Laboratoire DImmunologie Cellulaire et Tissulaire

Brié-et-Angonnes, France

Laboratoire DImmunologie Cellulaire et Tissulaire

Brié-et-Angonnes, France

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Xie J.,French Institute of Health and Medical Research | Lu W.,French Institute of Health and Medical Research | Samri A.,French Institute of Health and Medical Research | Samri A.,Laboratoire DImmunite et Infections | And 13 more authors.
AIDS | Year: 2010

Objectives: A superior capacity of controlling HIV has been attributed to CD8+ T cells directed against HIV-Gag compared to Nef, particularly in the context of some protective human leukocyte antigen (HLA) alleles. To further elucidate this protective effect, we compared the multifunctional and differentiation characteristics of CD8+ T cells specific for HIV-Gag and Nef in HLA-B57/5801-positive and negative nonprogressors. Methods: A head-to-head comparison of CD8+ T cells specific for HIV-Gag and Nef frequencies, cytokine production and differentiation was conducted, in 11 HLA-B57/5801 and 11 HLA-B57/5801 HIV-infected individuals selected from a cohort of 53 nonprogressors by using IFN-γ-ELISpot assay and flow cytometry analysis of intracellular cytokine production and differentiation profile. Correlations with HIV parameters were studied. Results: Frequencies of Gag-specific but not of Nef-specific CD8+ T cells correlated with peripheral blood mononuclear cell (PBMC)-associated HIV-DNA. The HIV-Gag and Nef-specific CD8+ T cells did not differ for IL-2 production in either HLA-B57/5801 or HLA-B57/5801 individuals. The IFN-γ-producing Gag-specific CD8+ T cells in HLA-B57/5801 individuals significantly differed from their Nef-specific counterparts by displaying higher proportions of central memory CD4+5RACCR7 cells positive for CD27+. This differentiation pattern was not observed in HLA-B57/5801 individuals. Only these HLA-B57/5801-positive Gag-specific CD27+ central memory CD8+ T cells, but not their Nef-specific counterparts, negatively correlated with cell-associated HIV-DNA. Conclusion: HLA-B57/5801 drives a preferential CD27+ differentiation of central memory CD8+ T cells directed against HIV-Gag but not Nef that may contribute to the ability of Gag-specific CD8+ T cells to better control HIV in HLA-B57/5801 nonprogressors. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Beziat V.,French Institute of Health and Medical Research | Beziat V.,University Pierre and Marie Curie | Beziat V.,Karolinska University Hospital | Dalgard O.,French Institute of Health and Medical Research | And 18 more authors.
European Journal of Immunology | Year: 2012

Natural killer (NK) cells are affected by infection with human cytomegalovirus (HCMV) manifested by increased expression of the HLA-E binding activating receptor NKG2C. We here show that HCMV seropositivity was associated with a profound expansion of NKG2C +CD56 dim NK cells in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Multi-color flow cytometry revealed that the expanded NKG2C +CD56 dim NK cells displayed a highly differentiated phenotype, expressed high amounts of granzyme B and exhibited polyfunctional responses (CD107a, IFN-γ, and TNF-α) to stimulation with antibody-coated as well as HLA-E expressing target cells but not when stimulated with IL-12/IL-18. More importantly, NKG2C +CD56 dim NK cells had a clonal expression pattern of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self-HLA class I molecules, with predominant usage of KIR2DL2/3. KIR engagement dampened NKG2C-mediated activation suggesting that such biased expression of self-specific KIRs may preserve self-tolerance and limit immune-pathology during viral infection. Together, these findings shed new light on how the human NK-cell compartment adjusts to HCMV infection resulting in clonal expansion and differentiation of educated and polyfunctional NK cells. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Le Guilloux J.,Service Route | Roubiou C.,Service de medecine interne et geriatrie | Mallet J.,Service Route | Bouvry D.,Service de pneumologie | And 7 more authors.
Revue Neurologique | Year: 2010

Introduction: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of central nervous system due to the JC virus. PML generally occurs in immunocompromised hosts and has a fatal outcome. Observation: We report a case of an atypical PML in a patient with pulmonary sarcoidosis: MRI showed multifocal and punctate contrast enhancements. The diagnostic was made by brain biopsy. Conclusion: The pathophysiology of this association is probably related to the immunodepression induced by sarcoidosis. © 2009 Elsevier Masson SAS. All rights reserved.


Campillo-Gimenez L.,Paris-Sorbonne University | Campillo-Gimenez L.,CNRS Immunology and Infectious Disease Center | Casulli S.,Paris-Sorbonne University | Casulli S.,CNRS Immunology and Infectious Disease Center | And 15 more authors.
Journal of Allergy and Clinical Immunology | Year: 2014

Background Despite control of HIV infection under antiretroviral therapy (ART), immune T-cell activation persists in patients with controlled HIV infection, who are at higher risk of inflammatory diseases than the general population. PMNs play a key role in host defenses against invading microorganisms but also potentiate inflammatory reactions in cases of excessive or misdirected responses. Objective The aim of our study was to analyze PMN functions in 60 ART-treated and controlled HIV-infected patients (viral load, <20 RNA copies/mL; CD4 count, ≥350 cells/mm3) with (HIV[I] group) and without (HIV[NI] group) diseases related to an inflammatory process and to compare them with 22 healthy control subjects. Methods Flow cytometry was used to evaluate PMN functions in whole-blood conditions. We studied in parallel the activation markers of T lymphocytes and monocytes and the proinflammatory cytokine environment. Results Blood samples from HIV-infected patients revealed basal PMN hyperactivation associated with deregulation of the apoptosis/necrosis equilibrium. Interestingly, this hyperactivation was greater in HIV(I) than HIV(NI) patients and contrasted with a lack of monocyte activation in both groups. The percentage of circulating cells producing IL-17 was also significantly higher in HIV-infected patients than in control subjects and was positively correlated with markers of basal PMN activation. In addition, the detection of IL-22 overproduction in HIV(NI) patients suggests that it might contribute to counteracting chronic inflammatory processes during HIV infection. Conclusions This study thus demonstrates the presence of highly activated PMNs in HIV-infected patients receiving effective ART and the association of these cells with a specific IL-17/IL-22 environment. © 2014 American Academy of Allergy, Asthma & Immunology.


Canestri A.,AP HP | Canestri A.,French Institute of Health and Medical Research | Krivine A.,Laboratoire Of Virologie | Assoumou L.,French Institute of Health and Medical Research | And 19 more authors.
AIDS | Year: 2010

Immune changes induced by the CCR5 antagonist maraviroc raise the question of an impairment of responses to vaccines. We evaluated the immunogenicity of the adjuvanted pandemic influenza A-H1N1v 2009 vaccine in HIV-1-infected patients with suppressed HIV viremia with or without a maraviroc-containing regimen. Seroprotection, seroconversion, and geometric mean titer ratio of specific antibody titers did not differ between groups. These results suggest that maraviroc does not significantly affect the immune response to this adjuvanted vaccine. Copyright © Lippincott Williams & Wilkins.


Beziat V.,French Institute of Health and Medical Research | Beziat V.,University Pierre and Marie Curie | Descours B.,French Institute of Health and Medical Research | Descours B.,University Pierre and Marie Curie | And 6 more authors.
PLoS ONE | Year: 2010

Background: Terminal differentiation of NK cells is crucial in maintaining broad responsiveness to pathogens and discriminating normal cells from cells in distress. Although it is well established that KIRs, in conjunction with NKG2A, play a major role in the NK cell education that determines whether cells will end up competent or hyporesponsive, the events underlying the differentiation are still debated. Methodology/Principal Findings: A combination of complementary approaches to assess the kinetics of the appearance of each subset during development allowed us to obtain new insights into these terminal stages of differentiation, characterising their gene expression profiles at a pan-genomic level, their distinct surface receptor patterns and their prototypic effector functions. The present study supports the hypothesis that CD56dim cells derive from the CD56bright subset and suggests that NK cell responsiveness is determined by persistent inhibitory signals received during their education. We report here the inverse correlation of NKG2A expression with KIR expression and explore whether this correlation bestows functional competence on NK cells. We show that CD56dimNKG2A-KIR+ cells display the most differentiated phenotype associated to their unique ability to respond against HLA-E+ target cells. Importantly, after IL-12 + IL-18 stimulation, reacquisition of NKG2A strongly correlates with IFN-γ production in CD56dimNKG2A- NK cells. Conclusions/Significance: Together, these findings call for the reclassification of mature human NK cells into distinct subsets and support a new model, in which the NK cell differentiation and functional fate are based on a stepwise decrease of NKG2A and acquisition of KIRs. © 2010 Béziat et al.


Billot K.,University Pierre and Marie Curie | Parizot C.,Laboratoire dImmunologie Cellulaire et Tissulaire | Arrouss I.,University Pierre and Marie Curie | Mazier D.,University Pierre and Marie Curie | And 3 more authors.
Leukemia Research | Year: 2010

The Aiolos transcription factor plays a crucial role in the control of lymphocyte differentiation and proliferation. The expression of Aiolos isoform has been studied in lymphoid pathologies but nothing is known about its expression in unaffected human hematopoietic subpopulations. In this manuscript we show for the first time the differential Aiolos expression at the RNA and protein level in hematopoietic cell subpopulations. B cells express higher levels of Aiolos than NK and T cells while monocytes express almost undetectable levels of Aiolos. Moreover, human CD34 (+) progenitors do not express Aiolos. We did not observe significant difference when comparing naive to memory T and B cells, but we observed an important difference between Bright and Dim NK cells. Furthermore, we show that, in addition to hematopoietic cells, non hematopoietic cell lines such as MCF-7, SW480, HEK, PC3 and HeLa also express Aiolos. © 2009 Elsevier Ltd.


Le Garff-Tavernier M.,French Institute of Health and Medical Research | Le Garff-Tavernier M.,University Pierre and Marie Curie | Decocq J.,French Institute of Health and Medical Research | Decocq J.,University Pierre and Marie Curie | And 22 more authors.
Leukemia | Year: 2011

Although anti-CD20 monoclonal antibodies (mAbs) show promise for the treatment of chronic lymphocytic leukemia (CLL), the success of the anti-CD20 mAb rituximab in CLL treatment has been limited. Novel anti-CD20 mAbs with more potent cytotoxic activity have recently been engineered, but so far most have only been tested in vitro with natural killer (NK) cells from healthy donors. Because it is still unclear whether these optimized cytotoxic mAbs will improve NK-cell killing of tumor cells in CLL patients, we characterized the relevant phenotypic and functional features of NK cells from CLL patients in detail. Expression of inhibitory and activating NK-cell receptors and of Fc gamma receptor IIIA (FcγRIIIA) is well preserved in CD16 CD56dim cytotoxic NK cells from these patients, independently of disease progression. These cells are fully functional following cytokine stimulation. In addition, the FcγRIIIA-optimized LFB-R603 anti-CD20 mAb mediates 100 times greater antibody-dependent cell-mediated cytotoxicity by NK cells from CLL patients and healthy donors than rituximab. Enhanced degranulation against autologous B-CLL cells is observed at lower concentrations of LFB-R603 than rituximab, regardless of CLL prognostic factors. These findings strongly justify further clinical development of anti-CD20 mAbs optimized for FcγR engagement in CLL patients. © 2011 Macmillan Publishers Limited All rights reserved.


Grassin-Delyle S.,University of Versailles | Buenestado A.,University of Versailles | Vallat L.,AP HP | Naline E.,University of Versailles | And 12 more authors.
Peptides | Year: 2011

Tachykinins are a family of structurally related peptides, including substance P (SP), hemokinin-1 (HK-1), neurokinin A (NKA), and neurokinin B. SP and NKA have been shown to modulate hematopoiesis and rat/mouse HK-1 has been found to be involved in the survival and differentiation of mouse B-cells. This study was designed to assess the expression of tachykinins with a focus on human HK-1 (hHK-1) in human B lymphocytes and the role of these peptides in cell differentiation, apoptosis and proliferation. Expression of tachykinin and tachykinin receptor mRNA was determined quantitatively in human B lymphoproliferative malignancies and compared to normal B-cells. Expression of hHK-1 and NK1 receptor, but not SP, was detected in human B-lymphocytes, and was up-regulated in B-lymphocytes from chronic lymphocytic leukemia and non-Hodgkin's lymphoma, while it was down-regulated in acute lymphoblastic leukemia. Moreover, hHK-1, in contrast to SP, was able to induce proliferation of human pre-B lymphocytes through a NK1 receptor-independent mechanism. These data suggest a role for hHK-1 in normal and pathological B lymphopoiesis, and open the door to a better understanding of the physiopathological mechanisms leading to lymphoproliferative malignancies. © 2011 Elsevier Inc. All rights reserved.


Nguyen S.,Service dHematologie Clinique | Nguyen S.,Laboratoire dImmunologie Cellulaire et Tissulaire | Nguyen S.,French Institute of Health and Medical Research | Beziat V.,Service dHematologie Clinique | And 32 more authors.
Transfusion | Year: 2011

BACKGROUND: Allogeneic donor natural killer (NK)-cell infusion (NK-DLI) is a promising immunotherapy for patients with hematologic disorders. CASE REPORT: This report describes the case of a patient who received a single haploidentical NK-DLI for a relapse of acute myeloid leukemia (AML) after haploidentical hematopoietic stem cell transplantation. He underwent a cytoreductive, immunosuppressive regimen before NK-DLI and received high-dose interleukin-2 in vivo for 8 weeks afterward. RESULTS: No major adverse effect was observed. Prospective phenotypic and functional studies of the NK cells showed major expansion of infused NK cells and, more importantly, of the alloreactive KIR2DL1+KIR2DL2/DL3-NKG2A- subset, which reached 117 × 106 cells/L on Day +14 after NK-DLI, the greatest expansion of infused alloreactive NK cells reported so far. Infused NK cells conserved their lytic capacities against K562 target cells and primary AML-mismatched blasts. CONCLUSION: We review the literature to clarify these data and to detail the indications for allogeneic NK-DLI, the criteria for determining the most suitable donor, the types of conditioning regimens, and the procedures for selecting and activating NK cells. © 2011 American Association of Blood Banks.

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