PubMed Health⌕ Search

Biomedical subjects

A Bensussan

Publications and source records attributed to A Bensussan.

At least 19 recordsLinked to original sources
PubMed2003

Isolation of a CD8alphaalpha+ CD4- tumour T-cell clone with cytotoxic activity from a CD4+ CD8- cutaneous T-cell lymphoma.

BACKGROUND: We have previously established tumour T-cell lines, both from the skin and from the blood of patients with a cutaneous T-cell lymphoma (CTCL). In one patient, the tumour cells and the derived cell lines had a CD3+ CD4+ CD8- phenotype and a trisomy of chromosome 7. They expressed three T-cell receptor (TCR) beta-chain transcripts, but only one was productively rearranged and expressed at the cell membrane. OBJECTIVES: In the present study, we tried to isolate a fast-growing new tumour T-cell line from the same patient. PATIENTS/METHODS: We performed direct cell cloning of the skin tumour lymphocyte population, which led to the isolation of an interleukin-2-dependent highly proliferative T-cell subclone, named Cou-L3, with a CD3+ TCR-Vbeta13+ CD4- CD8alphaalpha+ phenotype. RESULTS: We demonstrated that Cou-L3 was identical to the original clonal tumour CD3+ Vbeta13+ CD4+ CD8- cells, as it expressed the same rearranged TCR-Vbeta13 chain. We further studied the functional activity of these CD8alphaalpha+ Vbeta13+ Cou-L3 cells. We found that these cells exhibited CD3-redirected cytotoxic activity. CONCLUSIONS: An immunophenotypic shift, with a change from a CD4+ to a CD8+ phenotype, has been already reported in association with disease progression in CTCL. However, in these cases, there has been no demonstration that the phenotypic change involved the same T-cell clone. The present study is the first report of the phenotypic heterogeneity of the tumour clonal cell population in CTCL.

Aged↗
PubMed2002

Identification of cell surface molecules characterizing human cutaneous T-cell lymphomas.

Primary cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of malignant mature T-cell proliferations most often presenting as mycosis fungoides (MF) or its leukemic variant, Sezary syndrome (SS). No specific cell surface markers are presently available to distinguish the circulating malignant clone from normal lymphocytes. Using the previously established CTCL cell lines, Cou-LS and Pno, we have detected two leucocyte cell surface antigens with aberrant expression on CTCL cells. The NK-receptor (NKR) p140/KIR3DL2 normally expressed by NK and CD8+ T-cells was detected on the surface of CTCL cell lines as well as on freshly isolated CD4+PBL from SS patients. Further on, p140 marked in situ SS cells, distinguishing them from p140-negative tumor cells of patch plaque MF. SC5 is a newly described activation-related intracellular inhibitory receptor expressed on the surface of a minor PBL subset. We found that SC5 expression was significantly increased in SS cells and correlated to p140 expression. Moreover, cross-linking of SC5 molecules inhibited the malignant cell proliferation induced by anti-CD3 mAbs. The identification of these new structures on circulating SS tumor cells seems to be important both for the understanding of CTCL pathophysiology and for the clinical management of SS patients.

Antigens, Surface↗
PubMed2001

CD antigens 2001.

Explore the source record for details and available documents.

Antigens, CD↗
PubMed2001

Biological activity of soluble CD100. I. The extracellular region of CD100 is released from the surface of T lymphocytes by regulated proteolysis.

CD100 is the first semaphorin described in lymphoid tissues, where it has been shown to be associated with a serine kinase activity. Semaphorins are molecules involved in axon pathfinding during nerve development and act as repellent guidance cues. In the nervous system semaphorins exist as either membrane-bound or secreted forms. We report here a spontaneous processing of membrane CD100, suggesting that it is also produced as a diffusable semaphorin from lymphoid cells. Monomeric and homodimeric forms of CD100 are expressed by T lymphocytes and CD100-transfected fibroblasts. We demonstrate that CD100 is released through a proteolytic process blocked by metalloprotease inhibitors. In T cells, only soluble CD100 dimers are produced, suggesting that CD100 dimerization is required for proteolysis. In agreement, we observe that increasing membrane dimers strongly favors shedding of the molecule. By expressing a CD100 molecule mutated at cysteine 674 into a COS cell system, we additionally demonstrate that this particular residue in the extracellular domain of the molecule is required for dimerization. Finally, we show that staurosporine, a serine kinase inhibitor, enhances the membrane cleavage of CD100. Together these results demonstrate that membrane CD100 is cleaved by a metalloprotease-dependent process, which is probably regulated by phosphorylation. Mainly, these findings shed light on a possible function for the semaphorin region of CD100 as a long range guidance cue in the immune system.

3T3 Cells↗
PubMed2001

Biological activity of soluble CD100. II. Soluble CD100, similarly to H-SemaIII, inhibits immune cell migration.

CD100 is a human 150-kDa homodimer expressed at the surface of most hemopoietic cells, and its gene belongs to the Ig and semaphorin gene families. Semaphorin genes encode soluble and membrane-bound proteins, most of which have been shown to act as chemorepellents on growth cone guidance. CD100 is discrete, as it is a transmembrane leukocyte surface molecule that can also exist in a soluble form. While our previous studies using mAbs suggested that the transmembrane form of CD100 plays a role in lymphocyte activation, no function was shown for its soluble form. Here, we investigated the effect of soluble CD100 in a cell migration assay; both CD100 spontaneously shed from a stable transfectant and soluble recombinant CD100 inhibited spontaneous and chemokine-induced migration of human monocytes. Interestingly, only the dimeric form of CD100 exerted an effect. Moreover, soluble CD100 inhibited migration of cells from monocytic and B cell lineages. A similar inhibitory effect on migration was observed with H-SemaIII, but not H-SemaIV, semaphorins. In addition, both CD100 and H-SemaIII were recognized by two CD100 mAbs in an ELISA, and one of these mAb abolished the inhibitory effect of each of these semaphorins. We also provide evidence that CD100 and H-SemaIII act through the same receptor on immune cells, which is not neuropilin-1. Furthermore, we describe a function on immune cells for H-SemaIII, a semaphorin to date only studied in the nervous system.

3T3 Cells↗
PubMed2001

CD4(+) cutaneous T-cell lymphoma cells express the p140-killer cell immunoglobulin-like receptor.

Tumor cells of patients with cutaneous T-cell lymphoma (CTCL) have the cell surface phenotype of mature T-helper lymphocytes, and it may be impossible to differentiate them from nonmalignant lymphocytes in skin and blood. Until now, no specific cell membrane marker of CTCL has been reported. In the current study, it is reported for the first time that CTCL cells express the major histocompatibility complex class I binding p140-killer cell immunoglobulin-like receptor, which has been described on a minor subset of natural killer lymphocytes and on a marginal circulating CD8(+) T lymphocyte subset. Interestingly, the molecular characterization of this KIR expressed by CTCL allowed us to isolate a novel allelic form of p140-KIR3DL, resulting in 4 amino acid substitutions, 3 in the extracellular immunoglobulin-like domain of the protein and one in the cytoplasmic region. This finding is likely to be important both for the pathophysiology and for the clinical treatment of patients with CTCL.

Amino Acid Sequence↗
PubMed2001

CD antigens 2001.

The most recent Human Leucocyte Differentiation Antigen Workshop ("HLDA7") took place in 2000 in Harrogate, UK and the proceedings are about to be published (Leucocyte Typing VII). New Sections were introduced in this Workship (Dendritic cells, Stem/progenitor cells, Erythroid cells and Carbohydrate Structures) and monoclonal antibodies were selected for which at least some molecular data were already available (to avoid "blind" screening of reagents against known specificities). A total of more than 80 new CD specificities were established (previously the average was less than 30 new CD specificities per Workshop) and these are listed in this article. There is already evidence for the existence of many new leucocyte surface molecules for study at the next HLDA Workshop (in Adelaide in 2004), and we have listed in this article a number of such potential CD candidates (identified following the production of monoclonal antibodies or via gene cloning). There are also today an increasing number of lineage- and/or stage-restricted leucocyte-associated molecules localised within the cell cytoplasm (or nucleus): they will certainly prove of intense in the future for many laboratories studying human haematopoietic cells (regardless of whether a new "intracellular CD" categorisation scheme is devised for such molecules).

Antigens, CD↗
PubMed2001

Study of cord blood natural killer cell suppressor activity.

We tested the immunosuppressive effect of cord blood (CB) natural killer (NK) cells using highly purified CB NK cells in mixed lymphocyte cultures (MLC) containing autologous CB T cells as responders. Control cultures were done without NK cells. Our findings revealed that CB NK cells induced a dose-dependent inhibition of T lymphocyte proliferation as evidenced by decreased 3H-thymidine incorporation in MLC. The T cell alloproliferation was significantly decreased in the presence of an NK cell to responder cell ratio of 0.1, 0.2 or 0.4 compared with control cultures done without NK cells (p=0.02, 0.003 and 0.0002, respectively). T lymphocyte inhibition was also achieved using irradiated CB NK cells and still demonstrable on addition of disparate CB NK and T cells to the MLC. In agreement with previous reports, adult blood NK cells inhibited the alloreactive T cells in the MLC using adult T lymphocytes as responders. Compared to control cultures done without NK cells, statistically significant inhibition of 3H-thymidine incorporation in MLC was observed at a ratio of NK cells to responder cells ratio of 0.2 or 0.4 (p=0.02). To investigate the mechanism whereby CB NK cells can interfere with the development of alloreactive T cells in MLC, we measured the tumour necrosis factor-alpha (TNF-alpha) concentrations in MLC supernatants using NK cell-depleted or unseparated CB mononuclear cells (MNC) as responders. The results revealed significantly high levels of TNF-alpha in the absence of NK cells (p=0.007). We conclude that CB NK cells suppress alloreactive T lymphocytes as do their counterparts in adult blood. However, the high NK to T cell ratio in CB could contribute to a more marked suppressive potential compared to that in adult blood. The mechanism of NK-mediated inhibition is likely related to disruption of the TNF-alpha pathway of T-lymphocyte activation.

Adult↗
PubMed2001

Functional characterization of neurotensin receptors in human cutaneous T cell lymphoma malignant lymphocytes.

Cutaneous T cell lymphomas are a clonal proliferation of CD4+ T lymphocytes primarily involving the skin. Mycosis fungoides is an epidermotropic CD4+ cutaneous T cell lymphoma, and a more aggressive form, Sezary syndrome, occurs when the malignant cells become nonepidermotropic. The role of neuropeptides in the growth and chemotaxis capacity of cutaneous T cell lymphoma cells remains unknown. In this report, we found that cutaneous T cell lymphoma cells, similarly to normal resting or activated peripheral lymphocytes, were able to bind neurotensin. We used an interleukin-2-dependent cutaneous T cell lymphoma malignant T cell line derived from cutaneous T cell lymphoma lesions in order to study the role of neurotensin in the proliferation and migration of these malignant cells. First, we determined that the malignant cells expressed neurotensin receptors on their cell membrane. Functional results indicated that neurotensin did not stimulate the growth of the cell line. In contrast, this neuropeptide inhibited the proliferation of the tumor cells in response to exogenous interleukin-2. Furthermore, we found that neurotensin enhanced both spontaneous and chemoattractant-induced migration of the malignant cells. This suggests that neurotensin in skin can play a role in the disease by locally limiting the growth of the cutaneous T cell lymphoma tumor cells in response to cytokines and by enhancing their chemotaxis capacity.

CD4-Positive T-Lymphocytes↗
PubMed2001

Increased expression of a novel early activation surface membrane receptor in cutaneous T cell lymphoma cells.

Using a newly generated monoclonal antibody we identified the 96 kDa transmembrane receptor SC5 expressed simultaneously on a human Sezary cell line and a minor T cell subset in normal individuals. SC5 antigen was detected mostly on CD45RO+ lymphocytes from both CD4+ and CD8+ subsets as well as on natural killer and B lineage cells. SC5 surface expression increased very early after polyclonal stimulation of CD3+ cells due to the transfer of intracellular SC5 molecules to the cell membrane. Engagement of SC5 receptor by its monoclonal antibody inhibited the anti-CD3-induced proliferation and cytokine secretion of peripheral blood T cells and cell clones, whereas SC5 monoclonal antibody did not affect the cytotoxic activity of CD8+ T cell clones. Extensive phenotypic analysis revealed that the percentage of SC5+ CD4+ circulating lymphocytes in Sezary syndrome patients was significantly increased in comparison with controls (p < 0.01) and correlated with the morphologically detected percentage of Sezary syndrome cells in peripheral blood (p < 0.001). In one patient we clearly demonstrated that the circulating malignant T cells coexpress SC5 molecules. Importantly, ligation of SC5 receptor in a cutaneous T cell lymphoma cell line profoundly inhibited the anti-CD3-induced proliferation. Consequently, the expression of SC5 receptor in the peripheral blood of Sezary syndrome patients may serve not only to detect the presence of circulating malignant CD4+ cells but also as a target for immunotherapy.

Antibodies, Monoclonal↗
PubMed2001

Erythrodermic cutaneous T-cell lymphoma with disseminated pustulosis. Production of high levels of interleukin-8 by tumour cells.

Interleukin (IL) -8 is a neutrophil chemoattractant cytokine with proinflammatory and growth-promoting activities, which is involved in the pathogenesis of several inflammatory diseases. It is found in high amounts in lesional biopsies of pustular diseases such as psoriasis and palmoplantar pustulosis. We report a 50-year-old woman with a 10-year history of erythroderma with disseminated pustulosis. Skin biopsies showed an epidermotropic infiltrate composed of atypical CD4+ CD8+ lymphocytes with numerous admixed neutrophils. Peripheral blood flow cytometric analysis revealed a major clonal subset of CD3+ CD4+ CD8+ T-cell receptor Vbeta22+ atypical lymphocytes. Bone marrow biopsy, lymph node biopsy and computed thoracoabdominal tomography were normal. Serologies for human T-cell lymphotropic virus type I and human immunodeficiency virus were negative. Our patient's status deteriorated despite topical (nitrogen mustard, psoralen plus ultraviolet A) and systemic (interferon, methotrexate, multiagent chemotherapy) treatments, and she finally died. We showed that our patient's peripheral blood lymphocytes (PBL) spontaneously produced high amounts of IL-8. In contrast, PBL of patients with classical Sézary syndrome produced lower amounts of IL-8. The production of IL-8 by tumour T cells could explain this unusual clinical and histopathological presentation of cutaneous T-cell lymphoma as disseminated pustulosis.

Dermatitis, Exfoliative↗
PubMed2001

CD antigens 2001.

Explore the source record for details and available documents.

Antibodies, Monoclonal↗
PubMed2001

Multiple co-stimulatory signals are required for triggering proliferation of T cells from human secondary lymphoid tissue.

Vaccine-based therapies are being developed for a variety of cancers and their efficacy will be determined by their ability to stimulate T cells in the secondary lymphoid tissue. We found that T cells isolated from human secondary lymphoid organs (LT-T), in contrast to peripheral blood T cells (PB-T) are hyporesponsive to cross-linked anti-CD3 mAb (CD3c) even in the presence of exogenous IL-2. Using mAb to trigger CD2 and CD28 co-stimulatory molecules, we found that such dual co-stimulation of LT-T induces profound and sustained responses including CD25 expression, IL-2 secretion and proliferation. Different levels of co-stimulation produced a hierarchical pattern of responses in LT-T, which correlated with the degree of CD3-TCR down-regulation. Mature antigen-presenting cells (APC) restored the capacity of LT-T to proliferate to stimulation of the CD3-TCR complex. Blocking studies demonstrated that optimal proliferation was critically dependent on co-stimulation via CD2 and CD28 engaged by their ligands on the APC. Therefore, LT-T have increased co-stimulatory requirements as compared to PB-T, i.e. multiple co-stimulatory signals coupled to CD3-TCR triggering. Furthermore, LT-T were found to be dependent on APC for survival, in contrast to PB-T. Clearly, LT-T do not behave in a comparable way to PB-T and in vitro experiments assessing novel cancer vaccines should therefore use LT-T as the most appropriate population of responder T cells.

Adult↗
PubMed2001

CD antigens 2001.

Explore the source record for details and available documents.

Antigens, CD↗
PubMed2001

Crosstalk between tumor T lymphocytes and reactive T lymphocytes in cutaneous T cell lymphomas.

We have established several tumor T cell lines, both from the skin and from the blood of a patient with an MHC class II-/class I+, CD4+ cutaneous T cell lymphoma (CTCL). These cell lines, like the initial tumor cells, had a CD3+CD4+CD8- phenotype. We also isolated two cytotoxic T lymphocyte clones from the tumor site of this CTCL patient. These clones displayed a CD4+CD8dim+ (TC5) and CD4+CD8- (TC7) phenotype and mediated a specific MHC class I-restricted cytotoxic activity toward noncultured tumor cells and autologous tumor cell lines. Despite surface expression of Fas on tumor cells and Fas-L induction on TC5 and TC7 cell membrane after coculture with autologous tumor cells, the CD4+ CTL clones did not use this cytotoxic mechanism to lyse their specific target. TC7 used a granzyme/perforin-dependent pathway, whereas TC5 used a TRAIL-dependent mechanism. Quantitative analysis of cytokine mRNA expression indicated that while the tumor cells displayed a Th2-type profile, the CTL clones expressed Th1-type cytokines. Preincubation of TIL clones with autologous tumor cells in a short-term culture induced their activation and subsequent amplification of the Th1-type response, which indicates a direct contribution of the malignant cells in the Th1/Th2 imbalance. However, we found that tumor cells produced high amounts of TGF-beta, which could explain the inhibition of a specific antitumor immune response. Another mechanism to avoid the host immune response was the expression of CD158a, CD158b, p70, and CD94/NKG2A inhibitory receptors by tumor-specific lymphocytes. Finally, we present recent data on new antigen structures expressed both by long-term CTCL lines and uncultured tumor cells.

Antigens, Neoplasm↗
PubMed2001

The receptors regulating natural cytotoxic effector functions.

Natural cytotoxic effector functions are regulated by a multitude of opposing signals provided by immunoglobulin and lectin-like functional molecules. While inhibitory receptors possess immunoreceptor tyrosine-based inhibition motif (ITIM) cytoplasmic sequences recruiting tyrosine phosphatases, activatory receptors require association with accesory immunoreceptor tyrosine-based activation motif (ITAM)-bearing molecules. One considerable group of natural cytotoxic cell receptors are specific for classical and non-classical class I antigens and detect both qualitative and quantitative changes in the autologous MHC-I phenotype. Non-MHC-I-specific receptors provide signaling in the absence of MHC-I antigens or in response to not well-known stress-induced antigens. NK cell receptors may equally participate in the regulation of target cell functions through contact or souble mediator-dependent mechanisms. The identification of NK cell regulating molecules has led to the elucidation of more general principles underlying immune homeostasis.

Animals↗