CD antigens 2001.
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Antibodies, Monoclonal↗
Biomedical subjects
A Bensussan
Publications and source records attributed to A Bensussan.
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↗
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↗
CD antigens 2001: aims and results of HLDA Workshops.
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Antigens, CD↗
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↗
CD antigens 2001.
This paper reviews the Seventh Human Leucocyte Differentiation Antigen (HLDA7) workshop. Due to the limitations of "blind" antibody screening, which had been evident at the previous meeting in 1996, participants at HLDA7 adopted a more selective approach to the choice of antibodies by identifying new CD specificities. This resulted in the addition of more than 80 new CD specificities. Plans for the eighth and subsequent workshops are also previewed.
Antibodies, Monoclonal↗
Functional characterization of an IL-7-dependent CD4(+)CD8alphaalpha(+) Th3-type malignant cell line derived from a patient with a cutaneous T-cell lymphoma.
CDR3 of the functional rearranged T-cell receptor variable beta region (TCR-Vbeta) transcript was sequenced in order to demonstrate for the first time the identity between a long-term cultured T-cell line derived from a cutaneous T-cell lymphoma (CTCL) patient and the malignant T-cell clone present in the blood. The patient's peripheral blood lymphocyte-derived cultured T-cell line had a CD3(+)Vbeta22(+)CD4(+)CD8alphaalpha(+)CD25(-) phenotype. It was named Pno and had been cultured for more than 1 year. Both fresh and long-term-cultured tumor cells proliferated highly in response to interleukin-7 (IL-7), and exogeneous IL-7 prevented Pno lymphocytes from apoptosis and maintained high levels of Bcl-2 expression. This unique malignant cloned lymphocyte line was further used to carry out functional studies. The results indicated that the CD3/TCR structures expressed by the Pno lymphocytes were functional because an immobilized anti-CD3 monoclonal antibody (mAb) or the combination of a soluble anti-CD3 mAb with submitogenic doses of phorbol 12 beta-myristate 13 alpha-acetate induced a proliferative response. Further, the CD2 and CD28 coreceptors were functional because they were able to induce a strong proliferative response upon their specific stimulation. Finally, the Pno T cell line had a Th3-type cytokine profile because it produced high amounts of the immunosuppressor cytokine tumor growth factor-beta1 (TGF-beta1). This high production of TGF-beta1 may inhibit antitumor specific responses in CTCL.
CD4 Antigens↗
Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8.
The nonpolymorphic soluble HLA-G1 (sHLA-G1) isoform has been reported to be secreted by trophoblast cells at the materno-fetal interface, suggesting that it may act as immunomodulator during pregnancy. In this paper, we report that affinity-purified beta2-microglobulin-associated sHLA-G1 triggered apoptosis in activated, but not resting CD8+ peripheral blood cells. We demonstrate by Western blotting that sHLA-G1 enhanced CD95 ligand expression in activated CD8+ cells. Cytotoxicity was inhibited by preincubation of the cells with a CD95 antagonist mAb (ZB4) or a soluble recombinant CD95-Fc, indicating that apoptosis is mediated through the CD95/CD95 ligand pathway. Finally, we show that such sHLA-G1-induced apoptosis depends on the interaction with CD8 molecules, with cell death being blocked by various CD8 mAbs.
Adjuvants, Immunologic↗
Switch in the protein tyrosine phosphatase associated with human CD100 semaphorin at terminal B-cell differentiation stage.
Human CD100, the first semaphorin identified in the immune system, is a transmembrane protein involved in T-cell activation. In the present study, we showed that activation of peripheral blood or tonsillar B lymphocytes induced the expression of CD100 in CD38(+)CD138(-) cell populations, including in CD148(+) subpopulations, thus expressing a memory B-cell-like phenotype. Using an in vitro enzymatic assay, we found that protein tyrosine phosphatase (PTP) activities were immunoprecipitated with CD100 in these cell populations, which were isolated by cell sorting, as well as in most B-cell lines representing various stages of B-cell differentiation. Immunodepletion and Western blotting experiments demonstrated that CD45 was the PTP associated with CD100 in cell lines displaying pre-B, activated B, and pre-plasma cell phenotypes. CD45 also accounted for PTP activity immunoprecipitated with CD100 in CD38(+)CD138(-) cells sorted after activation of peripheral blood or tonsillar B lymphocytes. In contrast, no CD100-CD45 association was observed in plasma cell lines corresponding to the terminal B-cell differentiation stage. CD148, the other transmembrane PTP known to be implicated in lymphocyte signaling pathways, was either only partly involved in the CD100-associated PTP activity or not expressed in plasma cell lines, indicating the association of CD100 with another main PTP. Our data show that CD100 is differentially expressed and can functionally associate with distinct PTPs in B cells depending on their activation and maturation state. They also provide evidence for a switch in the CD100-associated PTP at terminal stage of B-cell differentiation.
ADP-ribosyl Cyclase↗
Triggering CD101 molecule on human cutaneous dendritic cells inhibits T cell proliferation via IL-10 production.
Since the CD101 molecule is expressed on a major subpopulation of HLA-DR(+), CD1a(+), CD1c(+) cutaneous dendritic cells (DC), we studied the functional role of CD101 on cutaneous DC. Anti-CD101 monoclonal antibody (mAb) inhibited the proliferation of T cells induced by cutaneous DC. There was a synergistic inhibition between anti-CD101 mAb and anti-CD86/anti-CD80 mAb. Anti-CD101 mAb exerted its inhibitory effect when binding to the CD101 expressed on cutaneous DC. No positive role of CD101 putative ligand expressed by T cells in T cell proliferation was demonstrated, as T cells proliferated in response to soluble anti-CD3 mAb in the presence of CD86-transfected cells but not in the presence of CD101-transfected cells. Of major significance is the fact that IL-10 was produced by cutaneous DC after CD101 triggering with anti-CD101 mAb, while IL-10 secretion was up-regulated in mixed cutaneous DC-T cell cultures after CD101 triggering. Furthermore, IL-10-neutralizing mAb could reverse the inhibition induced by anti-CD101 mAb. Our results demonstrate that the CD101 triggering on cutaneous DC inhibits T cell proliferation via IL-10 production, suggesting an important regulatory role played by the CD101 molecule on DC during T cell activation.
Animals↗
Comparative reactivity of different HLA-G monoclonal antibodies to soluble HLA-G molecules.
Different HLA-G monoclonal antibodies (mAbs) were first evaluated for their capability to identify soluble HLA-G (sHLA-G) in ELISA. Three of them, namely 87G, BFL.1 and MEM-G/9, when used as coating mAbs together with W6/32 capture mAb, identified beta2-microglobulin (beta2m)-associated-sHLA-G but not soluble HLA-B7 (sHLA-B7) in cell culture supernatants from transfected cells. By comparison, the anti-HLA class I mAb 90 did recognize both sHLA-G and sHLA-B7. By using these HLA-G mAbs, sHLA-G was identified in amniotic fluids as well as in culture supernatants of first trimester and term placental explants but not in cord blood. Intron 4-retaining sHLA-G isoforms were identified in some amniotic fluids by the use of an intron 4-specific mAb (16G1). Reactivity of these different HLA-G mAbs was then compared to determine their respective binding sites on soluble and membrane-bound HLA-G. Using both ELISA and flow cytometry analysis, we showed that they did not compete with each other, which suggested that they did not recognize the same determinants. Finally, we report that two mAbs directed against the alpha1 domain of HLA class I heavy chain (mAb 90 and YTH 862) did compete with 87G, therefore demonstrating that this latter mAb recognized an epitope localized on this external domain of HLA-G.
Antibodies, Monoclonal↗
Tubal versus uterine placentation: similar HLA-G expressing extravillous cytotrophoblast invasion but different maternal leukocyte recruitment.
The nonclassical HLA-G class I gene is expressed by extravillous cytotrophoblast that invades decidua in uterine pregnancy, suggesting that it may contribute to the immunological mechanisms that protect the fetus against maternal alloimmune response and/or pathogen infections. We first addressed the question of whether HLA-G expression was dependent on maternal tissue environment by comparing uterine and ectopic tubal pregnancies. Using HLA-G-specific mAb on placental cryosections, we found by immunohistochemistry that all subtypes of extravillous cytotrophoblast similarly expressed HLA-G in pregnant tubes, demonstrating that its expression was independent of the site of implantation. We next compared by immunohistochemistry the phenotype of maternal leukocytes recruited in both pregnant tissues. In contrast to decidua, pregnant tubes were characterized firstly, by the lack of natural killer (NK) cells and of cells expressing CD94 receptor specific for HLA-E, secondly, by a prominent increase of CD8+ T cells, dendritic cells, and macrophages, the latter co-expressing the LIR1/ILT2 killer immunoglobulin-like receptor (KIR), and finally, by the presence of cells expressing LIR2/ILT4 KIR or BY55 NK receptors, known to bind to HLA-G. Such cell types may favor a unique innate defense in pregnant tubes. These observations also suggest that trophoblast HLA-G expression does not influence the recruitment of particular maternal leukocytes in pregnant tissues.
Antibodies, Monoclonal↗
Blister fluid T lymphocytes during toxic epidermal necrolysis are functional cytotoxic cells which express human natural killer (NK) inhibitory receptors.
Toxic epidermal necrolysis (TEN) is a rare life-threatening adverse drug reaction characterized by a massive destruction of the epidermis. Immunohistological studies of skin biopsies of TEN showed infiltrates of predominantly CD8+ T lymphocytes even though other authors reported a prominent involvement of cells of the monocyte-macrophage lineage. The aim of this study was to characterize phenotypically and functionally the cells present in the cutaneous blister fluid of four patients with TEN. We first determined that lymphocytes were predominant in blister fluid obtained early, while monocytes/macrophages later became the most important population. We then showed that this lymphocyte population, mainly CD3+CD8+, corresponded to a peculiar cell subset as they expressed cutaneous leucocyte antigen, killer inhibitory receptors KIR/KAR and failed to express CD28 molecule. Functionally, we determined that blister T lymphocytes had a cytotoxic T lymphocyte (CTL)- and NK-like cytotoxicity. The role of this cytotoxic lymphocyte population present at the site of lesions during TEN remains to be understood.
Adult↗
CD101 expression by Langerhans cell histiocytosis cells.
AIMS: Our objective was to study the expression of a recently identified cell surface molecule, CD101 and in Langerhans cell histiocytosis (LCH) patients as CD101 has been shown to be present on dendritic cells. We wanted to determine if CD101 expression could be helpful for the diagnosis of LCH in conjunction with other markers (CD1a, S100 protein), and could be predictive of the evolution and dissemination of the disease. METHODS AND RESULTS: The expression of CD101 was studied by immunohistochemical technique in 11 cases of Langerhans cell histiocytosis on frozen sections. The expression of CD101 was positive in nine cases, high in six cases and low in three cases. There was no expression in the other two cases. No correlation with the evolution, the localization or the dissemination of the disease could be evidenced. CONCLUSIONS: CD101 is a new phenotypic marker that might be useful in combination with other markers for the diagnosis of LCH. However, as the anti-CD101 antibody works only in frozen sections, its value is limited compared to anti-CD1a antibody.
Antigen Presentation↗
Functional inhibitory receptors expressed by a cutaneous T cell lymphoma-specific cytolytic clonal T cell population.
Inhibitory receptors on natural killer cells and on a minority of T lymphocytes are major histocompatibility complex class Ia or Ib specific. We have previously reported several tumor-specific cytotoxic T cell clones infiltrating a CD4(+) V beta 13(+) cutaneous T cell lymphoma. These clones mediated a specific major histocompatibility complex class I-restricted cytotoxic activity toward the uncultured tumor cells and autologous long-term tumor T cell lines. In this study, we cultured with interleukin-2 the peripheral blood lymphocytes of the same patient a few weeks before invasion of the blood by tumor cells. We report the rapid and selective expansion of a CD8(+) V beta 13(+) lymphoid population. This population was clonal, as it expressed a unique T cell receptor-V beta junctional region. V beta 13(+) tumor cells and V beta 13(+) reactive T cells were shown to have different junctional sequences. The CD8(+) reactive clone was functional, as it had a specific autologous tumor-specific, human leukocyte antigen-A2 restricted, cytotoxic activity. This clone coexpressed high levels of CD158a, CD158b, p70, and CD94/NKG2A inhibitory receptors. Interestingly, we found that anti-CD158a and anti-CD158b monoclonal antibodies could inhibit anti-CD3 redirected cytotoxicity mediated by the reactive clonal population. Further, an anti-human leukocyte antigen-B/C monoclonal antibody enhanced the specific cytotoxic activity of the clone against autologous tumor cells. These results are the first evidence that inhibitory receptor expression can lead to the inhibition of cutaneous T cell lymphoma-specific T cell responses.
Aged↗
Cutaneous T cell lymphoma reactive CD4+ cytotoxic T lymphocyte clones display a Th1 cytokine profile and use a fas-independent pathway for specific tumor cell lysis.
We have previously described two cytotoxic T lymphocyte clones isolated from lymphocytes infiltrating a human major histocompatibility complex class II-/class I+, CD4+ cutaneous T cell lymphoma. These clones displayed a CD4+CD8dim+ (TC5) and CD4+ CD8- (TC7) phenotype and mediated a specific major histocompatibility complex class I-restricted cytotoxic activity toward Cou-LB autologous tumor cell line. Our studies were performed to elucidate the mechanism involved in T-cell-clone-mediated cytotoxicity and to determine the cytokine profile of both the lymphoma cell line and specific cytotoxic T lymphocyte clones. The results indicate that, despite surface expression of Fas receptor on Cou-LB and Fas ligand induction on TC5 and TC7 cell membranes, the CD4+ cytotoxic T lymphocyte clones do not use this cytotoxic mechanism to lyse their specific target. The TC7 clone uses instead a granzyme-perforin-dependent pathway. Furthermore, quantitative analysis of Th1 and Th2 cytokine mRNA expression in the cutaneous T cell lymphoma cell line as well as in TC5 and TC7 clones indicated that, whereas the tumor cells display a Th2-type profile (interleukin-4, interleukin-6, and interleukin-10), the cytotoxic T lymphocyte clones express Th1-type cytokines (interferon-gamma, granulocyte macrophage colony stimulating factor, and interleukin-2). In addition, preincubation of the tumor-infiltrating lymphocyte clones with autologous tumor cells induced their activation and subsequent amplification of the Th1-type response. These results indicate a direct contribution of the malignant cells in the Th1/Th2 imbalance observed frequently in cutaneous T cell lymphoma patients and suggest their potential role in depressed cell-mediated immunity. Identification of CD4+ Th1-type cytotoxic T lymphocyte clones, the tumor antigen they recognize, and optimization of their cytokine expression profile should be useful for the design of new immunotherapy protocols in cutaneous T cell lymphoma.
Aged↗
No modulation of circulating natural killer cell and natural killer receptor bearing memory T cell subsets in patients with atopic dermatitis.
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Dermatitis, Atopic↗