, preferential uptake of fatty acids, and long-term residency. Disease flares result from TRM activation by antigen, leading to CCL5-mediated recruitment of circulating effector cells. Correspondingly, TRM depletion ameliorates recurrence in a site-specific manner. Human rheumatoid arthritis joint tissues contain a comparable CD8+-predominant TRM population, which is most evident in late-stage leukocyte-poor synovium, exhibiting limited T cell receptor diversity and a pro-inflammatory transcriptomic signature. Together, these findings establish synovial TRM as a targetable mediator of disease chronicity in autoimmune arthritis.


Subject(s)
Arthritis, Rheumatoid/immunology , CD8-Positive T-Lymphocytes/immunology , Memory T Cells/immunology , Synovial Membrane/immunology , Transcriptome/immunology , Animals , Arthritis, Rheumatoid/pathology , CD8-Positive T-Lymphocytes/pathology , Humans , Memory T Cells/pathology , Mice , Mice, Knockout , Synovial Membrane/pathology
5.
J Clin Invest ; 131(18)2021 09 15.
Article in English | MEDLINE | ID: mdl-34343136

ABSTRACT

IL-1ß is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1ß contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1ß blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1ß accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1ß-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.


Subject(s)
Arthritis, Experimental/immunology , Arthritis, Rheumatoid/immunology , Interleukin-1beta/immunology , T-Lymphocytes, Regulatory/immunology , Adoptive Transfer , Animals , Arthritis, Experimental/etiology , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/etiology , Arthritis, Rheumatoid/pathology , Cell Differentiation/immunology , Female , Humans , Interleukin 1 Receptor Antagonist Protein/deficiency , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin 1 Receptor Antagonist Protein/immunology , Male , Mice , Mice, Inbred BALB C , Mice, Knockout , Osteoclasts/immunology , Osteoclasts/pathology , Osteogenesis/immunology , RANK Ligand/immunology , T-Lymphocytes, Regulatory/metabolism
6.
Nat Commun ; 12(1): 2856, 2021 05 17.
Article in English | MEDLINE | ID: mdl-34001893

ABSTRACT

Neutrophils are implicated in multiple homeostatic and pathological processes, but whether functional diversity requires discrete neutrophil subsets is not known. Here, we apply single-cell RNA sequencing to neutrophils from normal and inflamed mouse tissues. Whereas conventional clustering yields multiple alternative organizational structures, diffusion mapping plus RNA velocity discloses a single developmental spectrum, ordered chronologically. Termed here neutrotime, this spectrum extends from immature pre-neutrophils, largely in bone marrow, to mature neutrophils predominantly in blood and spleen. The sharpest increments in neutrotime occur during the transitions from pre-neutrophils to immature neutrophils and from mature marrow neutrophils to those in blood. Human neutrophils exhibit a similar transcriptomic pattern. Neutrophils migrating into inflamed mouse lung, peritoneum and joint maintain the core mature neutrotime signature together with new transcriptional activity that varies with site and stimulus. Together, these data identify a single developmental spectrum as the dominant organizational theme of neutrophil heterogeneity.


Subject(s)
Neutrophils/metabolism , Sequence Analysis, RNA/methods , Single-Cell Analysis/methods , Transcriptome/genetics , Animals , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Cells, Cultured , Female , Gene Ontology , Humans , Male , Mice, Inbred C57BL , Neutrophils/cytology , Peritonitis/genetics , Peritonitis/pathology , Pneumonia/genetics , Pneumonia/pathology , Spleen/cytology , Spleen/metabolism
7.
Gastroenterology ; 160(1): 287-301.e20, 2021 01.
Article in English | MEDLINE | ID: mdl-32980345

ABSTRACT

BACKGROUND AND AIMS: The presence of gastrointestinal symptoms and high levels of viral RNA in the stool suggest active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication within enterocytes. METHODS: Here, in multiple, large cohorts of patients with inflammatory bowel disease (IBD), we have studied the intersections between Coronavirus Disease 2019 (COVID-19), intestinal inflammation, and IBD treatment. RESULTS: A striking expression of ACE2 on the small bowel enterocyte brush border supports intestinal infectivity by SARS-CoV-2. Commonly used IBD medications, both biologic and nonbiologic, do not significantly impact ACE2 and TMPRSS2 receptor expression in the uninflamed intestines. In addition, we have defined molecular responses to COVID-19 infection that are also enriched in IBD, pointing to shared molecular networks between COVID-19 and IBD. CONCLUSIONS: These data generate a novel appreciation of the confluence of COVID-19- and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19. Preprint doi: https://doi.org/10.1101/2020.05.21.109124.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/enzymology , Inflammatory Bowel Diseases/enzymology , Intestinal Mucosa/enzymology , SARS-CoV-2/pathogenicity , Serine Endopeptidases/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/genetics , COVID-19/virology , Case-Control Studies , Clinical Trials as Topic , Cross-Sectional Studies , Disease Models, Animal , Female , Gene Regulatory Networks , Host-Pathogen Interactions , Humans , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/genetics , Intestinal Mucosa/drug effects , Intestinal Mucosa/virology , Longitudinal Studies , Male , Mice , SARS-CoV-2/drug effects , Serine Endopeptidases/genetics , Signal Transduction , COVID-19 Drug Treatment
8.
JCI Insight ; 4(15)2019 08 08.
Article in English | MEDLINE | ID: mdl-31391335

ABSTRACT

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication associated with systemic lupus erythematosus, vasculitis, and stem cell transplant. Little is known about the pathophysiology of DAH, and no targeted therapy is currently available. Pristane treatment in mice induces systemic autoimmunity and lung hemorrhage that recapitulates hallmark pathologic features of human DAH. Using this experimental model, we performed high-dimensional analysis of lung immune cells in DAH by mass cytometry and single-cell RNA sequencing. We found a large influx of myeloid cells to the lungs in DAH and defined the gene expression profile of infiltrating monocytes. Bone marrow-derived inflammatory monocytes actively migrated to the lungs and homed adjacent to blood vessels. Using 3 models of monocyte deficiency and complementary transfer studies, we established a central role of inflammatory monocytes in the development of DAH. We further found that the myeloid transcription factor interferon regulatory factor 8 is essential to the development of both DAH and type I interferon-dependent autoimmunity. These findings collectively reveal monocytes as a potential treatment target in DAH.


Subject(s)
Hemorrhage/immunology , Lung Diseases/immunology , Monocytes/immunology , Pulmonary Alveoli/pathology , Animals , Cell Separation , Female , Flow Cytometry , Hemorrhage/pathology , Humans , Lung Diseases/pathology , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/immunology , Male , Mice , Mice, Knockout , Monocytes/metabolism , Pulmonary Alveoli/immunology , RNA-Seq , Single-Cell Analysis , Stem Cell Transplantation/adverse effects
9.
Nat Genet ; 50(8): 1180-1188, 2018 08.
Article in English | MEDLINE | ID: mdl-30013183

ABSTRACT

Genome-wide association studies (GWAS) have identified many disease-associated noncoding variants, but cannot distinguish functional single-nucleotide polymorphisms (fSNPs) from others that reside incidentally within risk loci. To address this challenge, we developed an unbiased high-throughput screen that employs type IIS enzymatic restriction to identify fSNPs that allelically modulate the binding of regulatory proteins. We coupled this approach, termed SNP-seq, with flanking restriction enhanced pulldown (FREP) to identify regulation of CD40 by three disease-associated fSNPs via four regulatory proteins, RBPJ, RSRC2 and FUBP-1/TRAP150. Applying this approach across 27 loci associated with juvenile idiopathic arthritis, we identified 148 candidate fSNPs, including two that regulate STAT4 via the regulatory proteins SATB2 and H1.2. Together, these findings establish the utility of tandem SNP-seq/FREP to bridge the gap between GWAS and disease mechanism.


Subject(s)
Polymorphism, Single Nucleotide , Arthritis, Juvenile/genetics , CD40 Antigens/genetics , Cell Line, Tumor , Cells, Cultured , Genetic Loci , Genetic Predisposition to Disease , Genome-Wide Association Study/methods , High-Throughput Screening Assays/methods , Humans , Jurkat Cells
10.
Blood ; 130(19): 2092-2100, 2017 11 09.
Article in English | MEDLINE | ID: mdl-28807980

ABSTRACT

CD177 is a glycosylphosphatidylinositol (GPI)-anchored protein expressed by a variable proportion of human neutrophils that mediates surface expression of the antineutrophil cytoplasmic antibody antigen proteinase 3. CD177 associates with ß2 integrins and recognizes platelet endothelial cell adhesion molecule 1 (PECAM-1), suggesting a role in neutrophil migration. However, CD177pos neutrophils exhibit no clear migratory advantage in vivo, despite interruption of in vitro transendothelial migration by CD177 ligation. We sought to understand this paradox. Using a PECAM-1-independent transwell system, we found that CD177pos and CD177neg neutrophils migrated comparably. CD177 ligation selectively impaired migration of CD177pos neutrophils, an effect mediated through immobilization and cellular spreading on the transwell membrane. Correspondingly, CD177 ligation enhanced its interaction with ß2 integrins, as revealed by fluorescence lifetime imaging microscopy, leading to integrin-mediated phosphorylation of Src and extracellular signal-regulated kinase (ERK). CD177-driven cell activation enhanced surface ß2 integrin expression and affinity, impaired internalization of integrin attachments, and resulted in ERK-mediated attenuation of chemokine signaling. We conclude that CD177 signals in a ß2 integrin-dependent manner to orchestrate a set of activation-mediated mechanisms that impair human neutrophil migration.


Subject(s)
CD18 Antigens/metabolism , Chemokines/metabolism , Isoantigens/biosynthesis , MAP Kinase Signaling System/physiology , Neutrophils/metabolism , Receptors, Cell Surface/biosynthesis , Transendothelial and Transepithelial Migration/physiology , Adult , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , GPI-Linked Proteins/biosynthesis , Humans , Male , Neutrophils/cytology , Phosphorylation/physiology , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , src-Family Kinases/metabolism
11.
J Pathol ; 240(3): 262-268, 2016 11.
Article in English | MEDLINE | ID: mdl-27513300

ABSTRACT

CD1d-restricted invariant natural killer T (iNKT) cells are believed to play a key role in cancer immune surveillance, and are functionally deficient in patients with chronic myeloid leukaemia (CML). Herein, we have hypothesized that this defect might originate from BCR-ABL-dependent dysfunctions in myeloid dendritic cells (mDCs). Indeed, flow cytometry and confocal microscopy revealed that cell surface expression of CD1d was downregulated in CML mDCs, relative to healthy donor (HD) controls. The decreased cell surface display of CD1d could not be ascribed to defective mDC differentiation, as attested by normal expression of HLA-DR and the CD86 maturation marker. On the other hand, reduced membrane expression was not associated with decreased intracytoplasmic levels of CD1d or its mRNA transcripts, consistent with intracellular retention. In vitro treatment of CML mDCs with the Rho-associated protein kinase (ROCK) inhibitor Y-27632 partially restored both cell surface CD1d expression and CD1d-mediated antigen presentation, whereas it had no effect on HD mDCs. An inhibitor of BCR-ABL tyrosine kinase (TK), imatinib mesylate (IM), had no such activity. Similar recovery of CD1d expression occurred with fasudil, another ROCK inhibitor that is commonly used in clinical trials. Our data support the conclusion that BCR-ABL-dependent ROCK, but not TK, is involved in CD1d downregulation. We propose that ROCK, which is most likely activated by the DH/PH domain of BCR-ABL, mediates iNKT-cell immune subversion in CML patients by downregulating CD1d expression on CML mDCs. Our study reveals the ROCK-mDC axis as a new potential target to restore immune surveillance in patients with CML, offering new therapeutic perspectives for CML treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Subject(s)
Antigens, CD1d/immunology , Immunity, Innate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , rho-Associated Kinases/immunology , Amides/pharmacology , Cell Differentiation , Dendritic Cells/enzymology , Dendritic Cells/immunology , Enzyme Inhibitors/pharmacology , Fusion Proteins, bcr-abl/immunology , Humans , Imatinib Mesylate/pharmacology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Myeloid Cells/enzymology , Myeloid Cells/immunology , Natural Killer T-Cells/enzymology , Natural Killer T-Cells/immunology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , rho-Associated Kinases/antagonists & inhibitors
12.
J Immunol ; 197(5): 1708-19, 2016 09 01.
Article in English | MEDLINE | ID: mdl-27474075

ABSTRACT

IL-33 is strongly involved in several inflammatory and autoimmune disorders with both pro- and anti-inflammatory properties. However, its contribution to chronic autoimmune inflammation, such as rheumatoid arthritis, is ill defined and probably requires tight regulation. In this study, we aimed at deciphering the complex role of IL-33 in a model of rheumatoid arthritis, namely, collagen-induced arthritis (CIA). We report that repeated injections of IL-33 during induction (early) and during development (late) of CIA strongly suppressed clinical and histological signs of arthritis. In contrast, a late IL-33 injection had no effect. The cellular mechanism involved in protection was related to an enhanced type 2 immune response, including the expansion of eosinophils, Th2 cells, and type 2 innate lymphoid cells, associated with an increase in type 2 cytokine levels in the serum of IL-33-treated mice. Moreover, our work strongly highlights the interplay between IL-33 and regulatory T cells (Tregs), demonstrated by the dramatic in vivo increase in Treg frequencies after IL-33 treatment of CIA. More importantly, Tregs from IL-33-treated mice displayed enhanced capacities to suppress IFN-γ production by effector T cells, suggesting that IL-33 not only favors Treg proliferation but also enhances their immunosuppressive properties. In concordance with these observations, we found that IL-33 induced the emergence of a CD39(high) Treg population in a ST2L-dependent manner. Our findings reveal a powerful anti-inflammatory mechanism by which IL-33 administration inhibits arthritis development.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/immunology , Interleukin-33/therapeutic use , T-Lymphocytes, Regulatory/immunology , Th2 Cells/immunology , Animals , Antigens, CD/genetics , Apyrase/genetics , Arthritis, Experimental , Arthritis, Rheumatoid/chemically induced , Autoimmune Diseases/immunology , Collagen/administration & dosage , Cytokines/blood , Disease Models, Animal , Eosinophils , Interleukin-33/immunology , Interleukin-33/pharmacology , Mice , Mice, Inbred DBA , Spleen/cytology , Spleen/drug effects
13.
Front Immunol ; 7: 688, 2016.
Article in English | MEDLINE | ID: mdl-28138330

ABSTRACT

We recently identified a new human subset of NK-like [KIR/NKG2A(+)] CD8(+) T cells with a marked/memory phenotype, high Eomesodermin expression, potent antigen-independent cytotoxic activity, and the capacity to generate IFN-γ rapidly after exposure to pro-inflammatory cytokines. These features support the hypothesis that this new member of the innate T cell family in humans, hereafter referred to as innate CD8(+) T cells, has a role in cancer immune surveillance analogous to invariant natural killer T (iNKT) cells. Here, we report the first quantitative and functional analysis of innate CD8(+) T cells in a physiopathological context in humans, namely chronic myeloid leukemia (CML), a well-characterized myeloproliferative disorder. We have chosen CML based on our previous report that IL-4 production by iNKT cells was deficient in CML patients at diagnosis and considering the recent evidence in mice that IL-4 promotes the generation/differentiation of innate CD8(+) T cells. We found that the pool of innate CD8(+) T cells was severely reduced in the blood of CML patients at diagnosis. Moreover, like iNKT and NK cells, innate CD8(+) T cells were functionally impaired, as attested by their loss of antigen-independent cytotoxic activity and IFN-γ production in response to innate-like stimulation with IL-12 + IL-18. Remarkably, as previously reported for IL-4 production by iNKT cells, both quantitative and functional deficiencies of innate CD8(+) T cells were at least partially corrected in patients having achieved complete cytogenetic remission following tyrosine kinase inhibitor therapy. Finally, direct correlation between the functional potential of innate CD8(+) T and iNKT cells was found when considering all healthy donors and CML patients in diagnosis and remission, in accordance with the iNKT cell-dependent generation of innate CD8(+) T cells reported in mice. All in all, our data demonstrate that CML is associated with deficiencies of innate CD8(+) T cells that are restored upon remission, thereby suggesting their possible contribution to disease control. More generally, our study strongly supports the existence of an innate iNKT/innate CD8(+) T-cell axis in humans and reveals its potential contribution to the restoration of tumor immune surveillance.

14.
Endocrinology ; 157(1): 258-67, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26485613

ABSTRACT

Therapeutic strategies focused on restoring immune tolerance remain the main avenue to prevent type 1 diabetes (T1D). Because estrogens potentiate FoxP3+ regulatory T cells (Treg) and invariant natural killer T (iNKT) cells, two regulatory lymphocyte populations that are functionally deficient in nonobese diabetic (NOD) mice, we investigated whether estradiol (E2) therapy influences the course of T1D in this model. To this end, female NOD mice were sc implanted with E2- or placebo-delivering pellets to explore the course of spontaneous and cyclophosphamide-induced diabetes. Treg-depleted and iNKT-cell-deficient (Jα18(-/-)) NOD mice were used to assess the respective involvement of these lymphocyte populations in E2 effects. Early E2 administration (from 4 wk of age) was found to preserve NOD mice from both spontaneous and cyclophosphamide-induced diabetes, and a complete protection was also observed throughout treatment when E2 treatment was initiated after the onset of insulitis (from 12 wk of age). This delayed E2 treatment remained fully effective in Treg-depleted mice but failed to entirely protect Jα18(-/-) mice. Accordingly, E2 administration was shown to restore the cytokine production of iNKT cells in response to in vivo challenge with the cognate ligand α-galactosylceramide. Finally, transient E2 administration potentiated the previously described protective action of α-galactosylceramide treatment in NOD females. This study provides original evidence that E2 therapy strongly protects NOD mice from T1D and reveals the estrogen/iNKT cell axis as a new effective target to counteract diabetes onset at the stage of insulitis. Estrogen-based therapy should thus be considered for T1D prevention.


Subject(s)
Autoimmune Diseases/prevention & control , Diabetes Mellitus, Type 1/prevention & control , Estradiol/therapeutic use , Estrogens/therapeutic use , Killer Cells, Natural/drug effects , Lymphocyte Activation/drug effects , Prediabetic State/prevention & control , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Cytokines/blood , Cytokines/metabolism , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/metabolism , Drug Implants , Estradiol/administration & dosage , Estrogen Replacement Therapy , Estrogens/administration & dosage , Female , Galactosylceramides/agonists , Galactosylceramides/pharmacology , Galactosylceramides/therapeutic use , Immune Tolerance/drug effects , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lymphocyte Depletion/adverse effects , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Mutant Strains , Ovariectomy/adverse effects , Prediabetic State/drug therapy , Prediabetic State/immunology , Prediabetic State/metabolism , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism
15.
Eur J Immunol ; 45(7): 1926-33, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25903796

ABSTRACT

Polyclonal CD8(+) T cells, with a marked innate/memory phenotype, high eomesodermin (Eomes) expression, and the capacity to generate IFN-γ rapidly without prior exposure to antigen, have been described in mice. However, even though a pool of human CD8(+) T cells expressing killer Ig-like receptors (KIRs) was recently documented, the existence of a human equivalent of murine innate/memory CD8(+) T cells remains to be established. Here, we provide evidence for a population of KIR/NKG2A(+) CD8(+) T cells in healthy human adults sharing the same features, namely increased Eomes expression, prompt IFN-γ production in response to innate-like stimulation by IL-12+IL-18, and a potent antigen-independent cytotoxic activity along with a preferential terminally differentiated effector memory phenotype. None of the above functional characteristics applied to the KIR/NKG2A(-) fraction of the Eomes(+) CD8(+) T-cell population, thereby underlining the ability of KIR/NKG2A to distinguish between "innate/memory-like" and "conventional/memory" pools of CD8(+) T cells. Remarkably, KIR/NKG2A(+) Eomes(+) CD8(+) T cells with innate-like functions and a memory/terminally differentiated effector memory phenotype were also identified in human cord blood, suggesting that their development did not depend on cognate antigens. Taken together, our results support the conclusion that CD8(+) T cells co-expressing Eomes and KIR/NKG2A may represent a new, functionally distinct "innate/memory-like" subset in humans.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunity, Innate/immunology , Immunologic Memory/immunology , T-Box Domain Proteins/immunology , T-Lymphocyte Subsets/immunology , Adult , Fetal Blood/cytology , Fetal Blood/immunology , Flow Cytometry , Humans , NK Cell Lectin-Like Receptor Subfamily C/immunology
16.
Cancer Res ; 74(10): 2669-76, 2014 May 15.
Article in English | MEDLINE | ID: mdl-24675360

ABSTRACT

Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myelogenous leukemia (CML) and resistance to imatinib mesylate treatment remain poorly investigated. Here, we report that CD34(+) progenitors from patients with CML at diagnosis are selectively targeted by the cytokine/alarmin interleukin (IL)-33. Indeed, CML CD34(+) progenitors upregulate their cell surface expression of the IL-33-specific receptor chain ST2, proliferate and produce cytokines in response to IL-33, conversely to CD34(+) cells from healthy individuals. Moreover, ST2 overexpression is normalized following imatinib mesylate therapy, whereas IL-33 counteracts in vitro imatinib mesylate-induced growth arrest in CML CD34(+) progenitors via reactivation of the STAT5 pathway, thus supporting the notion that IL-33 may impede the antiproliferative effects of imatinib mesylate on CD34(+) progenitors in CML. Clinically, the levels of circulating soluble ST2, commonly considered a functional signature of IL-33 signaling in vivo, correlate with disease burden. Indeed, these elevated peripheral concentrations associated with a high Sokal score predictive of therapeutic outcome are normalized in patients in molecular remission. Finally, we evidenced a facilitating effect of IL-33 on in vivo maintenance of CD34(+) progenitors from patients with CML by using xenotransplant experiments in immunodeficient NOG mice, and we showed that engraftment of mouse BCR-ABL-transfected bone marrow progenitors was less efficient in IL-33-deficient mice compared with wild-type recipients. Taken together, our results provide evidence that IL-33/ST2 signaling may represent a novel cytokine-mediated mechanism contributing to CML progenitor growth and support a role for this pathway in CML maintenance and imatinib mesylate resistance.


Subject(s)
Antigens, CD34/biosynthesis , Fusion Proteins, bcr-abl/metabolism , Interleukins/metabolism , Leukemia, Myeloid, Chronic-Phase/metabolism , Neoplastic Stem Cells/metabolism , Receptors, Cell Surface/metabolism , Animals , Antigens, CD34/immunology , Benzamides/pharmacology , Cytokines/biosynthesis , Drug Interactions , Female , Fusion Proteins, bcr-abl/immunology , Humans , Imatinib Mesylate , Interleukin-1 Receptor-Like 1 Protein , Interleukin-33 , Interleukins/immunology , Interleukins/pharmacology , Janus Kinase 2/metabolism , Leukemia, Myeloid, Chronic-Phase/drug therapy , Leukemia, Myeloid, Chronic-Phase/immunology , Leukemia, Myeloid, Chronic-Phase/pathology , Mice , Mice, Inbred C57BL , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/pathology , Piperazines/pharmacology , Pyrimidines/pharmacology , Receptors, Cell Surface/biosynthesis , Receptors, Cell Surface/immunology , STAT5 Transcription Factor/metabolism , Signal Transduction/drug effects , Up-Regulation
17.
Eur J Immunol ; 42(7): 1870-5, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22585600

ABSTRACT

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem-cell malignancy characterized by the presence of the chimeric BCR-ABL oncoprotein with deregulated tyrosine-kinase (TK) activity. Although conventional T cells are acknowledged as important players in the control of CML, a possible modification of invariant NKT (iNKT) cells, known for their antitumoral activity, has not been established as yet. Here, we showed that the expression of perforin, CD95L, and promyelocytic leukemia zinc finger, a transcription factor required for maintenance of iNKT cell functions, was reduced or suppressed in CML patients at diagnosis, as compared with healthy individuals. The proliferation rate of blood iNKT cells in response to their cognate ligand was likewise diminished. These functional deficiencies were corrected in patients having achieved complete cytogenetic remission following TK inhibitor or IFN-α therapy. iNKT cells from CML patients in the chronic phase did not display increased TK activity, which argued against a direct autonomous action of BCR-ABL. Instead, we found that their anergic status originated from both intrinsic and APC-dependent dysfunctions. Our data demonstrate that chronic phase CML is associated with functional deficiencies of iNKT cells that are restored upon remission. These results suggest a possible contribution to disease control by TK inhibitor therapies.


Subject(s)
Interferon-alpha/pharmacology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Natural Killer T-Cells/immunology , Protein-Tyrosine Kinases/immunology , Benzamides , Fas Ligand Protein/blood , Flow Cytometry , Humans , Imatinib Mesylate , Kruppel-Like Transcription Factors/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Natural Killer T-Cells/enzymology , Perforin/blood , Piperazines/pharmacology , Promyelocytic Leukemia Zinc Finger Protein , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology
18.
J Immunol ; 186(6): 3289-93, 2011 Mar 15.
Article in English | MEDLINE | ID: mdl-21317388

ABSTRACT

Despite their increasing use in autoimmune, inflammatory, and allergic conditions, the mechanism of action of i.v. Igs (IVIg) is poorly understood. On the basis of the critical role of invariant NKT (iNKT) cells in allergic airway inflammation (AAI) and their constitutive expression of the low-affinity IgG receptor FcγRIIIA, we surmised that IVIg targets iNKT cells to exert their anti-inflammatory effect. We found that IVIg treatment significantly inhibited AAI in OVA-sensitized C57BL/6 mice and downregulated α-galactosylceramide-induced iNKT cell activation and cytokine production. Allergic responses were restored in iNKT cell-deficient mice by transferring iNKT cells from PBS- but not from IVIg-treated mice, suggesting that IVIg acts directly on activated iNKT cells that have a critical role in AAI. The inhibitory effects of IVIg on both iNKT cell activation/function and OVA-driven AAI were lost in FcγRIIIA(-/-) mice. Our data unravel an FcγRIIIA-dependent inhibitory effect of IVIg on activated iNKT cells that confers protection in AAI.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Immunoglobulins, Intravenous/physiology , Inflammation Mediators/physiology , Natural Killer T-Cells/immunology , Natural Killer T-Cells/pathology , Receptors, IgG/physiology , Respiratory Hypersensitivity/immunology , Respiratory Hypersensitivity/prevention & control , Adoptive Transfer , Allergens/immunology , Allergens/toxicity , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Bronchial Hyperreactivity/immunology , Bronchial Hyperreactivity/pathology , Bronchial Hyperreactivity/therapy , Cytokines/antagonists & inhibitors , Cytokines/biosynthesis , Galactosylceramides/antagonists & inhibitors , Galactosylceramides/pharmacology , Immunoglobulins, Intravenous/therapeutic use , Inflammation Mediators/therapeutic use , Lymphocyte Activation/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Natural Killer T-Cells/metabolism , Ovalbumin/immunology , Ovalbumin/toxicity , Receptors, IgG/therapeutic use , Respiratory Hypersensitivity/pathology , Spleen/immunology , Spleen/pathology , Spleen/transplantation
19.
Eur J Immunol ; 41(2): 299-305, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21268000

ABSTRACT

Activation of invariant natural killer T (iNKT) cells by treatment with their α-galactosyl ceramide ligand provides therapeutic benefits in several immune inflammatory settings. Given the artificial nature of this stimulation, the natural regulatory functions of iNKT remain uncertain. Addressing this issue in a mouse model of innate-cell-driven lung inflammation induced by the cytokine/alarmin IL-33 that targets iNKT cells, we found that eosinophil and neutrophil recruitment was markedly increased in treated iNKT cell-deficient (Jα18 KO) mice, as was the local production of eotaxin and keratinocyte chemoattractant chemokines. By contrast, lung inflammation decreased after adoptive transfer of iNKT cells, which restored the WT inflammatory response in Jα18 KO mice. Finally, we established that this natural anti-inflammatory function of iNKT cells depends on their IFN-γ production and on endogenous IL-12. Our study provides the first evidence of a protective role of iNKT cells during lung inflammation that does not require pharmacological TCR engagement.


Subject(s)
Bronchitis/immunology , Bronchitis/pathology , Immunity, Innate/immunology , Natural Killer T-Cells/immunology , Adoptive Transfer , Animals , Bronchitis/blood , Bronchitis/chemically induced , Bronchoalveolar Lavage Fluid/chemistry , Cell Count , Chemokines/blood , Chemokines/metabolism , DNA-Binding Proteins/genetics , Disease Models, Animal , Eosinophils/pathology , Female , Interferon-gamma/genetics , Interferon-gamma/metabolism , Interleukin-12/genetics , Interleukin-12/metabolism , Interleukin-33 , Interleukin-5/blood , Interleukins/pharmacology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Natural Killer T-Cells/metabolism , Natural Killer T-Cells/transplantation , Neutrophils/pathology , Receptors, Antigen, T-Cell, alpha-beta/genetics , Recombinant Proteins/pharmacology
20.
PLoS One ; 5(6): e11358, 2010 Jun 29.
Article in English | MEDLINE | ID: mdl-20613877

ABSTRACT

BACKGROUND: Studies on human genetic factors associated with malaria have hitherto concentrated on their role in susceptibility to and protection from disease. In contrast, virtually no attention has been paid to the role of human genetics in eliciting the production of parasite transmission stages, the gametocytes, and thus enhancing the spread of disease. METHODS AND FINDINGS: We analysed four longitudinal family-based cohort studies from Senegal and Thailand followed for 2-8 years and evaluated the relative impact of the human genetic and non-genetic factors on gametocyte production in infections of Plasmodium falciparum or P. vivax. Prevalence and density of gametocyte carriage were evaluated in asymptomatic and symptomatic infections by examination of Giemsa-stained blood smears and/or RT-PCR (for falciparum in one site). A significant human genetic contribution was found to be associated with gametocyte prevalence in asymptomatic P. falciparum infections. By contrast, there was no heritability associated with the production of gametocytes for P. falciparum or P. vivax symptomatic infections. Sickle cell mutation, HbS, was associated with increased gametocyte prevalence but its contribution was small. CONCLUSIONS: The existence of a significant human genetic contribution to gametocyte prevalence in asymptomatic infections suggests that candidate gene and genome wide association approaches may be usefully applied to explore the underlying human genetics. Prospective epidemiological studies will provide an opportunity to generate novel and perhaps more epidemiologically pertinent gametocyte data with which similar analyses can be performed and the role of human genetics in parasite transmission ascertained.


Subject(s)
Disease Reservoirs , Plasmodium falciparum/pathogenicity , Plasmodium vivax/pathogenicity , Anemia, Sickle Cell/parasitology , Animals , Cohort Studies , Humans , Reverse Transcriptase Polymerase Chain Reaction , alpha-Thalassemia/parasitology
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