Publications by authors named "Cédric Auffray"

28 Publications

  • Page 1 of 1

Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2-expressing Treg cells.

Proc Natl Acad Sci U S A 2021 Mar;118(13)

Sorbonne Université, INSERM, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI)-Paris, F-75013 Paris, France;

CD4Foxp3 regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell-mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We found that TNFR2-expressing Treg cells were critical to suppress EAE at peak disease in the central nervous system but had no impact on T cell priming in lymphoid tissues at disease onset. Mechanistically, TNFR2 signaling maintained functional Treg cells with sustained expression of CTLA-4 and Blimp-1, allowing active suppression of pathogenic T cells in the inflamed central nervous system. This late effect of Treg cells was further confirmed by treating mice with TNF and TNFR2 agonists and antagonists. Our findings show that endogenous Treg cells specifically suppress an autoimmune disease by acting in the target tissue during overt inflammation. Moreover, they bring a mechanistic insight to some of the adverse effects of anti-TNF therapy in patients.
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http://dx.doi.org/10.1073/pnas.2014043118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020675PMC
March 2021

The RanBP2/RanGAP1-SUMO complex gates β-arrestin2 nuclear entry to regulate the Mdm2-p53 signaling axis.

Oncogene 2021 Mar 1;40(12):2243-2257. Epub 2021 Mar 1.

Inserm, U1016, Institut Cochin, Paris, France.

Mdm2 antagonizes the tumor suppressor p53. Targeting the Mdm2-p53 interaction represents an attractive approach for the treatment of cancers with functional p53. Investigating mechanisms underlying Mdm2-p53 regulation is therefore important. The scaffold protein β-arrestin2 (β-arr2) regulates tumor suppressor p53 by counteracting Mdm2. β-arr2 nucleocytoplasmic shuttling displaces Mdm2 from the nucleus to the cytoplasm resulting in enhanced p53 signaling. β-arr2 is constitutively exported from the nucleus, via a nuclear export signal, but mechanisms regulating its nuclear entry are not completely elucidated. β-arr2 can be SUMOylated, but no information is available on how SUMO may regulate β-arr2 nucleocytoplasmic shuttling. While we found β-arr2 SUMOylation to be dispensable for nuclear import, we identified a non-covalent interaction between SUMO and β-arr2, via a SUMO interaction motif (SIM), that is required for β-arr2 cytonuclear trafficking. This SIM promotes association of β-arr2 with the multimolecular RanBP2/RanGAP1-SUMO nucleocytoplasmic transport hub that resides on the cytoplasmic filaments of the nuclear pore complex. Depletion of RanBP2/RanGAP1-SUMO levels result in defective β-arr2 nuclear entry. Mutation of the SIM inhibits β-arr2 nuclear import, its ability to delocalize Mdm2 from the nucleus to the cytoplasm and enhanced p53 signaling in lung and breast tumor cell lines. Thus, a β-arr2 SIM nuclear entry checkpoint, coupled with active β-arr2 nuclear export, regulates its cytonuclear trafficking function to control the Mdm2-p53 signaling axis.
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http://dx.doi.org/10.1038/s41388-021-01704-wDOI Listing
March 2021

Regulatory T Cells in Systemic Sclerosis.

Front Immunol 2018 15;9:2356. Epub 2018 Oct 15.

INSERM U1016, UMR8104, Cochin Institute, Paris Descartes University, Paris, France.

In recent years, accumulating evidence suggest that regulatory T cells (Tregs) are of paramount importance for the maintenance of immunological self-tolerance and immune homeostasis, even though they represent only about 5-10% of the peripheral CD4 T cells in humans. Their key role is indeed supported by the spontaneous development of autoimmune diseases after Tregs depletion in mice. Moreover, there is also a growing literature that investigates possible contribution of Tregs numbers and activity in various autoimmune diseases. The contribution of Tregs in autoimmune disease has opened up a new therapeutic avenue based on restoring a healthy balance between Tregs and effector T-cells, such as Treg-based cellular transfer or low-dose IL-2 modulation. These therapies hold the promise of modulating the immune system without immunosuppression, while several issues regarding efficacy and safety need to be addressed. Systemic sclerosis (SSc) is an orphan connective tissue disease characterized by extensive immune abnormalities but also microvascular injury and fibrosis. Recently, data about the presence and function of Tregs in the pathogenesis of SSc have emerged although they remain scarce so far. First, there is a general agreement in the medical literature with regard to the decreased functional ability of circulating Tregs in SSc. Second the quantification of Tregs in patients have led to contradictory results; although the majority of the studies report reduced frequencies, there are conversely some indications suggesting that in case of disease activity circulating Tregs may increase. This paradoxical situation could be the result of a compensatory, but inefficient, amplification of Tregs in the context of inflammation. Nevertheless, these results must be tempered with regards to the heterogeneity of the studies for the phenotyping of the patients and of the most importance for Tregs definition and activity markers. Therefore, taking into account the appealing developments of Tregs roles in autoimmune diseases, together with preliminary data published in SSc, there is growing interest in deciphering Tregs in SSc, both in humans and mice models, to clarify whether the promises obtained in other autoimmune diseases may also apply to SSc.
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http://dx.doi.org/10.3389/fimmu.2018.02356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196252PMC
September 2019

Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases.

Science 2018 06 17;360(6394). Epub 2018 May 17.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

The majority of patients with pancreatic ductal adenocarcinoma (PDA) develop metastatic disease after resection of their primary tumor. We found that livers from patients and mice with PDA harbor single disseminated cancer cells (DCCs) lacking expression of cytokeratin 19 (CK19) and major histocompatibility complex class I (MHCI). We created a mouse model to determine how these DCCs develop. Intraportal injection of immunogenic PDA cells into preimmunized mice seeded livers only with single, nonreplicating DCCs that were CK19 and MHCI The DCCs exhibited an endoplasmic reticulum (ER) stress response but paradoxically lacked both inositol-requiring enzyme 1α activation and expression of the spliced form of transcription factor XBP1 (XBP1s). Inducible expression of XBP1s in DCCs, in combination with T cell depletion, stimulated the outgrowth of macrometastatic lesions that expressed CK19 and MHCI. Thus, unresolved ER stress enables DCCs to escape immunity and establish latent metastases.
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http://dx.doi.org/10.1126/science.aao4908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547380PMC
June 2018

Profiling the lymphoid-resident T cell pool reveals modulation by age and microbiota.

Nat Commun 2018 01 4;9(1):68. Epub 2018 Jan 4.

Paris Descartes Université, Sorbonne Paris Cité, Institut Cochin, CNRS UMR8104, INSERM U1016, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France.

Despite being implicated in non-lymphoid tissues, non-recirculating T cells may also exist in secondary lymphoid organs (SLO). However, a detailed characterization of this lymphoid-resident T cell pool has not yet been done. Here we show that a substantial proportion of CD4 regulatory (Treg) and memory (Tmem) cells establish long-term residence in the SLOs of specific pathogen-free mice. Of these SLOs, only T cell residence within Peyer's patches is affected by microbiota. Resident CD4 Treg and CD4 Tmem cells from lymph nodes and non-lymphoid tissues share many phenotypic and functional characteristics. The percentage of resident T cells in SLOs increases considerably with age, with S1PR1 downregulation possibly contributing to this altered homeostasis. Our results thus show that T cell residence is not only a hallmark of non-lymphoid tissues, but can be extended to secondary lymphoid organs.
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http://dx.doi.org/10.1038/s41467-017-02458-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754350PMC
January 2018

IL-4-Induced Gene 1: A Negative Immune Checkpoint Controlling B Cell Differentiation and Activation.

J Immunol 2018 02 29;200(3):1027-1038. Epub 2017 Dec 29.

INSERM, U1016, Institut Cochin, 75014 Paris, France;

Emerging data highlight the crucial role of enzymes involved in amino acid metabolism in immune cell biology. IL-4-induced gene-1 (IL4I1), a secreted l-phenylalanine oxidase expressed by APCs, has been detected in B cells, yet its immunoregulatory role has only been explored on T cells. In this study, we show that IL4I1 regulates multiple steps in B cell physiology. Indeed, IL4I1 knockout mice exhibit an accelerated B cell egress from the bone marrow, resulting in the accumulation of peripheral follicular B cells. They also present a higher serum level of natural Igs and self-reactive Abs. We also demonstrate that IL4I1 produced by B cells themselves controls the germinal center reaction, plasma cell differentiation, and specific Ab production in response to T dependent Ags, SRBC, and NP-KLH. In vitro, IL4I1-deficient B cells proliferate more efficiently than their wild-type counterparts in response to BCR cross-linking. Moreover, the absence of IL4I1 increases activation of the Syk-Akt-S6kinase signaling pathway and calcium mobilization, and inhibits SHP-1 activity upon BCR engagement, thus supporting that IL4I1 negatively controls BCR-dependent activation. Overall, our study reveals a new perspective on IL4I1 as a key regulator of B cell biology.
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http://dx.doi.org/10.4049/jimmunol.1601609DOI Listing
February 2018

Calcium-mediated shaping of naive CD4 T-cell phenotype and function.

Elife 2017 12 14;6. Epub 2017 Dec 14.

Institut Cochin, Paris Descartes Université, CNRS UMR8104, INSERM U1016, Paris, France.

Continuous contact with self-major histocompatibility complex ligands is essential for the survival of naive CD4 T cells. We have previously shown that the resulting tonic TCR signaling also influences their fate upon activation by increasing their ability to differentiate into induced/peripheral regulatory T cells. To decipher the molecular mechanisms governing this process, we here focus on the TCR signaling cascade and demonstrate that a rise in intracellular calcium levels is sufficient to modulate the phenotype of mouse naive CD4 T cells and to increase their sensitivity to regulatory T-cell polarization signals, both processes relying on calcineurin activation. Accordingly, in vivo calcineurin inhibition leads the most self-reactive naive CD4 T cells to adopt the phenotype of their less self-reactive cell-counterparts. Collectively, our findings demonstrate that calcium-mediated activation of the calcineurin pathway acts as a rheostat to shape both the phenotype and effector potential of naive CD4 T cells in the steady-state.
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http://dx.doi.org/10.7554/eLife.27215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747519PMC
December 2017

Macrophages Induce Long-Term Trapping of γδ T Cells with Innate-like Properties within Secondary Lymphoid Organs in the Steady State.

J Immunol 2017 09 4;199(6):1998-2007. Epub 2017 Aug 4.

Institut Cochin, CNRS UMR8104, INSERM U1016, Paris Descartes Université, 75014 Paris, France;

So far, peripheral T cells have mostly been described to circulate between blood, secondary lymphoid organs (SLOs), and lymph in the steady state. This nomadic existence would allow them to accomplish their surveying task for both foreign Ags and survival signals. Although it is now well established that γδ T cells can be rapidly recruited to inflammatory sites or in certain tumor microenvironments, the trafficking properties of peripheral γδ T cells have been poorly studied in the steady state. In the present study, we highlight the existence of resident γδ T cells in the SLOs of specific pathogen-free mice. Indeed, using several experimental approaches such as the injection of integrin-neutralizing Abs that inhibit the entry of circulating lymphocytes into lymph nodes and long-term parabiosis experiments, we have found that, contrary to Ly-6CCD44 and Ly-6CCD44 γδ T cells, a significant proportion of Ly-6CCD44 γδ T cells are trapped for long periods of time within lymph nodes and the spleen in the steady state. Specific in vivo cell depletion strategies have allowed us to demonstrate that macrophages are the main actors involved in this long-term retention of Ly-6CCD44 γδ T cells in SLOs.
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http://dx.doi.org/10.4049/jimmunol.1700430DOI Listing
September 2017

Chronic Type I IFN Is Sufficient To Promote Immunosuppression through Accumulation of Myeloid-Derived Suppressor Cells.

J Immunol 2017 02 21;198(3):1156-1163. Epub 2016 Dec 21.

INSERM, U1016, Institut Cochin, 75014 Paris, France;

Failure of the immune system to eradicate viruses results in chronic viral infections, which are associated with increased susceptibility to secondary infections. Pathogenic HIV or lymphocytic choriomeningitis virus chronic infections display a persistent type I IFN signature. In chronic lymphocytic choriomeningitis virus infection, blockade of type I IFN signaling partially restores antiviral responses. In a mouse model, we tested whether chronic administration of type I IFN, at doses mimicking chronic viral infection, induced immunosuppression. Chronic exposure of mice to IFN-α alone was sufficient to strongly suppress specific CD8 T cells responses to subsequent vaccinia virus infection. It resulted in the accumulation of Ly6C monocytes. These monocytes were similar, phenotypically and functionally, to the myeloid-derived suppressor cells found in cancer because they exerted a potent suppression on CD8 T cell responses in vitro. They acted at least partly through the l-arginine pathway. In vivo, their elimination restored antiviral CD8 T cell responses. Our work provides a specific mechanism accounting for the role of IFN-α in immunosuppression and predicts that type I IFN modulation will be pivotal to cure human chronic infections, cancer, or autoimmune diseases.
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http://dx.doi.org/10.4049/jimmunol.1502638DOI Listing
February 2017

Sepsis-induced expansion of granulocytic myeloid-derived suppressor cells promotes tumour growth through Toll-like receptor 4.

J Pathol 2016 08 23;239(4):473-83. Epub 2016 Jun 23.

Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.

Severe sepsis remains a frequent and dreaded complication in cancer patients. Beyond the often fatal short-term outcome, the long-term sequelae of severe sepsis may also impact directly on the prognosis of the underlying malignancy in survivors. The immune system is involved in all stages of tumour development, in the detection of transforming and dying cells and in the prevention of tumour growth and dissemination. In fact, the profound and sustained immune defects induced by sepsis may constitute a privileged environment likely to favour tumour growth. We investigated the impact of sepsis on malignant tumour growth in a double-hit animal model of polymicrobial peritonitis, followed by subcutaneous inoculation of MCA205 fibrosarcoma cells. As compared to their sham-operated counterparts, post-septic mice exhibited accelerated tumour growth. This was associated with intratumoural accumulation of CD11b(+) Ly6G(high) polymorphonuclear cells (PMNs) that could be characterized as granulocytic myeloid-derived suppressor cells (G-MDSCs). Depletion of granulocytic cells in post-septic mice inhibited the sepsis-enhanced tumour growth. Toll-like receptor (TLR)-4 (Tlr4) and Myd88 deficiencies prevented sepsis-induced expansion of G-MDSCs and tumour growth. Our results demonstrate that the myelosuppressive environment induced by severe bacterial infections promotes malignant tumour growth, and highlight a critical role of CD11b(+) Ly6G(high) G-MDSCs under the control of TLR-dependent signalling. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4744DOI Listing
August 2016

Foxo1 Is a T Cell-Intrinsic Inhibitor of the RORγt-Th17 Program.

J Immunol 2015 Aug 13;195(4):1791-803. Epub 2015 Jul 13.

INSERM U1016, Institut Cochin, 75014 Paris, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; andUniversité Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France

An uncontrolled exaggerated Th17 response can drive the onset of autoimmune and inflammatory diseases. In this study, we show that, in T cells, Foxo1 is a negative regulator of the Th17 program. Using mixed bone marrow chimeras and Foxo1-deficient mice, we demonstrate that this control is effective in vivo, as well as in vitro during differentiation assays of naive T cells with specific inhibitor of Foxo1 or inhibitors of the PI3K/Akt pathway acting upstream of Foxo1. Consistently, expressing this transcription factor in T cells strongly decreases Th17 generation in vitro as well as transcription of both IL-17A and IL-23R RORγt-target genes. Finally, at the molecular level, we demonstrate that Foxo1 forms a complex with RORγt via its DNA binding domain to inhibit RORγt activity. We conclude that Foxo1 is a direct antagonist of the RORγt-Th17 program acting in a T cell-intrinsic manner.
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http://dx.doi.org/10.4049/jimmunol.1500849DOI Listing
August 2015

Adaptive Immune-like γ/δ T Lymphocytes Share Many Common Features with Their α/β T Cell Counterparts.

J Immunol 2015 Aug 29;195(4):1449-58. Epub 2015 Jun 29.

Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Paris 75014, France; INSERM, U1016, Cochin Institute, Paris 75014, France; and Cochin Institute, Paris Descartes University, Paris 75014, France

To better apprehend γ/δ T cell biological functions in the periphery, it appears crucial to identify markers highlighting the existence of distinct phenotypic and functional γ/δ T cell subsets. Interestingly, the expression of CD44 and Ly-6C subdivides murine peripheral γ/δ T cells into several subsets, with Ly-6C(-) CD44(hi) γ/δ T cells corresponding to the IL-17-producing CD27(-) γ/δ T cell subset exhibiting innate-like features. By comparing the other subsets to naive and memory CD8(+) α/β T cells, in this study, we show that Ly-6C(- or +) CD44(lo) and Ly-6C(+)CD44(hi) γ/δ T cells greatly resemble, and behave like, their CD8(+) α/β T cell counterparts. First, like memory CD8(+) α/β T cells, Ly-6C(+)CD44(hi) γ/δ T cells are sparse in the thymus but largely increased in proportion in tissues. Second, similarly to naive CD8 α/β T cells, CD44(lo) γ/δ T cells are poorly cycling in vivo in the steady state, and their proportion declines with age in secondary lymphoid organs. Third, CD44(lo) γ/δ T cells undergo spontaneous proliferation and convert to a memory-like Ly-6C(+)CD44(hi) phenotype in response to lymphopenia. Finally, CD44(lo) γ/δ T cells have an intrinsic high plasticity as, upon appropriate stimulation, they are capable of differentiating nonetheless into Th17-like and Th1-like cells but also into fully functional Foxp3(+) induced regulatory T cell-like γ/δ T cells. Thus, peripheral CD27(+) γ/δ T cells, commonly considered as a functionally related T cell compartment, actually share many common features with adaptive α/β T cells, as both lineages include naive-like and memory-like lymphocytes with distinct phenotypic, functional, and homeostatic characteristics.
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http://dx.doi.org/10.4049/jimmunol.1500375DOI Listing
August 2015

TCR signaling events are required for maintaining CD4 regulatory T cell numbers and suppressive capacities in the periphery.

J Immunol 2014 Dec 7;193(12):5914-23. Epub 2014 Nov 7.

Institut Cochin, Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Université Paris Descartes, 75014 Paris, France

CD4 regulatory T cells (Tregs) can be subdivided into two subsets according to Ly-6C expression in the periphery. Phenotypic analysis, imaging, and adoptive-transfer experiments of peripheral Ly-6C(-) and Ly-6C(+) Tregs reveal that the nonexpression of Ly-6C by ∼70% of peripheral Tregs depends on TCR signaling events. Interestingly, Ly-6C(-) Tregs express higher surface amounts of key immunosuppressive molecules than do Ly-6C(+) Tregs and produce constitutively anti-inflammatory cytokines. In line with their phenotype, Ly-6C(+) Tregs exhibit poor suppressive capacities in vitro and in vivo. Finally, although Ly-6C(-) Tregs maintain their numbers with age, Ly-6C(+) Tregs gradually disappear. Altogether, our data strongly suggest that both the survival and suppressive functions of peripheral CD4 Tregs rely on their ability to receive strong TCR signals.
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http://dx.doi.org/10.4049/jimmunol.1400477DOI Listing
December 2014

Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells.

Nat Commun 2013 ;4:2209

CNRS UMR8104, Cochin Hospital, 75014 Paris, France.

Upon activation, naive CD4 T cells differentiate into a variety of T-helper-cell subsets characterized by different cytokine production and functions. Currently, lineage commitment is considered to depend mostly on the environmental context to which naive CD4 T cells are exposed. Here we challenge this model based on the supposed homogeneity of the naive CD4 T-cell compartment. We show that peripheral naive CD4 T cells can be subdivided into two subsets according to Ly-6C expression. Furthermore, the two newly defined subsets (Ly-6C(-) and Ly-6C(+) naive CD4 T cells) are not equal in their intrinsic ability to commit into the induced regulatory T-cell lineage. Finally, phenotypic analysis, imaging and adoptive transfer experiments reveal that Ly-6C expression is modulated by self-recognition, allowing the dichotomization of the naive CD4 T-cell compartment into two cell subsets with distinct self-reactivity. Altogether, our results show that naive CD4 T cells with the highest avidity for self are prone to differentiate into regulatory T cells.
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http://dx.doi.org/10.1038/ncomms3209DOI Listing
February 2014

Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+ T cells.

Proc Natl Acad Sci U S A 2013 Aug 22;110(32):13085-90. Epub 2013 Jul 22.

Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, and Paris Descartes University, Cochin Hospital, 75014 Paris, France.

The present study evaluates the impact of immune cell populations on metastatic development in a model of spontaneous melanoma [mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice)]. In this model, cancer cells disseminate early but remain dormant for several weeks. Then, MT/ret mice develop cutaneous metastases and, finally, distant metastases. A total of 35% of MT/ret mice develop a vitiligo, a skin depigmentation attributable to the lysis of normal melanocytes, associated with a delay in tumor progression. Here, we find that regulatory CD4(+) T cells accumulate in the skin, the spleen, and tumor-draining lymph nodes of MT/ret mice not developing vitiligo. Regulatory T-cell depletion and IL-10 neutralization led to increased occurrence of vitiligo that correlated with a decreased incidence of melanoma metastases. In contrast, inflammatory monocytes/dendritic cells accumulate in the skin of MT/ret mice with active vitiligo. Moreover, they inhibit tumor cell proliferation in vitro through a reactive oxygen species-dependent mechanism, and both their depletion and reactive oxygen species neutralization in vivo increased tumor cell dissemination. Altogether, our data suggest that regulatory CD4(+) T cells favor tumor progression, in part, by inhibiting recruitment and/or differentiation of inflammatory monocytes in the skin.
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http://dx.doi.org/10.1073/pnas.1300314110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740849PMC
August 2013

Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal.

Cell 2013 Apr;153(2):362-75

Centre for Molecular and Cellular Biology of Inflammation, King's College London, London SE1 1UL, UK.

The functions of Nr4a1-dependent Ly6C(low) monocytes remain enigmatic. We show that they are enriched within capillaries and scavenge microparticles from their lumenal side in a steady state. In the kidney cortex, perturbation of homeostasis by a TLR7-dependent nucleic acid "danger" signal, which may signify viral infection or local cell death, triggers Gαi-dependent intravascular retention of Ly6C(low) monocytes by the endothelium. Then, monocytes recruit neutrophils in a TLR7-dependent manner to mediate focal necrosis of endothelial cells, whereas the monocytes remove cellular debris. Prevention of Ly6C(low) monocyte development, crawling, or retention in Nr4a1(-/-), Itgal(-/-), and Tlr7(host-/-BM+/+) and Cx3cr1(-/-) mice, respectively, abolished neutrophil recruitment and endothelial killing. Prevention of neutrophil recruitment in Tlr7(host+/+BM-/-) mice or by neutrophil depletion also abolished endothelial cell necrosis. Therefore, Ly6C(low) monocytes are intravascular housekeepers that orchestrate the necrosis by neutrophils of endothelial cells that signal a local threat sensed via TLR7 followed by the in situ phagocytosis of cellular debris.
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http://dx.doi.org/10.1016/j.cell.2013.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898614PMC
April 2013

IL-2 and IL-7 determine the homeostatic balance between the regulatory and conventional CD4+ T cell compartments during peripheral T cell reconstitution.

J Immunol 2012 Oct 29;189(7):3339-46. Epub 2012 Aug 29.

Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Cochin Hospital, 75014 Paris, France.

Work over the last decades has led to the identification of the factors that influence the survival and homeostasis of conventional T cells. IL-7 and TCR signaling promote the survival of naive CD4(+) and CD8(+) T cells in lymphoreplete mice and their proliferation in a lymphopenic environment, whereas survival and homeostatic proliferation of memory CD4(+) and CD8(+) T cells crucially depend on a combination of IL-7 and IL-15. In contrast, there is little information regarding the factors driving the proliferation of regulatory CD4(+) T cells in response to lymphopenia. In this study, we investigated whether regulatory CD4(+) T cell proliferation in response to lymphopenia was guided by classical homeostatic resources, such as IL-2, IL-7, or TCR-MHC interactions. Altogether, our data suggest that, although homeostatic proliferation of conventional naive CD4(+) T cells is closely related to IL-7 levels, the proliferation of regulatory CD4(+) T cells in response to lymphopenia appears to be primarily controlled by IL-2. The capacity of IL-7 to augment conventional T cell proliferation with minimal concomitant regulatory T cell expansion may be clinically exploitable in the treatment of patients with lymphopenia, especially in the case of chronic viral diseases or cancer immunotherapy.
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http://dx.doi.org/10.4049/jimmunol.1103152DOI Listing
October 2012

Semaphorin 3A elevates endothelial cell permeability through PP2A inactivation.

J Cell Sci 2012 Sep 8;125(Pt 17):4137-46. Epub 2012 Jun 8.

Cnrs, UMR8104, 75014 Paris, France.

VE-cadherin-mediated cell-cell junction weakening increases paracellular permeability in response to both angiogenic and inflammatory stimuli. Although Semaphorin 3A has emerged as one of the few known anti-angiogenic factors to exhibit pro-permeability activity, little is known about how it triggers vascular leakage. Here we report that Semaphorin 3A induced VE-cadherin serine phosphorylation and internalisation, cell-cell junction destabilisation, and loss of barrier integrity in brain endothelial cells. In addition, high-grade glioma-isolated tumour-initiating cells were found to secrete Semaphorin 3A, which promoted brain endothelial monolayer permeability. From a mechanistic standpoint, Semaphorin 3A impinged upon the basal activity of the serine phosphatase PP2A and disrupted PP2A interaction with VE-cadherin, leading to cell-cell junction disorganization and increased permeability. Accordingly, both pharmacological inhibition and siRNA-based knockdown of PP2A mimicked Semaphorin 3A effects on VE-cadherin. Hence, local Semaphorin 3A production impacts on the PP2A/VE-cadherin equilibrium and contributes to elevated vascular permeability.
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http://dx.doi.org/10.1242/jcs.108282DOI Listing
September 2012

Foxp3-independent loss of regulatory CD4+ T-cell suppressive capacities induced by self-deprivation.

Eur J Immunol 2012 May;42(5):1237-49

CNRS UMR8104, Cochin Hospital, Paris, France.

In the periphery, Foxp3 expression is considered sufficient to maintain natural regulatory CD4(+) T-cell suppressive function. In this study, we challenge this model. Indeed, in mouse chimeras in which major histocompatibility complex (MHC) class II expression is restricted to the thymus, peripheral regulatory CD4(+) T cells lack suppressive activity. In addition, regulatory CD4(+) T cells recovered 5 days after transfer into recipient mice lacking expression of MHC class II molecules (self-deprived) are unable to inhibit the proliferative response of conventional CD4(+) T cells both in vitro and in vivo. Disruption of TCR/MHC class II interactions rapidly leads to alterations in the regulatory CD4(+) T-cell phenotype, the ability to respond to stimulation and to produce interleukin-10, and the transcriptional signature. Interestingly, self-deprivation does not affect Foxp3 expression indicating that in regulatory CD4(+) T cells, self-recognition induces unique transcriptional and functional features that do not rely on Foxp3 expression.
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http://dx.doi.org/10.1002/eji.201142148DOI Listing
May 2012

Lymphopenia-induced spontaneous T-cell proliferation as a cofactor for autoimmune disease development.

Blood 2009 Aug 26;114(9):1784-93. Epub 2009 Jun 26.

Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Cochin Hospital, Paris, France.

Lymphopenia is thought to be a major cause of tolerance breakdown. In a lymphopenic environment, self-recognition events induce some T cells to expand strongly (a mechanism known as spontaneous proliferation). In this study, we show that in C57BL/6 mice, the repertoire resulting from lymphopenia-induced spontaneous CD4(+) T-cell proliferation included a proportion of regulatory T cells as large as that observed in a normal mouse, and no autoimmune disorder was observed. By contrast, in nonobese diabetic mice, differences in the ability of conventional and regulatory T cells to expand in response to lymphopenia led to an unbalance between these 2 T-cell compartments at the expense of regulatory T cells, resulting in the onset of autoimmune diseases. Notably, this accounted for the rapid transfer of diabetes with small numbers of BDC2.5 CD4(+) T cells. Thus, lymphopenia does not itself induce autoimmunity, but it should be considered as a cofactor for the development of autoimmune disorders.
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http://dx.doi.org/10.1182/blood-2008-12-192120DOI Listing
August 2009

CX3CR1+ CD115+ CD135+ common macrophage/DC precursors and the role of CX3CR1 in their response to inflammation.

J Exp Med 2009 Mar 9;206(3):595-606. Epub 2009 Mar 9.

Laboratory of Biology of the Mononuclear Phagocyte System, Institut National de la Santé et de la Recherche Médicale U838, Université Paris-Descartes, 75015 Paris, France.

CX(3)CR1 expression is associated with the commitment of CSF-1R(+) myeloid precursors to the macrophage/dendritic cell (DC) lineage. However, the relationship of the CSF-1R(+) CX(3)CR1(+) macrophage/DC precursor (MDP) with other DC precursors and the role of CX(3)CR1 in macrophage and DC development remain unclear. We show that MDPs give rise to conventional DCs (cDCs), plasmacytoid DCs (PDCs), and monocytes, including Gr1(+) inflammatory monocytes that differentiate into TipDCs during infection. CX(3)CR1 deficiency selectively impairs the recruitment of blood Gr1(+) monocytes in the spleen after transfer and during acute Listeria monocytogenes infection but does not affect the development of monocytes, cDCs, and PDCs.
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http://dx.doi.org/10.1084/jem.20081385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699130PMC
March 2009

Blood monocytes: development, heterogeneity, and relationship with dendritic cells.

Annu Rev Immunol 2009 ;27:669-92

INSERM U838, Université Paris-Descartes, 75015 Paris, France.

Monocytes are circulating blood leukocytes that play important roles in the inflammatory response, which is essential for the innate response to pathogens. But inflammation and monocytes are also involved in the pathogenesis of inflammatory diseases, including atherosclerosis. In adult mice, monocytes originate in the bone marrow in a Csf-1R (MCSF-R, CD115)-dependent manner from a hematopoietic precursor common for monocytes and several subsets of macrophages and dendritic cells (DCs). Monocyte heterogeneity has long been recognized, but in recent years investigators have identified three functional subsets of human monocytes and two subsets of mouse monocytes that exert specific roles in homeostasis and inflammation in vivo, reminiscent of those of the previously described classically and alternatively activated macrophages. Functional characterization of monocytes is in progress in humans and rodents and will provide a better understanding of the pathophysiology of inflammation.
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http://dx.doi.org/10.1146/annurev.immunol.021908.132557DOI Listing
May 2009

Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell responses.

Immunol Cell Biol 2008 Jul 8;86(5):398-408. Epub 2008 Apr 8.

INSERM U838, Paris, France.

Monocytes can have important effects on the polarization and expansion of lymphocytes and may contribute to shaping primary and memory T-cell responses in humans and mice. However, their precise contribution in terms of cellular subsets and the molecular mechanisms involved remains to be determined. Mouse monocytes originate from a bone marrow progenitor, the macrophage and DC precursor (MDP), which also gives rise to conventional dendritic cells through a separate differentiation pathway. Mouse monocytes may be grouped in different functional subsets. The CD115(+) Gr1(+) 'inflammatory' monocyte subset can give rise not only to immunostimulatory 'TipDCs' in infected mice but also to immunosuppressive 'myeloid-derived suppressor cells' in tumor-bearing mice. CD115(+) Gr1(+) monocytes can also contribute to the renewal of several resident subsets of macrophages and DCs, such as microglia and Langerhans cells, in inflammatory conditions. The CD115(+) Gr1(-) 'resident' monocyte subset patrols blood vessels in the steady state and extravasates during infection with Listeria monocytogenes or in the healing myocardium. CD115(+) Gr1(-) monocytes are responsible for an early and transient inflammatory burst during Lm infection, which may play a role in the recruitment of other effector cells and subsequently differentiate toward 'M2'-like macrophages that may be involved in wound healing. More research will no doubt confirm the existence of more functional subsets, the developmental relationship between mouse subsets as well as the correspondence between mouse subsets and human subsets of monocytes. We will discuss here the potential roles of monocytes in the immune response, the existence of functional subsets and their relationship with other myeloid cells, including dendritic cells.
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http://dx.doi.org/10.1038/icb.2008.19DOI Listing
July 2008

Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior.

Science 2007 Aug;317(5838):666-70

Institut Nationale de la Santé et de la Recherche Médicale (INSERM) U838, Laboratory of Biology of the Mononuclear Phagocyte System, and Cellular and Molecular imaging core facility, Institut Fédératif de Recherche Necker-Enfants Malades, Paris, France.

The cellular immune response to tissue damage and infection requires the recruitment of blood leukocytes. This process is mediated through a classical multistep mechanism, which involves transient rolling on the endothelium and recognition of inflammation followed by extravasation. We have shown, by direct examination of blood monocyte functions in vivo, that a subset of monocytes patrols healthy tissues through long-range crawling on the resting endothelium. This patrolling behavior depended on the integrin LFA-1 and the chemokine receptor CX(3)CR1 and was required for rapid tissue invasion at the site of an infection by this "resident" monocyte population, which initiated an early immune response and differentiated into macrophages.
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http://dx.doi.org/10.1126/science.1142883DOI Listing
August 2007

Heterogeneity of class I INS VNTR allele association with insulin secretion in obese children.

Physiol Genomics 2006 May 28;25(3):480-4. Epub 2006 Mar 28.

Pediatric Endocrinology and U561, Institut National de la Santé et de la Recherche Médicale, Hôpital Saint-Vincent de Paul, Paris V University, Paris, France.

On the basis of the near-complete linkage disequilibrium of the insulin variable number of tandem repeats (INS VNTR) allele with the neighboring -23Hph1 A/T single-nucleotide polymorphism, previous studies have documented the association of class I ("short") and class III ("long") INS VNTR alleles with metabolic parameters, including circulating insulin levels. Using a new method to sequence class I alleles, we revisited this association in 346 obese children. Class I alleles are made of several types of repeats, whose repartition determines subclasses IC and ID. Fasting insulin was found to be higher in obese children with ID/ID genotypes (135 +/- 12 pmol/l, n = 64) than with ID/IC or IC/IC genotypes (91 +/- 5 pmol/l, n = 97, P = 0.0005). In response to oral glucose, peak insulin levels and insulin-to-glucose area under the curve ratios were higher in ID/ID (872 +/- 122 pmol/l and 109 +/- 15, respectively) than in ID/IC or IC/IC patients (586 +/- 42 pmol/l and 76 +/- 5, P = 0.02 and P = 0.04, respectively). Fasting and postglucose insulin levels were comparable in carriers of IC and of class III alleles. Our results support that the molecular structure of the VNTR allele, not only its overall length, is associated with variations of insulin secretion. ID/ID homozygosity appears responsible for the increased insulin levels previously attributed to the whole class I VNTR group. It will be important to test the ramifications of this observation for class I association with Type 1 (susceptibility) and Type 2 diabetes (protection).
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http://dx.doi.org/10.1152/physiolgenomics.00311.2005DOI Listing
May 2006

An 8-bp deletion in mNOTCH4 intron 10 leads to its retention in mRNA and to synthesis of a truncated protein.

Exp Cell Res 2006 Feb 21;312(3):233-44. Epub 2005 Nov 21.

INSERM U561, Hôpital St. Vincent de Paul, 82 Avenue Denfert Rochereau, Paris 75014, France.

Notch signaling participates in the development of multicellular organisms by maintaining self-renewal potential or inducing differentiation of numerous tissues. In this study, we characterized Notch4, the evolutionary most distant and least studied Notch family member. We identified a Notch4 inter-strain polymorphism with a previously undescribed mRNA variant. This longer Notch4 mRNA, which represented up to one-third of total Notch4 mRNA, resulted from intron 10 retention. Analysis of Notch4 intron 10 revealed that an 8-bp deletion, reducing its length from 68 to 60 bp, strictly correlated with its retention. Further experiments demonstrated that intron length was the only cause of the mis-splicing. Moreover, this mRNA variant resulted in a truncated protein containing half the extracellular domain of Notch4, including the ligand-binding domain.
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http://dx.doi.org/10.1016/j.yexcr.2005.10.014DOI Listing
February 2006

Peripheral CD8+CD25+ T lymphocytes from MHC class II-deficient mice exhibit regulatory activity.

J Immunol 2005 Jul;175(1):246-53

Institut National de la Santé et de la Recherche Médicale U561, Hôpital Saint Vincent de Paul, Paris, France.

We characterized CD8(+) T cells constitutively expressing CD25 in mice lacking the expression of MHC class II molecules. We showed that these cells are present not only in the periphery but also in the thymus. Like CD4(+)CD25(+) T cells, CD8(+)CD25(+) T cells appear late in the periphery during ontogeny. Peripheral CD8(+)CD25(+) T cells from MHC class II-deficient mice also share phenotypic and functional features with regulatory CD4(+)CD25(+) T cells: in particular, they strongly express glucocorticoid-induced TNFR family-related gene, CTLA-4 and Foxp3, produce IL-10, and inhibit CD25(-) T cell responses to anti-CD3 stimulation through cell contacts with similar efficiency to CD4(+)CD25(+) T cells. However, unlike CD4(+)CD25(+) T cells CD8(+)CD25(+) T cells from MHC class II-deficient mice strongly proliferate and produce IFN-gamma in vitro in response to stimulation in the absence of exogenous IL-2.
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http://dx.doi.org/10.4049/jimmunol.175.1.246DOI Listing
July 2005