RESUMO
CD (cluster of differentiation) Ags are cell surface molecules expressed on leukocytes and other cells relevant for the immune system. CD nomenclature has been universally adopted by the scientific community and is officially approved by the International Union of Immunological Societies and sanctioned by the World Health Organization. It provides a unified designation system for mAbs, as well as for the cell surface molecules that they recognize. This nomenclature was established by the Human Leukocyte Differentiation Antigens Workshops. In addition to defining the CD nomenclature, these workshops have been instrumental in identifying and determining the expression and function of cell surface molecules. Over the past 30 y, the data generated by the 10 Human Leukocyte Differentiation Antigens Workshops have led to the characterization and formal designation of more than 400 molecules. CD molecules are commonly used as cell markers, allowing the identification and isolation of leukocyte populations, subsets, and differentiation stages. mAbs against these molecules have proven to be essential for biomedical research and diagnosis, as well as in biotechnology. More recently, they have been recognized as invaluable tools for the treatment of several malignancies and autoimmune diseases. In this article, we describe how the CD nomenclature was established, present the official updated list of CD molecules, and provide a rationale for their usefulness in the 21st century.
Assuntos
Anticorpos Monoclonais/imunologia , Antígenos CD/classificação , Terminologia como Assunto , Antígenos CD/imunologia , Biomarcadores , HumanosRESUMO
BACKGROUND: The increasing availability of different monoclonal antibodies (mAbs) opens the way to more specific biologic therapy of cancer patients. However, despite the significant success of therapy in breast and ovarian carcinomas with anti-HER2 mAbs as well as in non-Hodkin B cell lymphomas with anti-CD20 mAbs, certain B cell malignancies such as B chronic lymphocytic leukaemia (B-CLL) respond poorly to anti-CD20 mAb, due to the low surface expression of this molecule. Thus, new mAbs adapted to each types of tumour will help to develop personalised mAb treatment. To this aim, we analyse the biological and therapeutic properties of three mAbs directed against the CD5, CD71 or HLA-DR molecules highly expressed on B-CLL cells. RESULTS: The three mAbs, after purification and radiolabelling demonstrated high and specific binding capacity to various human leukaemia target cells. Further in vitro analysis showed that mAb anti-CD5 induced neither growth inhibition nor apoptosis, mAb anti-CD71 induced proliferation inhibition with no early sign of cell death and mAb anti-HLA-DR induced specific cell aggregation, but without evidence of apoptosis. All three mAbs induced various degrees of ADCC by NK cells, as well as phagocytosis by macrophages. Only the anti-HLA-DR mAb induced complement mediated lysis. Coincubation of different pairs of mAbs did not significantly modify the in vitro results. In contrast with these discrete and heterogeneous in vitro effects, in vivo the three mAbs demonstrated marked anti-tumour efficacy and prolongation of mice survival in two models of SCID mice, grafted either intraperitoneally or intravenously with the CD5 transfected JOK1-5.3 cells. This cell line was derived from a human hairy cell leukaemia, a type of malignancy known to have very similar biological properties as the B-CLL, whose cells constitutively express CD5. Interestingly, the combined injection of anti-CD5 with anti-HLA-DR or with anti-CD71 led to longer mouse survival, as compared to single mAb injection, up to complete inhibition of tumour growth in 100% mice treated with both anti-HLA-DR and anti-CD5. CONCLUSIONS: Altogether these data suggest that the combined use of two mAbs, such as anti-HLA-DR and anti-CD5, may significantly enhance their therapeutic potential.
Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos de Superfície/imunologia , Antineoplásicos/farmacologia , Animais , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Linhagem Celular Tumoral , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/imunologia , Humanos , Radioisótopos do Iodo , Leucemia de Células B/fisiopatologia , Linfoma/fisiopatologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos SCID , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Ligação Proteica , Análise de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The Human Leucocyte Differentiation Antigens Workshops (HLDA) have since 1984 provided a forum for the characterization and study of leucocyte surface molecules and antibodies against them. HLDA devised the CD nomenclature, which is sanctioned by IUIS. The HLDA Council reviewed and modified the objectives of HLDA in 2004, and changed the name of the organization to Human Cell Differentiation Molecules (HCDM) to reflect the broader objectives. Workshop studies under the HCDM banner proceeded during 2005 and early 2006, culminating in a meeting in May 2006. At that meeting the Council, acting as Nomenclature Committee, approved a number of new CD designations and changes to some pre-existing CD designations, which are summarized in this report.
Assuntos
Antígenos CD/classificação , Diferenciação Celular/imunologia , Terminologia como Assunto , Antígenos CD/genética , Antígenos CD/imunologia , Diferenciação Celular/genética , Humanos , Cooperação InternacionalAssuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antígenos CD20/imunologia , Antineoplásicos/imunologia , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citometria de Fluxo , Antígenos HLA-DR/imunologia , Humanos , TrastuzumabRESUMO
Semaphorins, a family of genes encoding guidance molecules in the nervous system, influence a variety of cellular mechanisms including migration, proliferation and cytoskeleton reorganization. Interestingly, many members are expressed throughout lymphoid tissues and by different immune cells like lymphocytes, NK, monocytes and dendritic cells. Besides, the array of functions semaphorins usually regulate during organogenesis coincide with several key events required for the initiation as well as the regulation of the host immune response. Thus, it is not surprising if a substantial number of them modulates immune processes such as the establishment of the immunological synapse, differentiation to effector and helper cells, clonal expansion, migration and phagocytosis. For this purpose, immune semaphorins can signal via their canonical plexin receptors but also possibly by unique discrete cell surface proteins or associations thereof expressed by, and critical to, leukocytes. A growing list of semaphorins, receptors or related molecules keep being reported in the immune system, and display nonredundant roles at controlling its integrity and efficacy.
Assuntos
Antígenos CD/fisiologia , Semaforinas/fisiologia , Transdução de Sinais/imunologia , Animais , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos CD/metabolismo , Humanos , Modelos Imunológicos , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Receptores de Superfície Celular/metabolismo , Receptores de Superfície Celular/fisiologia , Semaforinas/biossíntese , Semaforinas/genética , Semaforinas/metabolismoRESUMO
Semaphorins provide crucial attractive and repulsive cues involved in axon guidance. Several semaphorins have also been detected in cells of the immune system. Their influence on cell motility has been reported and is reminiscent of the biological function attributed to nervous system semaphorins. Receptors of the plexin and neuropilin family of proteins, also expressed by some immune cells, may be involved in semaphorin signaling in the immune system. However, semaphorins also affect the functioning of the immune system through receptors regulating lymphocyte activation. An important challenge in the future will be to determine whether, as in the nervous system, semaphorins help immune cells to establish connections with their appropriate targets.
Assuntos
Antígenos CD , Sistema Imunitário/fisiologia , Glicoproteínas de Membrana/fisiologia , Semaforinas , Animais , Antígenos de Diferenciação de Linfócitos T/química , Antígenos de Diferenciação de Linfócitos T/fisiologia , Humanos , Ativação Linfocitária/fisiologia , Linfócitos/fisiologia , Glicoproteínas de Membrana/química , Transdução de Sinais/fisiologiaRESUMO
Semaphorins are a large family of membrane-bound and secreted molecules involved in numerous functions, including axon guidance, morphogenesis, carcinogenesis, and immunomodulation. A growing number of semaphorins--namely, human CD100/SEMA4D, CD108/SEMA7A, and SEMA3A; viral semaphorins, SemaVA and SemaVB; and, very recently, mouse Sema4A--were reported to regulate immune cell responses. Among them, the role of CD100 has been well documented in both humans and mice. CD100, in particular, has been shown to influence monocyte migration, T-cell activation, B-cell survival as well as T/B and T/dendritic cell cooperation. In contrast to other semaphorins, CD100 is the only semaphorin for which membrane and soluble forms are endowed with functional properties, and for which bidirectional signaling has been suggested. The human membrane-bound CD100 engagement triggers costimulatory signals to T cells through its interaction with membrane protein tyrosine phosphatase CD45 and an intracellular serine kinase. Its soluble extracellular region acts most likely through its receptors, human PlexinB1 and mouse CD72, to promote T-cell priming, B-cell survival and antibody production in response to T-dependent antigens. Human soluble CD100 also induces monocyte paralysis and the arrest of its spontaneous and chemokine-induced migration by signaling through an as yet unknown receptor that is different from PlexinB1 and CD72. In this review, we discuss recent advances in research studies on human and murine CD100, and we describe the relationship of CD100 function to its expression and structure. The signaling events that support CD100 function are also discussed.
Assuntos
Antígenos CD , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/imunologia , Semaforinas , Transdução de Sinais/imunologia , Animais , Linfócitos B/imunologia , Humanos , Ativação Linfocitária , Monócitos/imunologia , Linfócitos T/imunologiaRESUMO
CD158k molecules belong to the family of killer cell immunoglobulin-like receptors (KIR) that are expressed on a minor population of circulating NK and CD8+ T lymphocytes. Here, we report a strong positive correlation between the percentage of CD158k+ blood lymphocytes analyzed by flow cytometry and the percentage of atypical circulating cells (Sezary cells) determined by cytomorphology in a large group of patients with Sezary syndrome. Moreover, we show that circulating CD4+CD158k+ lymphocytes correspond to the malignant clonal cell population. Our findings suggest that the CD158k marker could be a useful tool for the evaluation of the circulating tumoral burden and the follow-up of patients with Sezary syndrome.
Assuntos
Biomarcadores Tumorais/sangue , Linfócitos/química , Receptores Imunológicos/sangue , Síndrome de Sézary/diagnóstico , Neoplasias Cutâneas/diagnóstico , Citometria de Fluxo , Seguimentos , Humanos , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Receptores KIR , Receptores KIR2DL2 , Receptores KIR3DL2RESUMO
Circulating malignant Sezary cells are a clonal proliferation of CD4+CD45RO+ T lymphocytes primarily involving the skin. To study the biology of these malignant T lymphocytes, we tested their ability to migrate in chemotaxis assays. Previously, we had shown that the neuropeptide neurotensin (NT) binds to freshly isolated Sezary malignant cells and induces through NT1 receptors the cell migration of the cutaneous T cell lymphoma cell line Cou-L. Here, we report that peripheral blood Sezary cells as well as the Sezary cell line Pno fail to migrate in response to neurotensin although they are capable of migrating to the chemokine stromal-cell-derived factor 1 alpha. This is in contrast with normal circulating CD4+ or CD8+ lymphocytes, which respond to both types of chemoattractants except after ex vivo short-time anti-CD3 monoclonal antibody activation, which abrogates the neurotensin-induced lymphocyte migration. Furthermore, we demonstrate that neurotensin-responsive T lymphocytes express the functional NT1 receptor responsible for chemotaxis. In these cells, but not in Sezary cells, neurotensin induces recruitment of phosphatidylinositol-3 kinase, and redistribution of phosphorylated cytoplasmic tyrosine kinase focal adhesion kinase and filamentous actin. Taken together, these results, which show functional distinctions between normal circulating lymphocytes and Sezary syndrome cells, contribute to further understanding of the physiopathology of these atypical cells.
Assuntos
Linfócitos T CD4-Positivos/citologia , Quimiotaxia/imunologia , Receptores da Neurocinina-1/metabolismo , Síndrome de Sézary/imunologia , Síndrome de Sézary/patologia , Actinas/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Inibidores Enzimáticos/farmacologia , Quinase 1 de Adesão Focal , Proteína-Tirosina Quinases de Adesão Focal , Expressão Gênica/imunologia , Humanos , Células Jurkat , Antagonistas dos Receptores de Neurocinina-1 , Neurotensina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Pirazóis/farmacologia , Quinolinas/farmacologia , Receptores da Neurocinina-1/genéticaRESUMO
Toxic epidermal necrolysis is a rare disease observed as a consequence of adverse reactions to drugs. It results in the widespread apoptosis of epidermal cells and has a high mortality rate. The mechanisms leading to this apoptosis are not yet elucidated. We investigated whether the cytokines present in the blister fluid, which accumulates under necrotic epidermis, originated from T lymphocytes and may play a role in the propagation of keratinocyte apoptosis. Interferon gamma (IFN-gamma), soluble tumor necrosis factor alpha (TNF-alpha), soluble Fas ligand (sFas-L) were present in much higher concentration in the blister fluids of 13 toxic epidermal necrolysis (TEN) patients than in control fluids from burns. The results of RT-PCR studies, however, indicated that only IFN-gamma and to a lesser extent interleukin (IL)-18 were produced by mononuclear cells present in the fluid. That suggests that the other cytokines also present (TNF-alpha, sFas-L, IL-10) rather originated from activated keratinocytes. Fas-L was indeed overexpressed on the membranes of keratinocytes in lesional skin in situ. The Th1 profile of T lymphocyte activation found in the blister fluid of patients with TEN is consistent with a key role for drug-specific cytotoxic T lymphocytes (CTL) as previously reported, the activation of keratinocytes by IFN-gamma making them sensitive to cell-mediated cytolysis. We propose the hypothesis that the production of Fas-L, TNF-alpha, and IL-10 by keratinocytes could be a defense mechanism against CTL rather than a way of propagating apoptosis among epidermal cells.
Assuntos
Citocinas/imunologia , Síndrome de Stevens-Johnson/imunologia , Apoptose , Vesícula/imunologia , Vesícula/metabolismo , Líquidos Corporais/imunologia , Líquidos Corporais/metabolismo , Queimaduras/imunologia , Queimaduras/metabolismo , Citocinas/metabolismo , Proteína Ligante Fas , Humanos , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-18/imunologia , Interleucina-18/metabolismo , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Síndrome de Stevens-Johnson/metabolismo , Síndrome de Stevens-Johnson/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Receptor fas/imunologia , Receptor fas/metabolismoRESUMO
Toxic epidermal necrolysis is an extremely severe drug reaction, manifesting itself by widespread apoptosis of keratinocytes, generally considered to result from Fas/CD95-FasLigand interaction, but of unknown primary mechanism. We looked at the role of cells present in the skin blisters as probable effectors of this immune reaction. In a patient suffering from cotrimoxazole-induced toxic epidermal necrolysis, blister fluid cells were phenotyped by FACS and tested without prior restimulation for cytotoxicity on autologous and allogeneic cells in the presence of the drug. Blister fluid lymphocytes were predominantly CD8+, DR+, CLA+, CD56+ T lymphocytes, perforin positive and expressing preferentially two Vbeta chains of the T cell receptor repertoire. These lymphocytes were cytotoxic only in the presence of the drug towards autologous EBV transformed lymphocytes and towards allogeneic cells sharing HLA-Cw4. Cytotoxicity occurred in the presence of either cotrimoxazole, sulfamethoxazole, or the nitroso metabolite of sulfamethoxazole, but not with the hydroxylamine metabolite of sulfamethoxazole. The lysis was blocked by an anti-MHC class I monoclonal antibody. It was abolished by EGTA and CMA, but neither by anti-fas, brefeldin A, nor by anti-TRAIL receptor monoclonal antibodies, strongly suggesting perforin/granzyme-mediated cytotoxicity, without implication of Fas or TRAIL at this stage. This is direct evidence that T lymphocytes present within the lesions of toxic epidermal necrolysis may exhibit, without any re-stimulation, a drug-specific cytotoxicity against autologous cells. Harboring the markers of classical CTL and MHC class I restriction these lymphocytes reacted against the parent drug and one of its reactive metabolites. These results challenge several current concepts and could support new therapeutic approaches.
Assuntos
Síndrome de Stevens-Johnson/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Anti-Infecciosos/efeitos adversos , Vesícula/imunologia , Vesícula/patologia , Antígenos CD8/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Síndrome de Stevens-Johnson/patologia , Linfócitos T Citotóxicos/patologia , Combinação Trimetoprima e Sulfametoxazol/efeitos adversosRESUMO
The physiopathology of cutaneous T-cell lymphomas is poorly understood. Little is known about the factors that drive a mature T-cell clone to accumulate in the skin, despite the feedback mechanisms that normally control immune response. This article discusses the identification of tumor-specific antigens.
Assuntos
Antígenos de Neoplasias/análise , Linfoma Cutâneo de Células T/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Cutâneas/patologia , Subpopulações de Linfócitos T/patologia , Antígenos CD/análise , Linhagem Celular Tumoral/química , Linhagem Celular Tumoral/patologia , Humanos , Imunofenotipagem , Receptor B1 de Leucócitos Semelhante a Imunoglobulina , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/imunologia , Proteínas de Neoplasias/análise , Células-Tronco Neoplásicas/química , Receptores de Superfície Celular/análise , Receptores Imunológicos/análise , Receptores KIR , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/imunologia , Síndrome de Sézary/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/imunologia , Subpopulações de Linfócitos T/químicaRESUMO
Atherosclerosis is a complex disease in which vessels develop plaques comprising dysfunctional endothelium, monocyte derived lipid laden foam cells and activated lymphocytes. Considering that humans and animal models of the disease develop quite distinct plaques, we used human plaques to search for proteins that could be used as markers of human atheromas. Phage display peptide libraries were probed to fresh human carotid plaques, and a bound phage homologous to plexin B1, a high affinity receptor for CD100, was identified. CD100 is a member of the semaphorin family expressed by most hematopoietic cells and particularly by activated T cells. CD100 expression was analyzed in human plaques and normal samples. CD100 mRNA and protein were analyzed in cultured monocytes, macrophages and foam cells. The effects of CD100 in oxLDL-induced foam cell formation and in CD36 mRNA abundance were evaluated. Human atherosclerotic plaques showed strong labeling of CD100/SEMA4D. CD100 expression was further demonstrated in peripheral blood monocytes and in in vitro differentiated macrophages and foam cells, with diminished CD100 transcript along the differentiation of these cells. Incubation of macrophages with CD100 led to a reduction in oxLDL-induced foam cell formation probably through a decrease of CD36 expression, suggesting for the first time an atheroprotective role for CD100 in the human disease. Given its differential expression in the numerous foam cells and macrophages of the plaques and its capacity to decrease oxLDL engulfment by macrophages we propose that CD100 may have a role in atherosclerotic plaque development, and may possibly be employed in targeted treatments of these atheromas.
Assuntos
Antígenos CD/metabolismo , Biomarcadores/metabolismo , Células Espumosas/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/química , Semaforinas/metabolismo , Análise de Variância , Western Blotting , Antígenos CD36/metabolismo , Técnicas de Visualização da Superfície Celular , Células Cultivadas , Primers do DNA/genética , Imunofluorescência , Humanos , Imuno-Histoquímica , Proteínas do Tecido Nervoso/metabolismo , Placa Aterosclerótica/metabolismo , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: It was recently reported that CD101 surface expression discriminates potency among CD4+CD25+ FoxP3+ regulatory T cells in the mouse. We investigated whether CD101 may also have a role in the suppressor function of regulatory T cells in humans given that the latter population may affect the autoimmune response in patients with rheumatoid arthritis (RA). METHODS: Sorted T cells and monocyte/macrophage cell populations were analyzed by flow cyto metry using conjugated antibodies specific for cell-surface markers. T cell proliferation assays were conducted by [(3)H]thymidine incorporation and CD8(high) cytotoxicity measurements by Cyto-Scan-LDH cytotoxicity assays. ELISA were used to measure cytokines in cell culture supernatants and Western blotting was performed for profiling mitogen-activated protein (MAP) kinase activation using specific antiphospholipid antibodies. RESULTS: CD101 expression coincided with PMA-induced monocyte/leukocyte lineage differentiation. CD8(high)CD101- T cells exhibited greater cytotoxic activity than CD8(high)CD101+ T cells, while no difference was observed between CD4CD25(high)CD101+ and CD4CD25(high)CD101- Treg inhibitory activity through responder T cells. LPS-induced proinflammatory cytokine production and p38 MAP kinase activation were made possible by ligation of CD101 with an anti-CD101 antibody F(ab')(2) fragment. CONCLUSION: These results suggested a modulatory/coregulatory function of CD101 in the human immune system, in contrast to murine models, in which CD101 surface expression discriminates potency among FoxP3+ regulatory T cells. Cytotoxic CD8(high)CD101+ T cells were markedly less cytotoxic than CD8(high) T cells negative for the CD101 antigen and were conspicuously downregulated in patients with RA, suggesting a possible role for CD101 expression and function in the control of certain manifestations of RA pathology.
Assuntos
Antígenos CD/imunologia , Artrite Reumatoide/imunologia , Macrófagos/imunologia , Glicoproteínas de Membrana/imunologia , Monócitos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular , Proliferação de Células , Citocinas/imunologia , Humanos , Macrófagos/citologia , Camundongos , Monócitos/citologia , Subpopulações de Linfócitos T/citologia , Linfócitos T/citologia , Linfócitos T Reguladores/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Positive regulation of cell migration by chemotactic factors and downstream signaling pathways has been extensively investigated. In contrast, little is known about factors and mechanisms that induce migration arrest, a process important for retention of cells at inflammatory sites and homeostatic regulation of cell trafficking. In this study, we found that IFN-gamma directly inhibited monocyte migration by suppressing remodeling of the actin cytoskeleton and cell polarization in response to the chemokine CCL2. Inhibition was dependent on STAT1 and downstream genes, whereas STAT3 promoted migration. IFN-gamma altered monocyte responses to CCL2 by modulating the activity of Pyk2, JNK, and the GTPases Rac and Cdc42, and inhibiting CCL2-induced activation of the downstream p21-activated kinase that regulates the cytoskeleton and cell polarization. These results identify a new role for IFN-gamma in arresting monocyte chemotaxis by a mechanism that involves modulation of cytoskeleton remodeling. Crosstalk between Jak-STAT and Rac/Cdc42 GTPase-mediated signaling pathways provides a molecular mechanism by which cytokines can regulate cell migration.
Assuntos
Inibição de Migração Celular/imunologia , Interferon gama/fisiologia , Monócitos/imunologia , Fator de Transcrição STAT1/fisiologia , Transdução de Sinais/imunologia , Proteína cdc42 de Ligação ao GTP/antagonistas & inibidores , Proteínas rac de Ligação ao GTP/antagonistas & inibidores , Actinas/antagonistas & inibidores , Actinas/metabolismo , Animais , Células Cultivadas , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/fisiologia , Quimiotaxia de Leucócito/genética , Quimiotaxia de Leucócito/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Knockout , Monócitos/citologia , Fator de Transcrição STAT1/biossíntese , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/fisiologia , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteína cdc42 de Ligação ao GTP/fisiologia , Proteínas rac de Ligação ao GTP/metabolismo , Proteínas rac de Ligação ao GTP/fisiologiaRESUMO
We previously characterized several tumor-specific T cell clones from PBL and tumor-infiltrating lymphocytes of a lung cancer patient with identical TCR rearrangements and similar lytic potential, but with different antitumor response. A role of the TCR inhibitory molecule CD5 to impair reactivity of peripheral T cells against the tumor was found to be involved in this process. In this report, we demonstrate that CD5 also controls the susceptibility of specific T cells to activation-induced cell death (AICD) triggered by the tumor. Using a panel of tumor-infiltrating lymphocytes and PBL-derived clones expressing different levels of CD5, our results indicate that T lymphocyte AICD in response to the cognate tumor is inversely proportional to the surface expression level of CD5. They also suggest a direct involvement of CD5 in this process, as revealed by an increase in tumor-mediated T lymphocyte AICD following neutralization of the molecule with specific mAb. Mechanistically, our data indicate that down-regulation of FasL expression and subsequent inhibition of caspase-8 activation are involved in CD5-induced T cell survival. These results provide evidence for a role of CD5 in the fate of peripheral tumor-specific T cells and further suggest its contribution to regulate the extension of CTL response against tumor.
Assuntos
Antígenos de Neoplasias/imunologia , Antígenos CD5/fisiologia , Citotoxicidade Imunológica , Epitopos de Linfócito T/imunologia , Neoplasias Pulmonares/imunologia , Ativação Linfocitária/imunologia , Células Neoplásicas Circulantes/imunologia , Linfócitos T Citotóxicos/imunologia , Antígenos de Neoplasias/sangue , Antígenos CD5/imunologia , Antígenos CD5/metabolismo , Caspase 8/metabolismo , Inibidores de Caspase , Morte Celular/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/imunologia , Ativação Enzimática/imunologia , Epitopos de Linfócito T/sangue , Proteína Ligante Fas/antagonistas & inibidores , Proteína Ligante Fas/biossíntese , Proteína Ligante Fas/genética , Humanos , Células Jurkat , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/enzimologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Células Neoplásicas Circulantes/patologia , Linfócitos T Citotóxicos/enzimologia , Linfócitos T Citotóxicos/patologiaRESUMO
Semaphorin 4D (sema4D; CD100) is an integral membrane protein and the ligand for two receptors, CD72 and plexin-B1. Soluble sema4D has been shown to evoke angiogenic responses from endothelial cells and impair monocyte migration, but the origin of soluble sema4D, particularly at sites of vascular injury, has been unclear. Here we show that platelets express sema4D and both of its receptors and provide evidence that these molecules promote thrombus formation. We also show that the surface expression of sema4D and CD72 increases during platelet activation, followed by the gradual shedding of the sema4D extracellular domain. Shedding is blocked by metalloprotease inhibitors and abolished in mouse platelets that lack the metalloprotease ADAM17 (TACE). Mice that lack sema4D exhibit delayed arterial occlusion after vascular injury in vivo, and their platelets show impaired collagen responses in vitro. In resting platelets, as in B lymphocytes, CD72 is associated with the protein tyrosine phosphatase SHP-1. Platelet activation causes dissociation of the complex, as does the addition of soluble sema4D. These findings suggest a dual role for sema4D in vascular responses to injury. As thrombus formation begins, platelet-associated sema4D can bind to its receptors on nearby platelets, promoting thrombus formation. As thrombus formation continues, sema4D is shed from the platelet surface and becomes available to interact with receptors on endothelial cells and monocytes, as well as continuing to interact with platelets.
Assuntos
Antígenos CD/química , Plaquetas/metabolismo , Vasos Sanguíneos/lesões , Regulação da Expressão Gênica , Semaforinas/química , Proteínas ADAM/química , Proteína ADAM17 , Animais , Vasos Sanguíneos/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Ativação Plaquetária , Estrutura Terciária de Proteína , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Trombose/metabolismoRESUMO
Within human CD8+ T lymphocytes, the CD27-CD45RAhigh or CD56+ phenotypes contribute to precisely define the cells with CTL effector function. Novel markers were demonstrated to correlate with CTL properties, such as the 2B4 (CD244) receptor, a member of the CD2 subset of the immunoglobulin superfamily or the glycosylphosphatidylinositol-anchored CD160 receptor. We performed a study of these markers to further define the population of effectors with CTL functions. Here we show that cytotoxic subpopulations defined by surface markers CD160, CD56 and CD57 are mostly contained in the 2B4+CD8+ T cell population. Expression of CD160 identifies two populations in the 2B4+ population. The 2B4+CD160+ subset expresses a bona fide CTL phenotype. The co-expression of 2B4 and CD160 defines T cells containing high amounts of perforin and granzyme B. During CTL ontogeny, an up-regulation of 2B4 and CD160 is observed from a naive to a terminally differentiated phenotype. Finally, we demonstrated that CD160 triggering failed to induce cytotoxicity per se, but costimulated CD3-redirected killing. We conclude that the co-expression of 2B4 and CD160 defines a CD8+ T lymphocyte subpopulation with high CTL activity.
Assuntos
Antígenos CD/imunologia , Subpopulações de Linfócitos/citologia , Receptores Imunológicos/imunologia , Linfócitos T Citotóxicos/citologia , Antígenos CD/metabolismo , Antígeno CD56/imunologia , Antígeno CD56/metabolismo , Antígenos CD57/imunologia , Antígenos CD57/metabolismo , Diferenciação Celular/imunologia , Proteínas Ligadas por GPI , Humanos , Corpos de Inclusão/imunologia , Corpos de Inclusão/metabolismo , Subpopulações de Linfócitos/imunologia , Receptores Imunológicos/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária , Linfócitos T Citotóxicos/imunologiaRESUMO
The monoclonal antibody SC3 was raised against the NK leukaemia cell line YTindi. It detected a 98-kDa surface antigen with weak expression on a restricted number of leukaemia cell lines under reducing conditions. SC3 mAb labelled 5-10% of normal peripheral blood lymphocytes corresponding almost exclusively to B lymphocytes, and 60-70% of tonsillar B cells. It did not react with erythrocytes, platelets or monocytes whereas it stained granulocytes. The aim of the present study was to examine the expression and functional effects of SC3 mAb reactive epitope on normal and malignant B cells. Most SC3+ B cells from healthy donors were CD23+, some co-expressed CD5 and CD27 and a few were CD38+. SC3 epitope was expressed exclusively by B-lineage malignant proliferations, including B-lineage ALL. Practically, all B-CLL studied expressed SC3 mAb reactive epitope although with variable intensity, while MCL and PLL were negative. Other low grade and high grade B-NHL were variably stained. SC3 mAb alone triggered the proliferation of CD2-depleted PBL and significantly increased the proliferation induced by suboptimal concentrations of LPS. This effect was much weaker with B-CLL cells but was increased after cross-linking with an anti-IgM antibody. The restricted expression pattern combined with molecular weight and functional data indicate that SC3 mAb may detect a novel B-cell antigen mostly expressed by early and naive B cells. Although its expression in B-cell malignancies was not limited to a single differentiation stage, it might confer specific functional characteristics to the positive malignant cells.
Assuntos
Antígenos de Diferenciação de Linfócitos B/imunologia , Antígenos de Superfície/imunologia , Linfócitos B/imunologia , Leucemia de Células B/imunologia , Linfoma de Células B/imunologia , Animais , Anticorpos Monoclonais , Especificidade de Anticorpos , Antígenos de Diferenciação de Linfócitos B/química , Antígenos de Superfície/química , Epitopos de Linfócito B/imunologia , Humanos , Linfopoese , Camundongos , Camundongos Endogâmicos BALB C , Peso MolecularRESUMO
We investigated the circulating cytotoxic CD160+ CD8(high) subset in correlation to antiviral immunity and response to highly active antiretroviral therapy (HAART) in HIV+ subjects. The study included 45 treatment-naive patients receiving HAART for 18 months, retrospectively defined as good (n=29) and transient (n=16) responders. HIV-specific CD8 T lymphocyte levels were measured by IFNgamma production in response to p17 Gag, in the presence of immobilized anti-CD160 mAb. We report a significantly increased baseline level of CD160+ CD8(high) subset in good therapy responders. CD160+ CD8(high) subset correlates with CD4+ T cell count, immune activation, and viral load. CD160+ CD8(high) lymphocytes contain a high amount of Granzyme B and include virus-specific T lymphocytes in HIV-1+ subjects. Co-stimulation through CD160 molecules enhances IFNgamma production in response to p17 Gag. Therefore, the CD160+ CD8(high) subset may be useful for monitoring of virus-specific cellular immunity and predicting response to antiretroviral therapy in chronic HIV-1 infection.