Publications (25)141.68 Total impact
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Article: MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis.
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ABSTRACT: Melanoma is the most aggressive skin cancer in humans that often expresses MHC class II (MHC II) molecules, which could make these tumors eliminable by the immune system. However, this MHC II expression has been associated with poor prognosis, and there is a lack of immune-mediated eradication. The lymphocyte activation gene-3 (LAG-3) is a natural ligand for MHC II that is substantially expressed on melanoma-infiltrating T cells including those endowed with potent immune-suppressive activity. Based on our previous data showing the signaling capacity of MHC II in melanoma cells, we hypothesized that LAG-3 could contribute to melanoma survival through its MHC II signaling capacity in melanoma cells. In this study, we demonstrate that both soluble LAG-3 and LAG-3-transfected cells can protect MHC II-positive melanoma cells, but not MHC II-negative cells, from FAS-mediated and drug-induced apoptosis. Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3-induced protection from apoptosis. Altogether, our data suggest that the LAG-3-MHC II interaction could be viewed as a bidirectional immune escape pathway in melanoma, with direct consequences shared by both melanoma and immune cells. In the future, compounds that efficiently hinder LAG-3-MHC II interaction might be used as an adjuvant to current therapy for MHC II-positive melanoma.The Journal of Immunology 03/2011; 186(9):5173-83. · 5.79 Impact Factor -
Article: LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites.
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ABSTRACT: Human natural regulatory CD4(+) T cells comprise 5-10% of peripheral CD4(+)T cells. They constitutively express the IL-2Ralpha-chain (CD25) and the nuclear transcription Foxp3. These cells are heterogeneous and contain discrete subsets with distinct phenotypes and functions. Studies in mice report that LAG-3 has a complex role in T cell homeostasis and is expressed in CD4(+)CD25(+) T regulatory cells. In this study, we explored the expression of LAG-3 in human CD4(+) T cells and found that LAG-3 identifies a discrete subset of CD4(+)CD25(high)Foxp3(+) T cells. This CD4(+)CD25(high)Foxp3(+)LAG-3(+) population is preferentially expanded in the PBMCs of patients with cancer, in lymphocytes of tumor-invaded lymph nodes and in lymphocytes infiltrating visceral metastasis. Ex vivo analysis showed that CD4(+)CD25(high)Foxp3(+)LAG-3(+) T cells are functionally active cells that release the immunosuppressive cytokines IL-10 and TGF-beta1, but not IL-2. An in vitro suppression assay using CD4(+)CD25(high)LAG-3(+) T cells sorted from in vitro expanded CD4(+)CD25(high) regulatory T cells showed that this subset of cells is endowed with potent suppressor activity that requires cell-to-cell contact. Our data show that LAG-3 defines an active CD4(+)CD25(high)Foxp3(+) regulatory T cell subset whose frequency is enhanced in the PBMCs of patients with cancer and is expanded at tumor sites.The Journal of Immunology 06/2010; 184(11):6545-51. · 5.79 Impact Factor -
Article: First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity.
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ABSTRACT: IMP321 is a recombinant soluble LAG-3Ig fusion protein that binds to MHC class II with high avidity and mediates APC and then antigen-experienced memory CD8+ T cell activation. We report clinical and biological results of a phase I/II in patients with metastatic breast carcinoma (MBC) receiving first-line paclitaxel weekly, 3 weeks out of 4. MBC patients were administered one dose of IMP321 s.c. every two weeks for a total of 24 weeks (12 injections). The repeated single doses were administered the day after chemotherapy at D2 and D16 of the 28-day cycles of paclitaxel (80 mg/m2 at D1, D8 and D15, for 6 cycles). Blood samples were taken 13 days after the sixth and the twelfth IMP321 injections to determine sustained APC, NK and memory CD8 T cell responses. Thirty MBC patients received IMP321 in three cohorts (doses: 0.25, 1.25 and 6.25 mg). IMP321 induced both a sustained increase in the number and activation of APC (monocytes and dendritic cells) and an increase in the percentage of NK and long-lived cytotoxic effector-memory CD8 T cells. Clinical benefit was observed for 90% of patients with only 3 progressors at 6 months. Also, the objective tumor response rate of 50% compared favorably to the 25% rate reported in the historical control group. The absence of toxicity and the demonstration of activity strongly support the future development of this agent for clinical use in combined first-line regimens. ClinicalTrials.gov NCT00349934.Journal of Translational Medicine 01/2010; 8:71. · 3.41 Impact Factor -
Article: CD4+CD25+ regulatory T cells modulate human dendritic cell chemokines via multiple mechanisms: comment on the article by Kolar et al.
Arthritis & Rheumatism 09/2009; 60(9):2848-9; author reply 2849-51. · 7.87 Impact Factor -
Article: A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma.
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ABSTRACT: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of IMP321, a recombinant soluble LAG-3Ig fusion protein which agonizes MHC class II-driven dendritic cell activation. Patients with advanced renal cell carcinoma were treated with escalating doses of IMP321 s.c. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect human anti-IMP321 antibody formation, and determine long-lived CD8 T cell responses. Twenty-one advanced renal cell carcinoma patients received 119 injections of IMP321 at doses ranging from 0.050 to 30 mg/injection s.c. biweekly for 6 injections. No clinically significant adverse events were observed. Good systemic exposure to the product was obtained following s.c. injections of doses above 6 mg. IMP321 induced both sustained CD8 T-cell activation and an increase in the percentage of long-lived effector-memory CD8 T cells in all patients at doses above 6 mg. Tumor growth was reduced and progression-free survival was better in those patients receiving higher doses (>6 mg) of IMP321: 7 of 8 evaluable patients treated at the higher doses experienced stable disease at 3 months compared with only 3 of 11 in the lower dose group (P = 0.015). The absence of toxicity and the demonstration of activity at doses above 6 mg warrant further disease-directed studies of IMP321 in combined regimens (e.g., chemoimmunotherapy).Clinical Cancer Research 09/2009; 15(19):6225-31. · 7.74 Impact Factor -
Article: Human lymphocyte activation gene-3 molecules expressed by activated T cells deliver costimulation signal for dendritic cell activation.
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ABSTRACT: Data have been reported on the in vivo adjuvant role of soluble lymphocyte activation gene-3 (LAG-3) recombinant protein in mouse models and on its ability to support the in vitro generation of human, tumor-specific CTLs. In this study, we show that soluble human rLAG-3 protein (hLAG-3Ig) used in vitro as a single maturation agent induces phenotypic maturation of monocyte-derived dendritic cells and promoted the production of chemokines and TNF-alpha inflammatory cytokine. When given in association with optimal or suboptimal doses of CD40/CD40L, hLAG-3Ig functions as a strong costimulatory factor and induces full functional activation of monocyte-derived dendritic cells that includes the production of high level of IL-12p70. Moreover, evidence is here provided that this costimulatory function licensing dendritic cells to produce IL-12p70 is also a functional property of LAG-3 molecules when expressed in a physiological context by CD4(+) activated T cells. Altogether, these data show for the first time a role of LAG-3 in mediating dendritic cell activation when expressed on the T cell surface or released after specific Ag stimulation in the interspaces of immunological synapses.The Journal of Immunology 04/2008; 180(6):3782-8. · 5.79 Impact Factor -
Article: A soluble form of lymphocyte activation gene-3 (IMP321) induces activation of a large range of human effector cytotoxic cells.
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ABSTRACT: The principal antitumor immune response is mediated through the activation of type 1 cytotoxic (Tc1) CD8 T cells, NK cells, and monocytes/macrophages. In this study, we investigated the potency of a clinical-grade soluble form of lymphocyte activation gene-3 protein (IMP321), a physiological high-affinity MHC class II binder, at inducing in PBMCs an appropriate cytotoxic-type response in short-term ex vivo assays. We found that IMP321 binds to a minority (<10%) of MHC class II + cells in PBMCs, including all myeloid dendritic cells, and a small fraction of monocytes. Four hours after addition of IMP321 to PBMCs, these myeloid cells produce TNF-alpha and CCL4 as determined by intracellular staining. At 18 h, 1% of CD8+ T cells and 3.7% NK cells produce Tc1 cytokines such as IFN-gamma and/or TNF-alpha (mean values from 60 blood donors). Similar induction was observed in metastatic cancer patient PBMCs, but the values were lower for the NK cell subset. Early APC activation by IMP321 is needed for this Tc1-type activation because pure sorted CD8+ T cells could not be activated by IMP321. Only Ag-experienced, fully differentiated granzyme+ CD8 T cells (effector and effector memory but not naive or central memory T cells) are induced by IMP321 to full Tc1 activation. In contrast to IMP321, TLR1-9 agonists induce IL-10 and are therefore unable to induce this Tc1 IFN-gamma+ response. Thus, IMP321 has many properties that confirm its potential to be a new class of immunopotentiator in cancer patients.The Journal of Immunology 09/2007; 179(6):4202-11. · 5.79 Impact Factor -
Article: Rescuing CD4+CD25+ regulatory T-cell functions in rheumatoid arthritis by cytokine-targeted monoclonal antibody therapy.
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ABSTRACT: CD4+CD25+ regulatory T cells (Tregs) play a crucial role in controlling the development of autoimmune diseases such as rheumatoid arthritis (RA). However, despite an increased number of Tregs, the persistence of inflammation in the rheumatoid joints suggests that Tregs are unable to suppress ongoing disease, perhaps due to an inhibition of their functions by pro-inflammatory cytokines. Treatment of RA patients with anti-TNF-alpha monoclonal antibodies such as infliximab and adalimumab has been found to induce and restore the functions of Tregs. Thus, manipulation of the pro-inflammatory environment in the inflamed synovia via neutralization of inflammatory cytokines by monoclonal antibodies could represent a novel therapeutic strategy for restoring the suppressive functions of Tregs and induction and/or expansion of Tregs in order to reinforce tolerance mechanisms.Drug Discovery Today 08/2007; 12(13-14):548-52. · 6.83 Impact Factor -
Article: IMP321 (sLAG-3) safety and T cell response potentiation using an influenza vaccine as a model antigen: a single-blind phase I study.
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ABSTRACT: sLAG-3 (IMP321), a natural high affinity ligand for MHC class II, was tested for safety, tolerability and its ability to increase Th-1-type T cell responses to a commercial trivalent split influenza vaccine (Agrippal) in a phase I single-blinded, randomized, controlled clinical trial. Twenty healthy volunteers were first injected with increasing doses of IMP321 alone (safety for first-in-man use). Then 40 volunteers were recruited into 4 consecutive cohorts of 10 subjects, who were randomly assigned to receive the flu vaccine plus 3, 10, 30 or 100 microg IMP321 or the flu vaccine plus saline control. All vaccine formulations were found to be generally well tolerated with similar frequency and intensity of adverse reaction in groups receiving IMP321 as in controls. Post-vaccination humoral immune responses, as determined 29 and 57 days later by assay of hemagglutinin inhibition activity were similar for both IMP321 and control groups. In contrast, the addition of 10, 30 or 100 microg IMP321 to the flu vaccine resulted in higher levels of Th1-type (IFN-gamma, TNF-alpha or IL-2) flu-specific CD4 T cells in PBMC recovered at D29 and D57 and tested in a short-term ex vivo restimulation assay (6-colour FACS analysis after intra-cellular staining of cytokines). In summary, IMP321 as an adjuvant to a model antigen (Agrippal) was well-tolerated and may enhance T cell response vaccine immunogenicity.Vaccine 07/2007; 25(24):4641-50. · 3.77 Impact Factor -
Article: Human dendritic cells acquire a semimature phenotype and lymph node homing potential through interaction with CD4+CD25+ regulatory T cells.
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ABSTRACT: Interactions between dendritic cells (DC) and T cells are known to involve the delivery of signals in both directions. We sought to characterize the effects on human DC of contact with different subsets of activated CD4+ T cells. The results showed that interaction with CD25(high)CD4+ regulatory T cells (Tregs) caused DC to take on very different properties than contact with naive or memory phenotype T cells. Whereas non-Tregs stimulated DC maturation, culture with Tregs produced DC with a mixed phenotype. By many criteria, Tregs inhibited DC maturation, inducing down-regulation of costimulatory molecules and T cell stimulatory activity. However, DC exposed to Tregs also showed some changes typically associated with DC maturation, namely, increased expression of CCR7 and MHC class II molecules, and gained the ability to migrate in response to the CCR7 ligand CCL19. Both soluble factors and cell-associated molecules were shown to be involved in Treg modulation of DC, with lymphocyte activation gene 3 (LAG-3) playing a predominant role in driving maturation-associated changes. The data show that Tregs induce the generation of semimature DC with the potential to migrate into lymphoid organs, suggesting a possible mechanism by which Tregs down-modulate immune responses.The Journal of Immunology 05/2007; 178(7):4184-93. · 5.79 Impact Factor -
Article: IMP321 (sLAG-3), an immunopotentiator for T cell responses against a HBsAg antigen in healthy adults: a single blind randomised controlled phase I study.
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ABSTRACT: LAG-3 (CD223) is a natural high affinity ligand for MHC class II. The soluble form (sLAG-3) induces maturation of monocyte-derived dendritic cells in vitro and is used as a potent Th1-like immune enhancer with many antigens in animal models. To extend this observation to human, a proof of concept study was conducted with a clinical-grade sLAG-3, termed IMP321, coinjected with alum-non-absorbed recombinant hepatitis B surface antigen. In a randomised, single blind controlled phase I dose escalation study, 48 seronegative healthy volunteers aged 18-55 years were vaccinated at 0, 4 and 8 weeks by subcutaneous injection with 10 microg HBsAg mixed with saline (control) or with IMP321 at one of four doses (3, 10, 30 and 100 microg). To evaluate the efficacy of this three injections over 2 months immunization protocol, an additional control group was injected with the commercial vaccine Engerix-B. IMP321 was very well tolerated. Indeed, a lower incidence of adverse events was reported from the HBsAg plus IMP321 groups than from the Engerix-B group. HBsAg-specific antibody responses (anti-HBs) appeared sooner and were higher at 8 and 12 weeks in IMP321 recipients compared to HBsAg control subjects. More importantly, increased numbers of responders to HBsAg were found in IMP321 recipients compared HBsAg group, as revealed by higher post-vaccination frequencies of CD4 Th1 or CD8 Tc1 antigen specific T cells. IMP321 induced CD4 Th1 antigen-specific T cells in some of these naïve individuals after only one injection, especially in the 10 and 30 microg dose groups. IMP321 as an adjuvant to HBsAg was well-tolerated and enhanced T cell response vaccine immunogenicity (i.e. induced both CD4 Th1 and CD8 Tc1 antigen-specific T cells). This latter property has allowed the development of IMP321 as an immunopotentiator for therapeutic vaccines.Journal of Immune Based Therapies and Vaccines 01/2007; 5:5. -
Article: Low‐dose IL‐2 treatment: Activation of discrete T‐ and NK‐cell sub‐populations in vivo
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ABSTRACT: The activation of T- and NK-cell sub-populations in vivo was evaluated in a phase-l study (18 patients) with a 3-month course of low-dose s.c. IL-2, 1,3 and 6±10* IU/day once daily, 6 days a week. At the higher doses, we observed early on (day 15) an increase in CD3+ CD56−, CD3− CD56+ and CD56+ DR+ cell counts, as well as an increase in circulating slL-2R and non-MHC-restricted cytotoxicity against K562 and Daudi cells. In contrast, at the lowest dose, T- and NK-cell counts were not appreciably altered, while a substantial increase in NK cytotoxic activity was still observed. In addition, thyroid dysfunction resembling that described in auto-immune thyroiditis, was documented in 6 out of the 14 patients studied. Using a high-resolution method analyzing CDR3 sizes of TCRp transcripts, we observed the appearance of dominant T-cell clonotypes in I patient out of 2 analyzed, corresponding to the clonal expansion of T cells primed in vivo. Overall, these results show that long courses of low-dose s.c. IL-2 treatment lead to the activation of discrete T-and NK-cell sub-populations. © 1995 Wiley-Liss, Inc.International Journal of Cancer 07/2006; 62(5):523 - 528. · 5.44 Impact Factor -
Article: A soluble LAG-3 protein as an immunopotentiator for therapeutic vaccines: Preclinical evaluation of IMP321.
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ABSTRACT: A soluble LAG-3 (CD223) molecule (sLAG-3) is a natural high affinity ligand for MHC class II. It is known to induce maturation of monocyte-derived dendritic cells in vitro and is used as a vaccine adjuvant to induce CD4 Th1 and CD8 T cell responses in vivo. The work presented herein was performed to study the biological activity of a preclinical grade human sLAG-3 protein, called IMP321: (i) binding on murine APC, (ii) induction of dendritic cell maturation, (iii) safety of repeated injections in mice. The results show that IMP321 binds MHC class II(+) murine APC, induces the maturation of dendritic cells and is well tolerated either injected alone or as an adjuvant with strongly immunogenic antigens.Vaccine 07/2006; 24(26):5426-33. · 3.77 Impact Factor -
Article: A soluble lymphocyte activation gene-3 (sLAG-3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors.
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ABSTRACT: In contrast to the long-held belief that breast cancer is a weakly immunogenic tumor, accumulating evidence indicates an immune infiltrate is an invariable finding in breast cancers, raising hopes that immunotherapy for breast cancers may succeed in targeted patients, specifically those with either regional or minimal residual disease. However, no immunologically related prognostic factor has yet been established that may help to define subsets of patients who are more prone to respond to immunotherapy. High levels of soluble LAG-3 protein (sLAG-3) in sera has previously been shown to be associated, as a Th1 marker, to resistance to tuberculosis in large series of patients. We therefore hypothesized that, if cell-mediated immune mechanisms are indeed important for improved prognosis, high levels of sLAG-3 might be correlated with improved survival in some subsets of breast cancer patients. Studying a cohort of 246 patient's sera collected in 1994 at time of first diagnosis, we found that both disease-free and overall survival rates were greater in patients with estrogen or progesterone receptor positive tumor cells who had detectable levels of sLAG-3 at diagnosis versus patients with undetectable sLAG-3 levels. These results indicate that sLAG-3 may be a valuable marker for prognosis in some subsets of breast cancers and, more importantly, that cell-mediated mechanisms such as Th1 responses do have an impact on survival, a pre-requisite before the setting-up of immunotherapy protocols as a form of adjuvant therapy for breast cancer.Cancer Letters 05/2006; 235(1):147-53. · 4.24 Impact Factor -
Article: Soluble human LAG-3 molecule amplifies the in vitro generation of type 1 tumor-specific immunity.
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ABSTRACT: The adjuvant activities of the human lymphocyte activation gene-3 (LAG-3) molecule have been evaluated in a human setting by investigating the ability of a soluble recombinant human LAG-3 protein (hLAG-3Ig) to enhance the in vitro induction of viral- and tumor-specific CTLs. We found that soluble human LAG-3 significantly sustained the generation and expansion of influenza matrix protein Melan-A/MART-1 and survivin-specific CD8+ T lymphocytes in peripheral blood mononuclear cells (PBMC) of both cancer patients and healthy donors, showing its ability to boost CD8+ T-cell memory response or to prime naive T cells in vitro. The peptide-specific T cells generated in the presence of hLAG-3Ig were endowed with cytotoxic activity and enhanced release of type 1 cytotoxic T (Tc1) cytokines and were able to recognize tumor cells expressing their nominal antigen. Phenotype and cytokine/chemokines produced by antigen-presenting cells (APC) of PBMCs exposed in vitro for 2 days to peptide and hLAG-3Ig indicate that the LAG-3-mediated adjuvant effect may depend on a direct activation of circulating APCs. Our data revealed the activity of hLAG-3Ig in inducing tumor-associated, antigen-specific CD8+ T-cell responses in a human setting and strongly support the conclusion that this recombinant protein is a potential candidate adjuvant for cancer vaccines.Cancer Research 05/2006; 66(8):4450-60. · 7.86 Impact Factor -
Article: The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells.
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ABSTRACT: Accumulating evidence indicates that the CD4 homologue lymphocyte activation gene-3 (LAG-3) plays a down-regulatory role on T-cell responses. However, the role of LAG-3/major histocompatibility complex (MHC) class II interactions on primary human T-cell responses, as well as the mechanism by which down-regulation occurs, are not clear. Here, we show that LAG-3 colocalized with CD3, CD4 or CD8 in areas of cholesterol-rich raft aggregation during this primary response, as well as in the clustered raft region formed between T cells and antibody-coated beads. Addition of a blocking LAG-3-specific monoclonal antibody to both CD4 and CD8 primary resting T cells activated under conditions of antigen-presenting cell-driven stimulation and low antigen concentrations augments CD69 activation antigen expression, T-cell expansion and T helper 1 (Th1, but not Th2) cytokine production. Blocking LAG-3/MHC class II interactions leads to an increase in the number of cells entering division at these low concentrations of antigen and to more rounds of divisions with an accumulation of cells in the S-phase of the cell cycle. These results indicate that LAG-3 signalling inhibits early events in primary activation of human CD4 and CD8 T cells and further support a role for LAG-3 signalling in regulating the expansion of activated effector or memory T cells, either directly or indirectly through Treg suppressor activity.Immunology 07/2005; 115(2):170-8. · 3.32 Impact Factor -
Article: LAG-3 (CD223) reduces macrophage and dendritic cell differentiation from monocyte precursors.
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ABSTRACT: Major histocompatibility complex (MHC) class II molecules expressed on monocytes may play a role in the control of differentiation of antigen-presenting cells. A soluble LAG-3 (CD223) molecule (sLAG-3) is a natural, high-affinity ligand for MHC class II. It is known to induce maturation of monocyte-derived dendritic cells in vitro and is used as a vaccine adjuvant to induce CD4 T helper type 1 responses and CD8 T-cell responses in vivo. Here, we demonstrate that sLAG-3 (but not an MHC class II-specific monoclonal antibody) reduces the differentiation of monocytes into macrophages in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) as well as their differentiation into dendritic cells in the presence of GM-CSF and interleukin-4, as shown by a decrease in CD14 and CD1a expression, respectively. Dendritic cells derived from monocytes in the presence of sLAG-3 showed impaired antigen-presentation function, as assessed by the reduced capability to induce proliferation of T cells. Our results suggest that activated LAG-3(+) lymphocytes present at sites of inflammation may reduce the differentiation of monocytes into macrophages or fully competent antigen-presenting dendritic cells, thus limiting the magnitude of the ongoing T-cell immune responses.Immunology 04/2005; 114(3):369-74. · 3.32 Impact Factor -
Article: LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination.
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ABSTRACT: The function mediated by the engagement of the lymphocyte activation gene-3 (LAG-3, CD223) receptor expressed on activated T cells by its MHC class II ligand has remained enigmatic, partly owing to discrepancies between published results in human and mouse systems. Recent studies in mice have reconciled previous interpretations and clearly show that, as in human cells, LAG-3 negatively regulates T-cell function and homeostasis. As a soluble molecule, LAG-3 activates antigen-presenting cells through MHC class II signalling, leading to increased antigen-specific T-cell responses in vivo.Trends in Immunology 01/2004; 24(12):619-22. · 10.40 Impact Factor -
Article: MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223).
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ABSTRACT: On encountering a danger signal, dendritic cells (DCs) undergo a complex maturation process and become specialized in antigen presentation. We previously reported that engagement of major histocompatibility complex (MHC) class II molecules located on immature DCs in membrane rafts by lymphocyte activation gene-3 (LAG-3; CD223) leads to DC maturation. In contrast, exposure of DCs to class II-specific monoclonal antibodies (mAbs) did not lead to maturation. Here, we have investigated the signal transduction pathways involved in the LAG-3-induced maturation of human monocyte-derived DCs. We first show that areas of raft aggregation (both cholesterol rich and CDw78 microdomains) could be visualized using a soluble LAG-3 protein and confocal microscopy. Engagement of class II molecules by both its natural ligand LAG-3 and class II mAb induces rapid protein phosphorylation of phospholipase Cgamma2 (PLCgamma2) and p72syk as well as activation of phosphatidyl inositol 3-kinase/Akt, p42/44 extracellular signal-regulated protein kinase, and p38 mitogen-activated protein kinase pathways. Studies using inhibitors demonstrate that these 3 pathways are all important in inducing the maturation process of LAG-3-stimulated DCs. When class II molecules were ligated with LAG-3 versus specific antibody, differences in the phosphorylation pattern of c-Akt were observed. Thus, MHC class II signaling in DCs involves several pathways that have to be finely regulated to lead to cell activation and maturation.Blood 10/2003; 102(6):2130-7. · 9.90 Impact Factor -
Article: MHC class II engagement by its ligand LAG-3 (CD223) leads to a distinct pattern of chemokine and chemokine receptor expression by human dendritic cells.
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ABSTRACT: Upon stimulation by infectious agent products, dendritic cells (DC) become activated, express high levels of class I and class II antigens, CD80, CD86 and CD83 and migrate to secondary lymphoid organs where they can prime naive CD4-helper and CD8-cytotoxic T-cells. Cognate CD4(+) T-cell help mediated by CD40L along with DC stimulation with another T-cell effector molecule, termed lymphocyte activated gene-3 (LAG-3 or CD223, a ligand for MHC class II) have been shown to induce this maturation process. Both CD40L and LAG-3 have been used as vaccine adjuvants to induce CTL and CD4 Th1 responses. Here, we studied the effect of a soluble LAG-3Ig molecule on the chemokine and chemokine receptor profile of human immature monocyte-derived DC. LAG-3Ig, unlike CD40L, induced an inflammatory signal in terms of IL-8 and MIP-1alpha/CCL3 production and, in contrast to LPS, induced production of chemokines (MDC/CCL22 and TARC/CCL17) known to direct the migration of maturing DC to lymph nodes. In LAG-3-matured DC, surface expression of CCR5 (a receptor for MIP-1alpha/CCL3) was down-regulated and CCR7 (a receptor for MIP-3beta and SLC) was up-regulated. However, LAG-3-matured, but not LPS- or CD40L-matured DC retained their capacity to migrate in chemotaxis chambers and to respond to MIP-1alpha. Altogether, these data represent the first evidence that MHC class II signaling may affect DC migration to secondary lymphoid tissues.Vaccine 03/2003; 21(9-10):862-8. · 3.77 Impact Factor
Top co-authors
Top Journals
Institutions
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2010
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Istituto di Cura e Cura a Carattere Scientifico Basilicata
Rionero in Vulture, Basilicate, Italy
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2008
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Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
Milano, Lombardy, Italy
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2001–2006
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Université Paris-Sud 11
- Faculté de Pharmacie
Paris, Ile-de-France, France -
Institut de Cancérologie Gustave Roussy
Villejuif, Ile-de-France, France
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1997
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Institut national de la santé et de la recherche médicale
Paris, Ile-de-France, France
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