Honors & Awards


  • Fond de perfectionnement, Geneva University Hospitals (2016)
  • Postdoctoral Fellowship, Swiss Cancer League (2017)
  • Eugenio Litta Fellowship, Fondation Genevoise de bienfaisance Valeria Rossi di Montelera (2018)
  • New Investigator Award, American Society for Blood and Marrow Transplantation (ASBMT) (2018-2019)
  • Best Abstract Award, TCT-Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR (2019)

Boards, Advisory Committees, Professional Organizations


  • Member of the Scientific Committee, Swiss Transplant Cohort Study (STCS) (2018 - Present)
  • Member, American Society for Transplantation and Cellular Therapy (2018 - Present)

Professional Education


  • Doctor of Medicine, Universita Degli Studi Di Genova (2006)
  • Master of Science, Universite De Paris Vii (2007)
  • Doctor of Philosophy, Universite De Paris Xi (Paris-Sud) (2011)
  • Internship, Internal Medicine, Hôpital du Jura Bernois, Moutier, Switzerland, (2011-2012)
  • Residency, Internal Medicine, Geneva University Hospitals, Switzerland, (2012-2014)
  • Fellowship, Hematology, Geneva University Hospitals, Switzerland, (2014-2016)

Stanford Advisors


All Publications


  • Activation of the DR3-TL1A Axis in Donor Mice Leads to Regulatory T Cell Expansion and Activation With Reduction in Graft-Versus-Host Disease FRONTIERS IN IMMUNOLOGY Mavers, M., Simonetta, F., Nishikii, H., Ribado, J., Maas-Bauer, K., Alvarez, M., Hirai, T., Turkoz, M., Baker, J., Negrin, R. S. 2019; 10
  • Dynamics of Expression of Programmed Cell Death Protein-1 (PD-1) on T Cells After Allogeneic Hematopoietic Stem Cell Transplantation FRONTIERS IN IMMUNOLOGY Simonetta, F., Pradier, A., Bosshard, C., Masouridi-Levrat, S., Dantin, C., Koutsi, A., Tirefort, Y., Roosnek, E., Chalandon, Y. 2019; 10: 1034

    Abstract

    Immune exhaustion contributes to treatment failure after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Immune checkpoint blockade, including programmed cell death protein-1 (PD-1) blockade, is a promising strategy to improve the antitumor effect of allogeneic HSCT with high rates of response reported in patients treated for disease relapse. However, severe and sometimes fatal Graft- vs.-Host-Disease (GvHD) has been reported as a complication. Little is known about the dynamics of PD-1 expression on immune effector cells after allogeneic HSCT. In the present study, we analyzed PD-1 expression on T cell subpopulations isolated from 105 allogeneic HSCT recipients. Our analysis revealed a significant increase in proportions of PD-1-expressing CD4 and CD8 T cells early after allogeneic HSCT followed by a progressive normalization of PD-1 expression at CD8 but not CD4 T cell surface. Analysis of co-expression of two other exhaustion markers, 2B4 and CD160, revealed a preferential expansion of PD-1-single positive cells. Moreover, the analysis of granzyme B and perforin expression in PD-1+ and PD-1- CD8 T cells from HSCT recipients did not reveal any impairment in cytotoxic molecules production by PD-1-expressing CD8 T cells. Analyzing the association between clinical factors and the expression of PD-1 on T cells, we identified the use of in vivo and/or ex vivo T-cell depletion as the factor most strongly associated with elevated PD-1 levels on T cells. Our results extend our knowledge of the regulation of PD-1 expression at T cell surface after allogeneic HSCT, a crucial information for the optimization of post-transplantation PD-1 blocking therapies.

    View details for DOI 10.3389/fimmu.2019.01034

    View details for Web of Science ID 000468113100001

    View details for PubMedID 31156625

    View details for PubMedCentralID PMC6531929

  • Engineered immune cells as highly sensitive cancer diagnostics NATURE BIOTECHNOLOGY Aalipour, A., Chuang, H., Murty, S., D'Souza, A. L., Park, S., Gulati, G. S., Patel, C. B., Beinat, C., Simonetta, F., Martinic, I., Gowrishankar, G., Robinson, E. R., Aalipour, E., Zhian, Z., Gambhir, S. S. 2019; 37 (5): 531-+
  • Activation of the DR3-TL1A Axis in Donor Mice Leads to Regulatory T Cell Expansion and Activation With Reduction in Graft-Versus-Host Disease. Frontiers in immunology Mavers, M., Simonetta, F., Nishikii, H., Ribado, J. V., Maas-Bauer, K., Alvarez, M., Hirai, T., Turkoz, M., Baker, J., Negrin, R. S. 2019; 10: 1624

    Abstract

    Death receptor 3 (DR3) is a tumor necrosis factor receptor superfamily member (TNFRSF25), which is minimally expressed on resting conventional T cells (though readily inducible upon cell activation), yet highly expressed on resting FoxP3+ regulatory T cells (Treg). We recently demonstrated that activation of DR3 with an agonistic antibody (4C12) leads to selective expansion and activation of Treg in healthy mice and suppression of graft-versus-host disease (GVHD) in recipient mice when donor mice are treated. However, given the long antibody half-life and concomitant safety concerns, along with the lack of a humanized agonistic antibody to DR3, both human and murine fusion proteins incorporating the natural DR3 ligand TL1A (TL1A-Ig) have been developed. Herein, we show that DR3 activation with 4C12 or with TL1A-Ig, with or without the addition of low dose IL-2 to the treatment regimen, led to a significant expansion of murine Treg in spleen, lymph nodes, and peripheral blood. Bioluminescent imaging revealed peak Treg expansion around day 7-8, with return to near baseline after 2-3 weeks. In addition to expansion, all DR3 agonist treatment regimens led to increased activation of Tregs, with significant upregulation of the activation markers ICOS, KLRG-1, PD-1, and CD103, and the proliferation marker Ki-67. The near absence of activated Treg populations in control treated spleens was also detected on tSNE analysis of flow cytometry data. Subtly different patterns of splenic Treg activation by the different DR3 agonists were noted in both tSNE analysis of flow cytometry data and RNA-sequencing analysis. However, upregulation of gene transcripts which play important roles in cell proliferation, trafficking, activation, and effector function were observed regardless of the DR3 agonist treatment regimen used. In the major MHC-mismatch model of hematopoietic cell transplantation, DR3 agonist-mediated expansion and activation of Tregs in donor mice led to a significant improvement in GVHD in recipient mice. These data provide important preclinical information regarding the outcome of DR3 activation with an agonistic antibody or natural ligand and provide insight into the therapeutic use of this approach to reduce GVHD in recipients and improve outcomes of hematopoietic cell transplantation.

    View details for DOI 10.3389/fimmu.2019.01624

    View details for PubMedID 31379829

    View details for PubMedCentralID PMC6652149

  • A rare case of immune thrombocytopenia secondary to breast cancer. Clinical case reports Hugli, S., Hugli, A., Simonetta, F., Chalandon, Y. 2019; 7 (1): 170–74

    Abstract

    Immune Thrombocytopenic Purpura (ITP) is in rare cases secondary to solid tumors, particularly breast cancer. In these cases, the clinical course of the ITP may follow the clinical course of the primary tumor, and remission of the ITP may be induced by treatment of the primary tumor.

    View details for PubMedID 30656035

  • Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway. JCI insight Alvarez, M., Simonetta, F., Baker, J., Pierini, A., Wenokur, A. S., Morrison, A. R., Murphy, W. J., Negrin, R. S. 2019; 5

    Abstract

    NK cell exhaustion (NCE) due to sustained proliferation results in impaired NK cell function with loss of cytokine production and lytic activity. Using murine models of chronic NK cell stimulation, we have identified a phenotypic signature of NCE characterized by up-regulation of the terminal differentiation marker KLRG1 and by down-regulation of eomesodermin and the activating receptor NKG2D. Chronic stimulation of mice lacking NKG2D resulted in minimized NCE compared to control mice, thus identifying NKG2D as a crucial mediator of NCE. NKG2D internalization and downregulations on NK cells has been previously observed in the presence of tumor cells with high expression of NKG2D ligands (NKG2DL) due to the activation of the DNA damage repair pathways. Interestingly, our study revealed that during NK cell activation there is an increase of MULT1, and NKG2DL, that correlates with an induction of DNA damage. Treatment with the ATM DNA damage repair pathway inhibitor KU55933 (KU) during activation reduced NCE by improving expression of activation markers and genes involved in cell survival, by sustaining NKG2D expression and by preserving cell functionality. Importantly, NK cells expanded ex vivo in the presence of KU displayed increased anti-tumor efficacy in both NKG2D-dependent and -independent mouse models. Collectively, these data demonstrate that NCE is caused by DNA damage and regulated, at least in part, by NKG2D. Further, the prevention of NCE is a promising strategy to improve NK cell-based immunotherapy.

    View details for DOI 10.1172/jci.insight.127729

    View details for PubMedID 31211693

  • Invariant Natural Killer T Cell Subsets Have Diverse Functions: iNKT2 and iNKT17 Protect from Graft-Versus-Host-Disease, Whereas iNKT1 Have Antitumor Potential Maas-Bauer, K., Simonetta, F., Hirai, T., Wenokur, A., Fazal, F., Kambham, N., Ribado, J., Mavers, M., Baker, J., Bhatt, A. S., Chang, H. Y., Negrin, R. S. AMER SOC HEMATOLOGY. 2018
  • Tracking T Cell Activation By OX40 Immuno-PET: A Novel Strategy for Imaging of Graft Versus Host Disease Simonetta, F., Alam, I. S., Mayer, A. T., Murty, S., Vermesh, O., Hirai, T., Nobashi, T., Lau, K., Gambhir, S. S., Negrin, R. S. AMER SOC HEMATOLOGY. 2018
  • Treatment of Donors with Death Receptor 3 Agonistic Fusion Protein TL1A-Ig (with and Without Low Dose IL-2) Leads to Regulatory T Cell Expansion and Activation with Reduction in Graft-Versus-Host Disease Mayers, M., Maas-Bauer, K., Nishikii, H., Simonetta, F., Alvarez, M., Hirai, T., Turkoz, M., Baker, J., Negrin, R. S. ELSEVIER SCIENCE INC. 2018: S191–S192
  • IL-2 Plus IL-15 Leads to Enhanced Ex Vivo Expansion of Human Invariant Natural Killer T Cells Mayers, M., Simonetta, F., Lee, A. W., Hirai, T., Maas-Bauer, K., Alvarez, M., Turkoz, M., Baker, J., Meyer, E., Negrin, R. S. ELSEVIER SCIENCE INC. 2018: S166–S167
  • Impact of T-cell depletion on outcome of patients undergoing allogeneic hematopoietic cell transplantation for myelodysplastic syndrome. Bone marrow transplantation Raboud, M., Beauverd, Y., Simonetta, F., Dantin, C., Pradier, A., Tsopra, O., Koutsi, A., Mamez, A. C., Stephan, C., Rodriguez Morales, J. F., Polchlopek-Blasiak, K., Tirefort, Y., Masouridi-Levrat, S., Chalandon, Y. 2018

    View details for DOI 10.1038/s41409-018-0136-2

    View details for PubMedID 29515245

  • Human pegivirus persistence in the human blood virome after allogeneic haematopoietic stem cell transplantation. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases Vu, D. L., Cordey, S., Simonetta, F., Brito, F., Docquier, M., Turin, L., van Delden, C., Boely, E., Dantin, C., Pradier, A., Roosnek, E., Chalandon, Y., Zdobnov, E. M., Masouridi-Levrat, S., Kaiser, L. 2018

    Abstract

    As commensal viruses are defined by the immunological tolerance afforded to them, any immunomodulation, such as is received during haematopoietic stem cell transplantation, may shift the demarcation between innocuous viral resident and disease-causing pathogen.We analysed by deep-sequencing the plasma virome of 40 allogeneic haematopoietic stem cell transplant (allo-HSCT) patients 1 month post-transplantation. As human pegivirus (HPgV) was highly prevalent, we performed a one-year screening of 122 plasma samples by specific rRT-PCR assay. We used log rank test and the Gray test to assess association with outcomes and Mann-Whitney test and multivariable linear regression model to assess association with T-cell reconstitution.Polyomaviruses (PyV) (20/40 patients), anelloviruses (16/40), pegiviruses (14/40) and herpesviruses (14/40) were most frequently identified, including 10 cytomegalovirus, 3 Epstein-Barr, 2 herpes simplex-1, 1 human herpesvirus (HHV)-6b and 1 HHV-7; 18 Merkel cell-PyV, 2 BK-PyV, 3 PyV-6 and 1 JC-PyV. Papillomavirus and adenovirus were identified in 11 and 2 patients, respectively. The HPgV-specific rRT-PCR screening identified 51/122 positive samples, high viral loads and persistent infections up to one year post-transplantation. Comparison between patients with or without HPgV infection at time of transplantation didn't reveal significant difference in infections, engraftment, survival, graft-versus-host disease, relapse or immune reconstitution.The blood virome after allo-HSCT includes several DNA viruses notably herpesviruses and polyomaviruses. Among RNA viruses, HPgV is highly prevalent, persisting for several months and thus may deserve special attention in further research on immune reconstitution.

    View details for DOI 10.1016/j.cmi.2018.05.004

    View details for PubMedID 29787887

  • Central nervous system graft-versus-host disease (CNS-GvHD) after allogeneic haematopoietic stem cell transplantation. BMJ case reports Polchlopek Blasiak, K., Simonetta, F., Vargas, M. I., Chalandon, Y. 2018; 2018

    Abstract

    A 60-year-old man presented with impaired consciousness and psychomotor agitation after a second allogeneic haematopoietic stem cell transplantation (HSCT) from a matched unrelated donor for acute myeloid leukaemia. Clinical, biological and radiological evidence suggested a diagnosis of central nervous system graft-versus-host disease (CNS-GvHD). After intrathecal infusion of methylprednisolone, the clinical symptoms as well as the radiological abnormalities disappeared. The present report illustrates the difficulties in the diagnosis and the management of CNS-GvHD, a very rare and still challenging neurological complication that can occur after allogeneic HSCT.

    View details for DOI 10.1136/bcr-2017-221840

    View details for PubMedID 29330269

  • Natural Killer Cells in Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation FRONTIERS IN IMMUNOLOGY Simonetta, F., Alvarez, M., Negrin, R. S. 2017; 8

    Abstract

    Allogeneic hematopoietic cell transplantation (HCT) is a well-established therapeutic modality effective for a variety of hematological malignancies but, unfortunately, is associated with significant morbidity and mortality related to cancer relapse as well as to transplant-related complications including graft-versus-host-disease (GvHD). Natural killer (NK) cells are the first donor-derived lymphocyte subset to recover after HCT, and their crucial role in protection against cancer relapse and infections is well established. Conversely, the role played by NK cells in GvHD is still controversial. Early studies suggested a participation of NK cells in GvHD induction or exacerbation. Subsequently, experimental evidence obtained in mice as well observational studies performed in humans led to a model in which NK cells play a regulatory role in GvHD by repressing alloreactive T cell responses. This widely accepted model has been recently challenged by clinical evidence indicating that NK cells can in some cases promote GvHD. In this review, we summarize available knowledge about the role of NK cells in GVHD pathogenesis. We review studies uncovering cellular mechanisms through which NK cells interact with other immune cell subsets during GvHD leading to a model in which NK cells naturally suppress GvHD through their cytotoxic ability to inhibit T cell activation unless exogenous hyperactivation lead them to produce proinflammatory cytokines that can conversely sustain T cell-mediated GvHD induction.

    View details for DOI 10.3389/fimmu.2017.00465

    View details for PubMedID 28487696

  • Torque Teno Virus Load and Acute Rejection after Orthotopic Liver Transplantation. Transplantation Simonetta, F., Pradier, A., Masouridi-Levrat, S., van Delden, C., Giostra, E., Morard, I., Müller, N., Müllhaupt, B., Valli, P. V., Semmo, N., Seebach, J., Chalandon, Y., Kaiser, L., Roosnek, E. 2017

    View details for DOI 10.1097/TP.0000000000001723

    View details for PubMedID 28263221

  • Partial T-cell depletion improves the composite endpoint graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic stem cell transplantation. Leukemia & lymphoma Simonetta, F., Masouridi-Levrat, S., Beauverd, Y., Tsopra, O., Tirefort, Y., Koutsi, A., Stephan, C., Polchlopek-Blasiak, K., Pradier, A., Dantin, C., Ansari, M., Roosnek, E., Chalandon, Y. 2017: 1–11

    Abstract

    Graft-versus-host disease (GvHD)-free, relapse-free survival (GRFS) is a recently reported composite endpoint that allows to simultaneously estimate risk of death, relapse and GvHD after allogeneic hematopoietic stem cell transplantation (HSCT). In this retrospective study comprising 333 patients transplanted for hematologic malignancies, we compared GRFS in patients receiving partial T-cell-depleted (pTCD) grafts with patients receiving T-cell-replete grafts (No-TCD). pTCD was associated with a significantly improved GRFS. The beneficial effect of pTCD on GRFS remained highly significant in multivariable analysis taking into account clinical factors differing between patient groups. We observed no effect of pTCD on overall survival, progression-free survival, and relapse cumulative incidence, while non-relapse mortality cumulative incidence was significantly lower in patients receiving pTCD. The results of our retrospective analysis suggest that pTCD could improve GRFS in allogeneic HSCT recipients without significantly affecting OS and PFS, thus improving patients' quality of life without impairing the curative potential of allogeneic HSCT.

    View details for DOI 10.1080/10428194.2017.1344844

    View details for PubMedID 28679328

  • [Reactive hemophagocytic syndrome]. Revue medicale suisse Novotny, F., Simonetta, F., Samii, K., Chalandon, Y., Serratrice, J. 2017; 13 (579): 1797–1803

    Abstract

    The reactive hemophagocytic syndrome comes from an overstimulation of the immune system which causes a cytokine storm. This is a life-threatening condition caracterised by a febrile cytopenia, hepatosplenomegaly and multi-organ failure. The diagnosis is not easy and the HScore can be useful, looking at hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia. The evidence of hemophagocytosis in the bone marrow is not necessary nor sufficient to make the diagnosis but is part of the workup. The underlying cause has to be actively sought, typically an infectious, malignant or autoimmune disorder. This syndrome should be supported in conjunction with the hematologist, and initiation of a treatment is a medical emergency.

    View details for PubMedID 29064197

  • T-bet and Eomesodermin in NK Cell Development, Maturation, and Function FRONTIERS IN IMMUNOLOGY Simonetta, F., Pradier, A., Roosnek, E. 2016; 7

    Abstract

    Recent reports give insights into the role of the T-box transcription factors, T-bet and Eomesodermin (Eomes), in NK cell biology. In this mini-review, we recapitulate the initial reports that delineate T-bet and Eomes as master regulators of NK cell development, maturation, and function. We discuss how T-bet and Eomes expression is regulated during NK cell development and peripheral maturation. Furthermore, we summarize the current literature on the role of T-bet and Eomes in the transcriptional regulation of NK cell function and review possible effects of T-box transcription factor anomalies during aging, infection, cancer, and after hematopoietic stem cell transplantation. We discuss how the current data argue in favor of a model of T-bet and Eomes synergy in transcriptional regulation of NK cell function and identify T-box transcription factors as potential targets for therapeutic interventions.

    View details for DOI 10.3389/fimmu.2016.00241

    View details for Web of Science ID 000378376500001

    View details for PubMedID 27379101

  • Excellent outcome with a high proportion of mixed chimerism in patients with severe aplastic anemia treated with partially T-cell-depleted peripheral hematopoietic stem cell transplants BONE MARROW TRANSPLANTATION Masouridi-Levrat, S., Simonetta, F., Beauverd, Y., Tsopra, O., Tirefort, Y., Stephan, C., Levrat, E., Ansari, M., Verholen, F., Roosnek, E., Passweg, J. R., Chalandon, Y. 2016; 51 (6): 860-862

    View details for DOI 10.1038/bmt.2015.356

    View details for Web of Science ID 000376827900021

    View details for PubMedID 26855156

  • Torque teno virus in patients undergoing allogeneic hematopoietic stem cell transplantation for hematological malignancies BONE MARROW TRANSPLANTATION Masouridi-Levrat, S., Pradier, A., Simonetta, F., Kaiser, L., Chalandon, Y., Roosnek, E. 2016; 51 (3): 440-442

    View details for DOI 10.1038/bmt.2015.262

    View details for Web of Science ID 000371357500023

    View details for PubMedID 26551776

  • Reversible encephalopathy with photoparoxysmal response during imipenem/cilastatin treatment JOURNAL OF THE NEUROLOGICAL SCIENCES Gschwind, M., Simonetta, F., Vulliemoz, S. 2016; 360: 23-24

    View details for DOI 10.1016/j.jns.2015.11.038

    View details for Web of Science ID 000369681100006

    View details for PubMedID 26723966

  • Successful treatment of refractory lupus nephritis by the sequential use of rituximab and belimumab. Joint, bone, spine : revue du rhumatisme Simonetta, F., Allali, D., Roux-Lombard, P., Chizzolini, C. 2016

    View details for DOI 10.1016/j.jbspin.2016.01.008

    View details for PubMedID 27238199

  • Immunological Basis of Bone Marrow Failure after Allogeneic Hematopoietic Stem Cell Transplantation. Frontiers in immunology Masouridi-Levrat, S., Simonetta, F., Chalandon, Y. 2016; 7: 362

    Abstract

    Bone marrow failure (BMF) syndromes are severe complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this paper, we distinguish two different entities, the graft failure (GF) and the poor graft function (PGF), and we review the current understanding of the interactions between the immune and hematopoietic compartments in these conditions. We first discuss how GF occurs as the result of classical alloreactive immune responses mediated by residual host cellular and humoral immunity persisting after conditioning and prevented by host and donor regulatory T cells. We next summarize the current knowledge about the contribution of inflammatory mediators to the development of PGF. In situations of chronic inflammation complicating allo-HSCT, such as graft-versus-host disease or infections, PGF seems to be essentially the result of a sustained impairment of hematopoietic stem cells (HSC) self-renewal and proliferation caused by inflammatory mediators, such as interferon-γ (IFN-γ) and tumor necrosis factor-α, and of induction of apoptosis through the Fas/Fas ligand pathway. Interestingly, the production of inflammatory molecules leads to a non-MHC restricted, bystander inhibition of hematopoiesis, therefore, representing a promising target for immunological interventions. Finally, we discuss immune-mediated impairment of bone marrow microenvironment as a potential mechanism hampering hematopoietic recovery. Better understanding of immunological mechanisms responsible for BMF syndromes after allo-HSCT may lead to the development of more efficient immunotherapeutic interventions.

    View details for DOI 10.3389/fimmu.2016.00362

    View details for PubMedID 27695456

  • Modulation of T-bet and Eomes during Maturation of Peripheral Blood NK Cells Does Not Depend on Licensing/Educating KIR. Frontiers in immunology Pradier, A., Simonetta, F., Waldvogel, S., Bosshard, C., Tiercy, J., Roosnek, E. 2016; 7: 299-?

    Abstract

    Peripheral natural killer (NK) cells upregulate T-bet and downregulate Eomes, the key transcription factors regulating NK cell maturation and function during the last maturation steps toward terminally differentiated effector cells. During this process, NK cells acquire killer immunoglobulin-like receptors (KIR) and effector functions, such as cytotoxicity and target cell-induced cytokine production. Inhibitory KIR are pivotal in the control of effector functions, but whether they also modulate T-bet/Eomes expression is unknown. We have measured T-bet/Eomes levels, KIR expression, and effector functions of maturing CD94(neg)CD56(dim)NK cells using CD57 as surface marker for maturation. Our cohort consisted of 23 healthy blood donors (HBD) homozygous for the KIR A haplotype that contains only inhibitory KIR2DL1 (ligand HLA-C2), KIR2DL3 (ligand HLA-C1), and KIR3DL1 (ligand HLA-Bw4). We confirm that during maturation of NK cells, the number of KIR increases, levels of T-bet/Eomes are modulated, and that cells acquire effector functions, such as cytotoxicity (CD107) and target cell-induced cytokine production (TNF-α). Because maturation was associated with the increase of the number of KIR as well as with the modulation of T-bet/Eomes, the number of KIR correlated with the extent of T-bet/Eomes modulation. However, whether the KIR were triggered by their cognate HLA ligands or not had no impact on T-bet and Eomes expression, indicating that modulation of T-box transcription factors during NK cell maturation does not depend on signals conveyed by KIR. We discuss the relevance of this finding in the context of models of NK cell maturation while cautioning that results obtained in a perhaps quite heterogeneous cohort of HBD are not necessarily conclusive.

    View details for DOI 10.3389/fimmu.2016.00299

    View details for PubMedID 27605928

  • NK Cell Functional Impairment after Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Reduced Levels of T-bet and Eomesodermin JOURNAL OF IMMUNOLOGY Simonetta, F., Pradier, A., Bosshard, C., Masouridi-Levrat, S., Chalandon, Y., Roosnek, E. 2015; 195 (10): 4712-4720

    Abstract

    NK cells play a major role in protection against tumor recurrence and infection after allogeneic hematopoietic stem cell transplantation (HSCT). It has been shown that NK cell function after HSCT is impaired, but underlying molecular mechanisms are not well-known. In this report we show that the level of T-bet and Eomesodermin (Eomes), two T-box transcription factors regulating lymphocyte effector functions, is strongly reduced in NK cells from HSCT recipients compared with healthy control subjects. Reduction of T-bet and Eomes expression appeared early and persisted for years after HSCT, affecting all peripheral blood NK cells independently of their differentiation status. Reduced T-bet levels in NK cells from allogeneic HSCT recipients significantly correlated with reduced perforin expression. Acute, but not chronic, graft-versus-host disease, as well as CMV reactivation, was associated with further downregulation of T-bet expression in NK cells. Lower levels of T-bet expression in NK cells were associated with less favorable outcome after HSCT as a result of increased nonrelapse mortality. Collectively, our results provide a possible molecular explanation for the previously reported functional exhaustion of NK cells after allogeneic HSCT and suggest an impact of the NK transcriptional machinery status on HSCT outcome.

    View details for DOI 10.4049/jimmunol.1501522

    View details for Web of Science ID 000364822800021

    View details for PubMedID 26438526

  • Restoration of hematopoiesis in a case of myelodysplastic syndrome associated with systemic lupus erythematosus treated with rituximab ANNALS OF HEMATOLOGY Simonetta, F., Posa, M., Villard, J., Marceau-Renaut, A., Preudhomme, C., Samii, K., Chizzolini, C. 2015; 94 (7): 1247-1249

    View details for DOI 10.1007/s00277-015-2363-6

    View details for Web of Science ID 000354470600024

    View details for PubMedID 25847363

  • Complete and sustained remission of spondyloarthritis after allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome JOINT BONE SPINE Simonetta, F., Guerne, P., Tirefort, Y., Masouridi-Levrat, S., Roosnek, E., Chalandon, Y. 2015; 82 (3): 216-217

    View details for DOI 10.1016/j.jbspin.2014.10.011

    View details for Web of Science ID 000355767600024

    View details for PubMedID 25547608

  • Interleukin-7 Optimizes FOXP3+CD4+Regulatory T Cells Reactivity to Interleukin-2 by Modulating CD25 Expression PLOS ONE Simonetta, F., Gestermann, N., Bloquet, S., Bourgeois, C. 2014; 9 (12)

    Abstract

    The vast majority of Foxp3 regulatory T cells (Treg) exhibits constitutive expression of CD25 (IL-2Rα), which allows the constitution of the high affinity IL-2Rαβγ receptor, ensuring efficient IL-2 binding by Treg. Maintenance of CD25 expression at Treg surface depends on both cell intrinsic factors and environmental stimuli such as IL-2 itself. Whether other factors can participate to maintenance of CD25 expression in vivo is at present unknown. In the present work we demonstrated that IL-7, a gamma-chain cytokine exerting a crucial role in T cell development and homeostasis, is able and necessary to sustain the expression of high levels of CD25 at Treg surface. We demonstrated that, during in vitro cultures performed in the absence of IL-2, IL-7 is able to sustain CD25 expression at Treg surface through a transcriptional mechanism. By studying mice in which IL-7 signaling is either genetically impaired or increased and by employing adoptive transfer murine models, we demonstrated that IL-7 is necessary for sustained expression of CD25 at Treg surface in vivo. To ascertain the biological impact of IL-7 mediated modulation of CD25 expression, we demonstrated that IL-7 modulation of CD25 expression at Treg surface affected their ability to efficiently bind IL-2 and transduce IL-2 signaling. Finally, we demonstrated that IL-7 dependent modulation of CD25 associated with potentiated IL-2 induced expansion of Treg in vivo. Collectively, our results identify IL-7 as a necessary factor contributing to sustained CD25 expression at Treg surface in vivo thereby affecting their ability to efficiently react to IL-2.

    View details for DOI 10.1371/journal.pone.0113314

    View details for Web of Science ID 000346907600018

    View details for PubMedID 25485946

  • High Eomesodermin Expression among CD57(+) CD8(+) T Cells Identifies a CD8(+) T Cell Subset Associated with Viral Control during Chronic Human Immunodeficiency Virus Infection JOURNAL OF VIROLOGY Simonetta, F., Hua, S., Lecuroux, C., Gerard, S., Boufassa, F., Saez-Cirion, A., Pancino, G., Goujard, C., Lambotte, O., Venet, A., Bourgeois, C. 2014; 88 (20): 11861-11871

    Abstract

    During HIV infection, increased CD57 expression among CD8(+) T cells has been associated with immune senescence and defective immune responses. Interestingly, CD57-expressing CD8(+) T cells exhibit a dual profile, being simultaneously highly cytotoxic (terminally differentiated effectors) and poorly proliferative (replicative senescent). Recent publications point toward a positive role of CD57-expressing CD8(+) T cell subsets, presumably due to their high cytolytic activity. We further investigated the phenotype of CD57-expressing CD8(+) T cells in healthy donors and during HIV infection combining CD57 expression to Eomesodermin (EOMES), a T box transcription factor which determines, coordinately with T-bet, effector and memory CD8(+) T cell differentiation. We defined in healthy donors two functionally distinct CD57-expressing CD8(+) T cell subsets exhibiting different levels of EOMES expression: EOMES(hi) CD57(+) and EOMES(int) CD57(+) CD8(+) T cells. EOMES(hi) CD57(+) cells exhibited low cytotoxic activity but preserved proliferative capacity and interleukin 7 (IL-7) receptor expression, whereas EOMES(int) CD57(+) cells exhibited obvious cytotoxic functions and a more terminally differentiated phenotype. We next performed a similar analysis in different contexts of HIV infection: primary infected patients, long-term viremic patients, aviremic patients treated with antiretroviral therapy, and HIV controllers; we demonstrated a higher percentage of CD57-expressing cells in all HIV-infected patients regardless of virological status. When heterogeneity in EOMES expression among CD57 cells was taken into account, we detected significantly higher proportions of EOMES(hi) CD57(+) cells among HIV-specific and nonspecific CD8(+) T cells from HIV controllers than in aviremic antiretroviral-treated patients and viremic patients. Importantly, such a peculiar non-terminally differentiated EOMES(hi) CD57(+) phenotypic profile was associated with viral control. Importance: This study demonstrates that functional heterogeneity exists among CD57-expressing CD8 T cells, which include both terminally differentiated, highly cytotoxic EOMES(int) CD57(+) CD8(+) T cells and less differentiated EOMES(hi) CD57(+) CD8 T cells, which do not exhibit immediate cytotoxic functions but present high proliferative capacity. Interestingly, HIV controllers present a high proportion of EOMES(hi) CD57 cells among CD57-expressing HIV-specific CD8 T cells compared to both long-term viremic and aviremic antiretroviral therapy (ART)-treated patients, suggesting a beneficial role for this cell subset in viral control.

    View details for DOI 10.1128/JVI.02013-14

    View details for Web of Science ID 000342688000021

    View details for PubMedID 25100841

  • Walking unsteadily: a case of acute cerebellar ataxia. BMJ case reports Simonetta, F., Christou, F., Vandoni, R. E., Nierle, T. 2013; 2013

    Abstract

    Acute cerebellar ataxia is an infrequent neurological syndrome in adults especially if complicated by additional neurological deficits. We report the case of a 69-year-old woman who presented with sudden onset of left facial droop, dizziness, slurred speech and impaired balance. Her medical history included paroxysmal atrial fibrillation and a sigmoid diverticular abscess treated with ciprofloxacin and metronidazole. Cranial computed tomographic angiography and MRI showed no signs of acute ischaemia or haemorrhage but demonstrated symmetrically distributed lesions in the cerebellar dentate nuclei. A diagnosis of metronidazole-induced encephalopathy was suspected. Metronidazole was stopped and the patient completely recovered. Metronidazole is a commonly prescribed medication. Clinicians should be aware of the clinical and radiological presentation of metronidazole-induced encephalopathy so that this serious but completely reversible condition can be promptly diagnosed.

    View details for DOI 10.1136/bcr-2012-007688

    View details for PubMedID 23283615

  • CD4+FOXP3+ Regulatory T-Cell Subsets in Human Immunodeficiency Virus Infection. Frontiers in immunology Simonetta, F., Bourgeois, C. 2013; 4: 215-?

    Abstract

    The role of CD4+FOXP3+ regulatory T cells (Treg) in human immunodeficiency virus (HIV) infection has been an area of intensive investigation and remains a matter of ardent debate. Investigation and interpretation suffered from uncertainties concerning Treg quantification. Firstly, Treg quantification and function in HIV infection remain controversial in part because of the lack of reliable and specific markers to identify human Tregs. Secondly, analyzing Treg percentages or absolute numbers led to apparent discrepancies that are now solved: it is now commonly accepted that Treg are targets of HIV infection, but are preferentially preserved compared to conventional CD4 T cells. Moreover, the duality of immune defects associated to HIV infection, i.e., low grade chronic inflammation and defects in HIV-specific responses also casts doubts on the potential impact of Treg on HIV infection. Tregs may be beneficial or/and detrimental to the control of HIV infection by suppressing chronic inflammation or HIV-specific responses respectively. Indeed both effects of Treg suppression have been described in HIV infection. The discovery in recent years of the existence of phenotypically and functionally distinct human CD4+FOXP3+ Treg subsets may provide a unique opportunity to reconcile these contrasting results. It is tempting to speculate that different Treg subsets exert these different suppressive effects. This review summarizes available data concerning Treg fate during HIV infection when considering Treg globally or as subsets. We discuss how the identification of naïve and effector Treg subsets modulates our understanding of Treg biology during HIV infection and the potential impact of HIV infection on mechanisms governing peripheral differentiation of adaptive Tregs.

    View details for DOI 10.3389/fimmu.2013.00215

    View details for PubMedID 23908654

  • Early and Long-Lasting Alteration of Effector CD45RA(-)Foxp3(high) Regulatory T-Cell Homeostasis During HIV Infection JOURNAL OF INFECTIOUS DISEASES Simonetta, F., Lecuroux, C., Girault, I., Goujard, C., Sinet, M., Lambotte, O., Venet, A., Bourgeois, C. 2012; 205 (10): 1510-1519

    Abstract

    Regulatory T-cell (Treg) quantification in human immunodeficiency virus (HIV) infection remains ill defined because of the lack of reliable specific markers to identify human Tregs and the diversity of clinical stages of HIV infection. Using a recently described Treg identification strategy based on CD45RA and Foxp3 expression, we performed an extensive quantification of total, naive (CD45RA(+)Foxp3(low)), and effector (CD45RA(-)Foxp3(high)) Tregs in different contexts of HIV infection: primary HIV infection, long-term viremic patients, aviremic patients treated with highly active antiretroviral therapy, and HIV controllers. We showed that although total Treg percentages were mildly affected by HIV infection, Treg absolute numbers were significantly reduced in all groups studied. We demonstrated that although naive Treg numbers were essentially preserved, effector Tregs were consistently affected during HIV infection. Finally, we demonstrated that effector but not total or naive Treg numbers were negatively correlated with the magnitude of HIV-specific CD8 T-cell responses.

    View details for DOI 10.1093/infdis/jis235

    View details for Web of Science ID 000303329200006

    View details for PubMedID 22457280

  • Interleukin-7 Influences FOXP3(+)CD4(+) Regulatory T Cells Peripheral Homeostasis PLOS ONE Simonetta, F., Gestermann, N., Martinet, K. Z., Boniotto, M., Tissieres, P., Seddon, B., Bourgeois, C. 2012; 7 (5)

    Abstract

    Mechanisms governing peripheral CD4+ FOXP3+ regulatory T cells (Treg) survival and homeostasis are multiple suggesting tight and complex regulation of regulatory T cells homeostasis. Some specific factors, such as TGF-β, interleukin-2 (IL-2) and B7 costimulatory molecules have been identified as essentials for maintenance of the peripheral Treg compartment. Conversely, Treg dependency upon classical T cell homeostatic factors such as IL-7 is still unclear. In this work, we formally investigated the role of IL-7 in Treg homeostasis in vivo in murine models. We demonstrated that IL-7 availability regulated the size of peripheral Treg cell pool and thus paralleled the impact of IL-7 on conventional T cell pool. Moreover, we showed that IL-7 administration increased Treg cell numbers by inducing thymic-independent Treg peripheral expansion. Importantly the impact of IL-7 on Treg expansion was detected whether conventional T cells were present or absent as IL-7 directly participates to the peripheral expansion of Treg after adoptive transfer into lymphopenic hosts. Our results definitively identify IL-7 as a central factor contributing to Treg peripheral homeostasis, thus reassembling Treg to other T cell subsets in respect of their need for IL-7 for their peripheral maintenance.

    View details for DOI 10.1371/journal.pone.0036596

    View details for Web of Science ID 000305335000042

    View details for PubMedID 22586481

  • Molecular characterization of human cutaneous melanoma-derived cell lines. Anticancer research Ogbah, Z., Puig-Butille, J. A., Simonetta, F., Badenas, C., Cervera, R., Milá, J., Benitez, D., Malvehy, J., Vilella, R., Puig, S. 2012; 32 (4): 1245-1251

    Abstract

    Several studies have demonstrated that different genetic profiles contribute to melanoma development and progression.To evaluate the existence of different molecular aberration patterns in melanoma associated with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) or 9p21 locus alterations, eleven patient-derived melanoma cell lines were characterized. Multiplex ligation probe amplification (MLPA) was used to detect chromosomal alterations. Single- strand conformation analysis and sequencing were performed to study BRAF, neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (c-KIT), melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor) (MC1R), cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4) genes.BRAFV600E mutation was detected in 54% of cell lines. NRAS was mutated in one cell line also carrying multiple copies of NRAS. All cell lines with MC1R variants harboured BRAFV600E. Concurrent loss of MUTYH (1p33), gains of c-MYC (8q24) and of CDK6 (7q21) were found to be significantly associated in cell lines (45%) that harboured biallelic 9p21 deletions including CDKN2B-CDKN2A-MTAP.These data suggest the existence of a specific pattern of somatic alterations in genes that are involved in DNA repair (MUTYH) and in cell cycle regulation (c-MYC, CDK6, CDKN2A and CDKN2B). Interestingly, all MC1R variants were associated with BRAFV600E and all cell lines from visceral metastases harboured BRAFV600E.

    View details for PubMedID 22493355

  • Increased CD127 expression on activated FOXP3(+)CD4(+) regulatory T cells EUROPEAN JOURNAL OF IMMUNOLOGY Simonetta, F., Chiali, A., Cordier, C., Urrutia, A., Girault, I., Bloquet, S., Tanchot, C., Bourgeois, C. 2010; 40 (9): 2528-2538

    Abstract

    Regulatory T cells (Treg) are commonly identified by CD25 (IL-2R alpha) surface expression and/or intracellular expression of the FOXP3 transcription factor. In addition, Treg are also characterized by low CD127 (IL-7R alpha) expression when compared to conventional T cells and their biology in the periphery is considered essentially independent of IL-7. We further investigated CD127 expression on Treg and we demonstrated differential CD127 expression depending on Treg subsets considered. Notably, we observed high CD127 expression on inducible costimulatory molecule (ICOS)- and CD103-expressing Treg subsets. Since these two markers reflect activation status, we addressed whether Treg activation modulated CD127 expression. We demonstrated that in contrast to conventional T cells, Treg significantly upregulated CD127 expression during in vitro and in vivo activation using adoptive transfer and contact dermatitis models. High CD127 expression on Treg was also predominantly detected ex vivo in some specific sites, notably bone marrow and skin. Importantly, higher CD127 expression on Treg correlated with higher phosphorylation of STAT5 upon IL-7 exposure. High CD127 expression on Treg also provided survival advantage upon in vitro incubation with IL-7. We thus demonstrated that low CD127 expression is not an intrinsic characteristic of Treg and we identified activated Treg as a potential target of endogenous or therapeutic IL-7.

    View details for DOI 10.1002/eji.201040531

    View details for Web of Science ID 000282305400020

    View details for PubMedID 20690182

  • Heterospecific CD4 Help to Rescue CD8 T Cell Killers JOURNAL OF IMMUNOLOGY de Herve, M. d., Cariou, A., Simonetta, F., Taoufik, Y. 2008; 181 (9): 5974-5980

    Abstract

    Help from CD4 T cells may be required for optimal generation and maintenance of memory CD8 T cells and also for optimal Ag reactivation. We examined whether the helper cell and the CD8 killer cell need to have the same Ag specificity for help to be effective during interactions of memory T cells with mature APC. This is important because virus and tumor Ag-specific CD4 T cell responses are selectively impaired in several chronic viral infections and malignancies. We performed studies in vitro and in vivo and found that functional memory CD4 T cells generated from a distinct antigenic source (heterospecific helpers) could provide direct and effective help to memory CD8 T cells. Functional heterospecific memory CD4 T cells could also rescue secondary CD8 T cell responses in an experimental tumor model in which homospecific CD4 help was impaired. This could provide a rationale for immunotherapy strategies designed to bypass impaired homospecific help.

    View details for Web of Science ID 000260659000021

    View details for PubMedID 18941186

  • DNA damage-induced expression of p53 suppresses mitotic checkpoint kinase hMps1 - The lack of this suppression in p53(MUT) cells contributes to apoptosis JOURNAL OF BIOLOGICAL CHEMISTRY Bhonde, M. R., Hanski, M. L., Budczies, J., Cao, M., Gillissen, B., Moorthy, D., Simonetta, F., Scherubl, H., Truss, M., Hagemeier, C., Mewes, H. W., Daniel, P. T., Zeitz, M., Hanski, C. 2006; 281 (13): 8675-8685

    Abstract

    DNA damage induced by the topoisomerase I inhibitor irinotecan (CPT-11) triggers in p53(WT) colorectal carcinoma cells a long term cell cycle arrest and in p53MUT cells a transient arrest followed by apoptosis (Magrini, R., Bhonde, M. R., Hanski, M. L., Notter, M., Scherübl, H., Boland, C. R., Zeitz, M., and Hanski, C. (2002) Int. J. Cancer 101, 23-31; Bhonde, M. R., Hanski, M. L., Notter, M., Gillissen, B. F., Daniel, P. T., Zeitz, M., and Hanski, C. (2006) Oncogene 25, 165-175). The mechanism of the p53-independent apoptosis still remains largely unclear. Here we used five p53WT and five p53MUT established colon carcinoma cell lines to identify gene expression alterations associated with apoptosis in p53MUT cells after treatment with SN-38, the irinotecan metabolite. After treatment, 16 mitosis-related genes were found to be expressed at least 2-fold stronger in the apoptosis-executing p53MUT cells than in the cell cycle-arrested p53WT cells by oligonucleotide microarray analysis. One of the genes whose strong post-treatment expression was associated with apoptosis was the mitotic checkpoint kinase hMps1 (human ortholog of the yeast monopolar spindle 1 kinase). hMps1 mRNA and protein expression were suppressed by the treatment-induced and by the exogenous adenovirus-coded p53 protein. The direct suppression of hMps1 on RNA level or inhibition of its activity by a dominant-negative hMps1 partly suppressed apoptosis. Together, these data indicate that the high expression of mitotic genes in p53MUT cells after SN-38 treatment contributes to DNA damage-induced apoptosis, whereas their suppression in p53WT cells acts as a safeguard mechanism preventing mitosis initiation and the subsequent apoptosis. hMps1 kinase is one of the mitotic checkpoint proteins whose expression after DNA damage in p53MUT cells activates the checkpoint and contributes to apoptosis.

    View details for DOI 10.1074/jbc.M511333200

    View details for Web of Science ID 000236247100045

    View details for PubMedID 16446370

  • Differential effect of agonistic anti-CD40 on human mature and immature dendritic cells: the Janus face of anti-CD40 BLOOD de Herve, M. G., Durali, D., Tran, T. A., Maigne, G., Simonetta, F., Leclerc, P., Delfraissy, J. F., Taoufik, Y. 2005; 106 (8): 2806-2814

    Abstract

    Agonistic monoclonal antibodies to CD40 (CD40 mAbs) have a puzzling dual therapeutic effect in experimental animal models. CD40 mAbs induce tumor regression by potentiating antitumoral T-cell responses, yet they also have immunosuppressive activity in chronic autoimmune inflammatory processes. CD40 mAbs are thought to act on antigen presentation by dendritic cells (DCs) to T cells. DCs can be distinguished as either immature or mature by their phenotype and their ability to generate an effective T-cell response. Here we found that, on human cells, although anti-CD40 led immature DCs to mature and became immunogenic, it also reduced the capacity of lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNF-alpha)-matured DCs to generate a specific CD4 T-cell response. This inhibitory effect was related to rapid and selective apoptosis of mature DCs. Anti-CD40-mediated apoptosis was due to an indirect mechanism involving cooperation with the death domain-associated receptor Fas, leading to activation of Fas-associated death domain protein (FADD) and caspase-8. On human cells, CD40 activation by such agonists could, therefore, trigger immune responses to antigens presented by immature DCs, which are otherwise nonimmunogenic, by inducing maturation. On the other hand, anti-CD40 mAbs, by rapidly inducing apoptosis, may reduce the capacity of inflammatory signal-matured immunogenic DCs to generate an effective T-cell response. These results call for caution in CD40 mAb-based immunotherapy strategies.

    View details for DOI 10.1182/blood-2004-12-4678

    View details for Web of Science ID 000232466000038

    View details for PubMedID 15994291