RESUMEN
Little is known about the functional differences between the human skin myeloid dendritic cell (DC) subsets, epidermal CD207(+) Langerhans cells (LCs) and dermal CD14(+) DCs. We showed that CD14(+) DCs primed CD4(+) T cells into cells that induce naive B cells to switch isotype and become plasma cells. In contrast, LCs preferentially induced the differentiation of CD4(+) T cells secreting T helper 2 (Th2) cell cytokines and were efficient at priming and crosspriming naive CD8(+) T cells. A third DC population, CD14(-)CD207(-)CD1a(+) DC, which resides in the dermis, could activate CD8(+) T cells better than CD14(+) DCs but less efficiently than LCs. Thus, the human skin displays three DC subsets, two of which, i.e., CD14(+) DCs and LCs, display functional specializations, the preferential activation of humoral and cellular immunity, respectively.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/metabolismo , Células de Langerhans/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Citocinas/inmunología , Epidermis/inmunología , Granzimas/metabolismo , Humanos , Memoria Inmunológica , Células de Langerhans/metabolismo , Receptores de Lipopolisacáridos/inmunología , Activación de Linfocitos , Piel/inmunología , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Antiviral immunity requires early and late mechanisms in which IFN-alpha and IL-12 play major roles. However, the initial events leading to their production remain largely unclear. Given the crucial role of TLR in innate recognition, we investigated their role in antiviral immunity in vivo. Upon murine CMV (MCMV) infection, both MyD88-/- and TLR9-/- mice were more susceptible and presented increased viral loads compared with C57BL/6, TLR2-/-, TLR3-/-, or TLR4-/- mice. However, in terms of resistance to infection, IFN-alpha production and in many other parameters of early inflammatory responses, the MyD88-/- mice showed a more defective response than TLR9-/- mice. In the absence of the TLR9/MyD88 signaling pathway, cytokine production was dramatically impaired with a complete abolition of bioactive IL-12p70 serum release contrasting with a high flexibility for IFN-alpha release, which is initially (36 h) plasmacytoid dendritic cell- and MyD88-dependent, and subsequently (44 h) PDC-, MyD88-independent and, most likely, TLR-independent. NK cells from MCMV-infected MyD88-/- and TLR9-/- mice displayed a severely impaired IFN-gamma production, yet retained enhanced cytotoxic activity. In addition, dendritic cell activation and critical inflammatory cell trafficking toward the liver were still effective. In the long term, except for isotype switching to MCMV-specific IgG1, the establishment of Ab responses was not significantly altered. Thus, our results demonstrate a critical requirement of TLR9 in the process of MCMV sensing to assure rapid antiviral responses, coordinated with other TLR-dependent and -independent events that are sufficient to establish adaptive immunity.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Antígenos de Diferenciación/inmunología , Infecciones por Citomegalovirus/inmunología , Interferón-alfa/biosíntesis , Muromegalovirus/inmunología , Receptores Inmunológicos/inmunología , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Anticuerpos Antivirales/biosíntesis , Antígenos de Diferenciación/genética , Secuencia de Bases , Diferenciación Celular , Infecciones por Citomegalovirus/patología , Infecciones por Citomegalovirus/virología , Citotoxicidad Inmunológica , ADN Viral/genética , Células Dendríticas/clasificación , Células Dendríticas/inmunología , Células Dendríticas/patología , Femenino , Cambio de Clase de Inmunoglobulina , Interferón gamma/biosíntesis , Interleucina-12/biosíntesis , Células Asesinas Naturales/inmunología , Hígado/inmunología , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Muromegalovirus/genética , Muromegalovirus/patogenicidad , Factor 88 de Diferenciación Mieloide , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Receptor Toll-Like 2/deficiencia , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 3/deficiencia , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/inmunología , Receptor Toll-Like 4/deficiencia , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 9/deficiencia , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/inmunologíaRESUMEN
BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, characterized by mesangial IgA1 deposits. We have previously demonstrated that IgAN patients have a hampered IgA immune response after mucosal challenge with a neoantigen. Dendritic cells are critically involved in the initiation of humoral immune responses, not only via activation of T-helper cells, but also via direct effect on naïve B cells. The aim of this study was to investigate the capacity of dendritic cells from IgAN patients to regulate IgA production. METHODS: Dendritic cells were generated by culturing monocytes for 7 days in the presence of interleukin (IL)-4 and granulocyte macrophage-colony-stimulating factor (GM-CSF). Dendritic cells from either IgAN patients (N= 12) or controls (N= 12) were cultured for 14 days with naïve B cells in the presence of CD40L-transfected mouse fibroblasts (L-CD40L cells) and medium with or without IL-2 or IL-10. Supernatants were tested for the presence of immunoglobulins by specific enzyme-linked immunosorbent assay (ELISA). RESULTS: In the presence of CD40L and IL-10, dendritic cells were able to increase immunoglobulin production by naïve B cells. Dendritic cells of IgAN patients induced significantly (P= 0.026) less IgA production than dendritic cells of control persons (2.30 microg/mL vs. 5.24 microg/mL), whereas no differences were found in the IgG and IgM production. When dendritic cells were replaced by supernatant of CD40L-stimulated dendritic cells of patients and controls, IgA production was increased, but no difference was seen between the two groups. CONCLUSION: In the present study we show that dendritic cells of IgAN patients have an impaired capacity to induce IgA production in naïve B cells, which might explain the observed IgA hyporesponse upon mucosal challenge with a neoantigen.
Asunto(s)
Linfocitos B/inmunología , Comunicación Celular/inmunología , Células Dendríticas/inmunología , Glomerulonefritis por IGA/inmunología , Inmunoglobulina A/metabolismo , Adulto , Linfocitos B/citología , Linfocitos B/metabolismo , Ligando de CD40/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Medios de Cultivo Condicionados , Células Dendríticas/citología , Células Dendríticas/metabolismo , Femenino , Humanos , Inmunoglobulina A/biosíntesis , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/metabolismo , Inmunoglobulina M/biosíntesis , Inmunoglobulina M/metabolismo , Inmunofenotipificación , Masculino , Persona de Mediana EdadRESUMEN
Depending on the activation status, plasmacytoid dendritic cells (PDC) and myeloid DC have the ability to induce CD4 T cell development toward T helper cell type 1 (Th1) or Th2 pathways. Thus, we tested whether different activation signals could also have an impact on the profile of chemokines produced by human PDC. Signals that induce human PDC to promote a type 1 response (i.e., viruses) and a type 2 response [i.e., CD40 ligand (CD40L)] also induced PDC isolated from tonsils to secrete chemokines preferentially attracting Th1 cells [such as interferon-gamma (IFN-gamma)-inducible protein (IP)-10/CXC chemokine ligand 10 (CXCL10) and macrophage inflammatory protein-1beta/CC chemokine ligand 4 (CCL4)] or Th2 cells (such as thymus and activation-regulated chemokine/CCL17 and monocyte-derived chemokine/CCL22), respectively. Activated natural killer cells were preferentially recruited by supernatants of virus-activated PDC, and supernatants of CD40L-activated PDC attracted memory CD4(+) T cells, particularly the CD4(+)CD45RO(+)CD25(+) T cells described for their regulatory activities. It is striking that CD40L and virus synergized to trigger the production of IFN-gamma by PDC, which induces another Th1-attracting chemokine monokine-induced by IFN-gamma/CXCL9 and cooperates with endogenous type I IFN for IP-10/CXCL10 production. In conclusion, our studies reveal that PDC participate in the selective recruitment of effector cells of innate and adaptive immune responses and that virus converts the CD40L-induced Th2 chemokine patterns of PDC into a potent Th1 mediator profile through an autocrine loop of IFN-gamma.
Asunto(s)
Ligando de CD40/farmacología , Quimiocinas/biosíntesis , Células Dendríticas/inmunología , Interferón gamma/inmunología , Células TH1/inmunología , Células Th2/inmunología , Comunicación Autocrina/inmunología , Ligando de CD40/inmunología , Quimiocina CXCL9 , Quimiocinas/inmunología , Quimiocinas CXC/biosíntesis , Quimiocinas CXC/inmunología , Quimiotaxis de Leucocito/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/virología , Humanos , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Péptidos y Proteínas de Señalización Intercelular/inmunología , Interferón gamma/biosíntesis , Interferón gamma/efectos de los fármacos , Interferón gamma/farmacología , Interleucina-3/farmacología , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/virología , Orthomyxoviridae/inmunología , Proteínas Recombinantes , Células TH1/efectos de los fármacos , Células TH1/virología , Células Th2/efectos de los fármacos , Células Th2/virologíaRESUMEN
Human TLR10 is an orphan member of the TLR family. Genomic studies indicate that TLR10 is in a locus that also contains TLR1 and TLR6, two receptors known to function as coreceptors for TLR2. We have shown that TLR10 was not only able to homodimerize but also heterodimerized with TLRs 1 and 2. In addition, unlike TLR1 and TLR6, TLR10 was expressed in a highly restricted fashion as a highly N-glycosylated protein, which we detected in B cell lines, B cells from peripheral blood, and plasmacytoid dendritic cells from tonsil. We were also able to detect TLR10 in a CD1a(+) DC subset derived from CD34(+) progenitor cells which resemble Langerhans cells in the epidermis. Although we were unable to identify a specific ligand for TLR10, by using a recombinant CD4TLR10 molecule we also demonstrated that TLR10 directly associates with MyD88, the common Toll IL-1 receptor domain adapter. Additionally, we have characterized regions in the Toll IL-1 receptor domain of TLR10 that are essential in the activation of promoters from certain inflammatory cytokines. Even though TLR10 expression has not been detected in mice, we have identified a partial genomic sequence of the TLR10 gene that was present but nonfunctional and disrupted by a retroviral insertion in all mouse strains tested. However, a complete TLR10 sequence could be detected in the rat genome, indicating that a functional copy may be preserved in this species.
Asunto(s)
Antígenos de Diferenciación/fisiología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Regulación de la Expresión Génica/inmunología , Receptores de Superficie Celular/fisiología , Receptores Inmunológicos/fisiología , Proteínas Adaptadoras Transductoras de Señales , Adulto , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Animales , Antígenos CD4/genética , Antígenos CD4/metabolismo , Línea Celular , Glicosilación , Humanos , Glicoproteínas de Membrana/genética , Ratones , Datos de Secuencia Molecular , Factor 88 de Diferenciación Mieloide , Regiones Promotoras Genéticas , Estructura Terciaria de Proteína/genética , Ratas , Receptores de Superficie Celular/biosíntesis , Receptores de Interleucina-1/genética , Homología de Secuencia de Aminoácido , Transducción de Señal/genética , Transducción de Señal/inmunología , Receptor Toll-Like 10RESUMEN
A reciprocal activating interaction between NK cells and dendritic cells (DC) has been suggested to play a role in the functional regulation of these cells in immunity, but it has been studied only using in vitro generated bone marrow- or monocyte-derived DC. We report that human peripheral blood plasmacytoid DC (pDC) and myeloid DC are necessary to induce NK cell function depending on the type of microbial stimulus. pDC and myeloid DC are required for strongly increased NK cytolytic activity and CD69 expression, in response to inactivated influenza virus or CpG-containing oligonucleotides and poly(I:C), respectively. Secreted type I IFN is required and sufficient for the augmentation of NK cell cytolytic activity in the coculture with pDC or myeloid DC, whereas CD69 expression is dependent on both type I IFN and TNF. In addition, in response to poly(I:C), myeloid DC induce NK cells to produce IFN-gamma through a mechanism dependent on both IL-12 secretion and cell contact between NK cells and myeloid DC, but independent of type I IFN. IL-2-activated NK cells have little to no cytolytic activity for immature myeloid DC and pDC, but are able to induce maturation of these cells. Moreover, IL-2-activated NK cells induce, in the presence of a suboptimal concentration of CpG-containing oligonucleotides, a strong IFN-alpha and TNF production. These data suggest that the reciprocal functional interaction between NK cells and either pDC or myeloid DC may play an important physiological role in the regulation of both innate resistance and adaptive immunity to infections.
Asunto(s)
Comunicación Celular/inmunología , Citotoxicidad Inmunológica , Células Dendríticas/inmunología , Células Asesinas Naturales/inmunología , Células Mieloides/inmunología , Antígenos CD/biosíntesis , Antígenos CD/toxicidad , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Antígenos de Diferenciación de Linfocitos T/toxicidad , Células Cultivadas , Células Dendríticas/metabolismo , Células Dendríticas/virología , Humanos , Inmunidad Innata , Interferón Tipo I/metabolismo , Interleucina-12/fisiología , Interleucina-2/farmacología , Células Asesinas Naturales/metabolismo , Lectinas Tipo C , Activación de Linfocitos/inmunología , Células Mieloides/metabolismo , Orthomyxoviridae/inmunologíaRESUMEN
This work aims to further characterize the newly described leukemic plasmacytoid dendritic cells (LPDC), for which we had previously demonstrated their normal, PDC-like ability to produce IFN-alpha. In addition, LPDC also express the specific antigens BDCA-2 and BDCA-4. Importantly, they become fully competent antigen-presenting cells (APC) after a short maturation induced by IL-3 + CD40L or virus, exhibiting a characteristic APC phenotype (high expression of CD83 and of the costimulatory molecules CD40, CD80, CD86). Whereas IL-3 + CD40L-activated LPDC prime naive CD4(+) T cells towards a Th2 pathway (IL-4-secreting T cells), virus-activated LPDC drive a Th1 profile (IFN-gamma-secreting T cells). Moreover, we show in one case that LPDC are able to capture, process and present exogenous antigens, leading to the activation of both CD4(+) and CD8(+) T cell clones in an antigen-specific manner. This study further characterizes the phenotype and immunological functions of LPDC.
Asunto(s)
Células Dendríticas/inmunología , Leucemia/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Presentación de Antígeno , Antígenos de Superficie/inmunología , Ligando de CD40/inmunología , Diferenciación Celular/inmunología , Niño , Citocinas/inmunología , Citocinas/metabolismo , Células Dendríticas/citología , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Interleucina-3/inmunología , Leucemia/patología , Masculino , Persona de Mediana Edad , Orthomyxoviridae/inmunologíaRESUMEN
We report in this study the generation of a novel rat mAb that recognizes mouse plasmacytoid dendritic cells (pDC). This Ab, named 120G8, stains a small subset of CD11c(low) spleen cell with high specificity. This population produces high amounts of IFN-alpha upon in vitro viral stimulation. Both ex vivo- and in vitro-derived 120G8(+) cells display a phenotype identical with that of the previously described mouse pDC (B220(high)Ly6C(high)Gr1(low)CD11b(-)CD11c(low)). Mice treated with 120G8 mAb are depleted of B220(high)Ly6C(high)CD11c(low) cells and have a much-reduced ability to produce IFN-alpha in response to in vivo CpG stimulation. The mAb 120G8 stains all and only B220(high)Ly6C(high)CD11c(low) pDC in all lymphoid organs. Immunohistochemical studies performed with this mAb indicate that pDC are located in the T cell area of spleen, lymph nodes, and Peyer's patches. Although the Ag recognized by 120G8 is not yet known, we show that its expression is up-regulated by type I IFN on B cells and DC. Using this mAb in immunofluorescence studies demonstrates strain- and organ-specific differences in the frequency of pDC and other DC subsets. 129Sv mice have a much higher frequency of pDC, together with a lower frequency of conventional CD8alpha(+)CD11c(high) DC, compared with C57BL/6 mice, both in spleen and blood. The higher ability of 129Sv mice to produce IFN-alpha in vivo is related to a higher number of pDC, but also to a higher ability of pDC from 129Sv mice to produce IFN-alpha in vitro in response to viral stimulation.
Asunto(s)
Anticuerpos Monoclonales/metabolismo , Células Dendríticas/citología , Células Dendríticas/inmunología , Animales , Anticuerpos Bloqueadores/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/análisis , Anticuerpos Monoclonales/biosíntesis , Linfocitos B/inmunología , Linfocitos B/metabolismo , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Antígeno CD11c/biosíntesis , Diferenciación Celular/inmunología , Células Cultivadas , Células Dendríticas/química , Células Dendríticas/metabolismo , Femenino , Inmunohistoquímica , Inmunofenotipificación , Interferón Tipo I/farmacología , Interferón gamma/antagonistas & inhibidores , Interferón gamma/biosíntesis , Antígenos Comunes de Leucocito/biosíntesis , Recuento de Leucocitos , Leucopenia/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Ratones Desnudos , Ratones SCID , Orthomyxoviridae/inmunología , Ratas , Especificidad de la Especie , Bazo/citología , Bazo/inmunología , Bazo/metabolismo , Coloración y Etiquetado , Regulación hacia Arriba/inmunologíaRESUMEN
The recruitment of selected dendritic cell (DC) subtypes conditions the class of the immune response. Here we show that the migration of human plasmacytoid DCs (pDCs), the blood natural interferon alpha-producing cells, is induced upon the collective action of inducible and constitutive chemokines. Despite expression of very high levels of CXCR3, pDCs do not respond efficiently to CXCR3 ligands. However, they migrate in response to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12 and CXCR3 ligands synergize with SDF-1/CXCL12 to induce pDC migration. This synergy reflects a sensitizing effect of CXCR3 ligands, which, independently of a gradient and chemoattraction, decrease by 20-50-fold the threshold of sensitivity to SDF-1/CXCL12. Thus, the ability of the constitutive chemokine SDF-1/CXCL12 to induce pDC recruitment might be controlled by CXCR3 ligands released during inflammation such as in virus infection. SDF-1/CXCL12 and the CXCR3 ligands Mig/CXCL9 and ITAC/CXCL1 display adjacent expression both in secondary lymphoid organs and in inflamed epithelium from virus-induced pathologic lesions. Because pDCs express both the lymph node homing molecule l-selectin and the cutaneous homing molecule cutaneous lymphocyte antigen, the cooperation between inducible CXCR3 ligands and constitutive SDF-1/CXCL12 may regulate recruitment of pDCs either in lymph nodes or at peripheral sites of inflammation.
Asunto(s)
Quimiocinas CXC/inmunología , Células Dendríticas/inmunología , Receptores de Quimiocina/fisiología , Antígenos CD/inmunología , Antígeno CD11c/inmunología , Quimiocina CXCL12 , Células Dendríticas/efectos de los fármacos , Humanos , Interferón-alfa/sangre , Ligandos , Activación de Linfocitos/inmunología , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/inmunología , Receptores CXCR3 , Células del Estroma/inmunologíaRESUMEN
BACKGROUND AND OBJECTIVES: The CD4+ CD56+ lin- immunophenotype characterizes rare malignancies, so far considered as arising from the transformation of NK progenitors, and therefore classified as blastic NK-cell leukemia/lymphoma by the WHO committee. Recently it was formally demonstrated that such malignancies do, in fact, develop from plasmacytoid dendritic cells (pDC), according to immunophenotypic and functional criteria. The clinico-biological features of this neoplasm were moreover recently summarized from a large series of 23 patients. INFORMATION SOURCES: The main symptoms at presentation were cutaneous lesions and bone marrow failure, due to invasion by blastic cells, all of which were EBV negative and agranular. Most patients were initially sensitive to chemotherapy regimens, but they rapidly relapsed and died within 3 years. Only 2 allotransplanted patients were long survivors. Recurrent chromosomal aberrations involving chromosomes 5q, 6q, 12p, 13q, 15q and 9 were described and it was characteristic that these were associated in the same cell. In the present review we compared these findings to those in the literature. STATE OF THE ART AND PERSPECTIVES: The concordant characteristics led us to confirm that this neoplasm actually represents a new entity, that we propose to rename early pDC leukemia/lymphoma. The diagnosis is primarily based on a characteristic immunophenotypic profile i.e. CD4+ CD56+ CD3- CD13- CD33- CD19-. Complementary analyses assessing the expression of more specific pDC-related markers showed the cells to be HLA-DR+, CD123high, CD116low, CD45RA+, BDCA-2+ or BDCA-4+. Such complementary investigations are necessary only in the case of an atypical phenotype, in order to confirm a pDC origin and exclude another hematologic disease. This presently regards the expression of CD33 or cytoplasmic CD3e (cyCD3e) and the negativity of CD56.
Asunto(s)
Antígenos CD4/biosíntesis , Antígeno CD56/biosíntesis , Células Dendríticas/patología , Leucemia/etiología , Leucemia/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Células Dendríticas/química , Femenino , Humanos , Lactante , Leucemia/diagnóstico , Masculino , Persona de Mediana EdadRESUMEN
Human plasmacytoid dendritic cells (pDCs), also called type 2 dendritic cell precursors or natural interferon (IFN)-producing cells, represent a cell type with distinctive phenotypic and functional features. They are present in the thymus and probably share a common precursor with T and natural killer (NK) cells. In an effort to identify genes that control pDC development we searched for genes of which the expression is restricted to human pDC using a cDNA subtraction technique with activated monocyte-derived DCs (Mo-DCs) as competitor. We identified the transcription factor Spi-B to be expressed in pDCs but not in Mo-DCs. Spi-B expression in pDCs was maintained on in vitro maturation of pDCs. Spi-B was expressed in early CD34(+)CD38(-) hematopoietic progenitors and in CD34(+)CD1a(-) thymic precursors. Spi-B expression is down-regulated when uncommitted CD34(+)CD1a(-) thymic precursors differentiate into committed CD34(+)CD1a(+) pre-T cells. Overexpression of Spi-B in hematopoietic progenitor cells resulted in inhibition of development of T cells both in vitro and in vivo. In addition, development of progenitor cells into B and NK cells in vitro was also inhibited by Spi-B overexpression. Our results indicate that Spi-B is involved in the control of pDC development by limiting the capacity of progenitor cells to develop into other lymphoid lineages.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Células Dendríticas/citología , Células Dendríticas/metabolismo , Factores de Transcripción/fisiología , Apoptosis/efectos de los fármacos , Linfocitos B/citología , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Linaje de la Célula/efectos de los fármacos , Proteínas de Unión al ADN/análisis , Proteínas de Unión al ADN/genética , Células Dendríticas/clasificación , Humanos , Inmunofenotipificación , Células Asesinas Naturales/citología , Linfocitos T/citología , Factores de Transcripción/análisis , Factores de Transcripción/genética , Transducción GenéticaRESUMEN
Human plasmacytoid dendritic cells represent a rare population of leukocytes which produce high amounts of type I interferon in response to certain viruses. Although those cells were first described in 1958, there are still unsolved issues related to their origin and function. Recently, a leukemic counterpart of plasmacytoid dendritic cells was identified. Molecular approaches using either normal or leukemic plasmacytoid dendritic cells provide some new insights into the controversial lymphoid origin of those cells. The need for specific markers is still a critical aspect for the identification of plasmacytoid dendritic cells, whatever stage of differentiation, in normal as well as in pathological conditions. Hopefully, novel markers will allow delineation of the relationships between dendritic cells at different stages of differentiation/maturation along the myeloid and lymphoid lineages.
Asunto(s)
Antígenos CD/biosíntesis , Diferenciación Celular/inmunología , Células Dendríticas/inmunología , Interferón Tipo I/biosíntesis , Animales , Células Dendríticas/citología , Humanos , Células Plasmáticas , Linfocitos T/citología , Linfocitos T/inmunologíaRESUMEN
Recent studies in humans have highlighted the importance of a distinct cellular entity, the plasmacytoid dendritic cell (PDC). To identify genes for which expression is restricted to human PDCs, a cDNA subtraction technique was applied using cDNA from activated monocyte-derived DCs (MDDCs) as competitor. In the 650 sequences analyzed, 25% were for B-cell transcripts. We also found lymphoid-related genes, immunoglobulinlike transcript 7 (ILT7), granzyme B (GrB), Spi-B, and the receptor tyrosine kinase Eph-B1. Granzyme B was up-regulated on activation, and protein was detected only in PDCs. Eph-B1 protein was expressed in the cytoplasm and the nuclei of PDCs and MDDCs, respectively. Interestingly, several novel molecules have been identified that were predicted to encode for a type 2 transmembrane protein (BRI(3)), a putative cytokine (C-15, a cysteine-rich-secreted protein), and a type 1 leucine-rich repeat protein (MAPA). The identification of genes expressed in PDCs provides new insights into their function and origin.
Asunto(s)
Células Dendríticas/metabolismo , Efrina-B1/biosíntesis , ARN Mensajero/biosíntesis , Serina Endopeptidasas/biosíntesis , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Mapeo Cromosómico , Citocinas/biosíntesis , Citocinas/genética , ADN Complementario/genética , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/genética , Células Dendríticas/clasificación , Efrina-B1/genética , Etiquetas de Secuencia Expresada , Perfilación de la Expresión Génica , Biblioteca de Genes , Granzimas , Humanos , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Ratones , Datos de Secuencia Molecular , Monocitos/citología , Familia de Multigenes , Especificidad de Órganos , Biosíntesis de Proteínas , Proteínas/genética , ARN Mensajero/genética , Secuencias Repetitivas de Aminoácido , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Serina Endopeptidasas/genética , Especificidad de la Especie , Técnica de Sustracción , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Transcripción GenéticaRESUMEN
Myeloid and plasmacytoid dendritic cells (MDC, PDC) play a key role in the initiation of immune responses. We found a reduction of DC subsets among 20 chronic myeloid leukaemia (CML) patients in chronic phase (MDC, mean, 0.10% +/- 0.10, P = 0.02; PDC, mean, 0.11% +/- 0.08, P = 0.006 versus controls). The maintenance of blood DC correlated with the presence of high percentages of circulating CD34+/CD38- progenitors that were able to give rise in vitro to CD1a+ DC. The reduced DC numbers may contribute to leukaemia escape from immune control and restoration of DC may be a goal for CML immunotherapy.
Asunto(s)
ADP-Ribosil Ciclasa/inmunología , Antígenos CD34/inmunología , Antígenos CD/inmunología , Células Dendríticas/inmunología , Células Madre Hematopoyéticas/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , ADP-Ribosil Ciclasa 1 , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD1/inmunología , Femenino , Humanos , Masculino , Glicoproteínas de Membrana , Persona de Mediana EdadRESUMEN
Interferon (IFN)-alpha/beta and interleukin (IL)-12 are cytokines critical in defense against viruses, but their cellular sources and mechanisms of regulation for in vivo expression remain poorly characterized. The studies presented here identified a novel subset of dendritic cells (DCs) as major producers of the cytokines during murine cytomegalovirus (MCMV) but not lymphocytic choriomeningitis virus (LCMV) infections. These DCs differed from those activated by Toxoplasma antigen but were related to plasmacytoid cells, as assessed by their CD8alpha(+)Ly6G/C(+)CD11b(-) phenotype. Another DC subset (CD8alpha(2)Ly6G/C(-)CD11b(+)) also contributed to IL-12 production in MCMV-infected immunocompetent mice, modestly. However, it dramatically increased IL-12 expression in the absence of IFN-alpha/beta functions. Conversely, IFN-alpha/beta production was greatly reduced under these conditions. Thus, a cross-regulation of DC subset cytokine responses was defined, whereby secretion of type I IFNs by CD8alpha(+) DCs resulted in responses limiting IL-12 expression by CD11b(+) DCs but enhancing overall IFN-alpha/beta production. Taken together, these data indicate that CD8alpha(+)Ly6G/C(+)CD11b(-) DCs play important roles in limiting viral replication and regulating immune responses, through cytokine production, in some but not all viral infections. They also illustrate the plasticity of cellular sources for innate cytokines in vivo and provide new insights into the roles of IFNs in shaping immune responses to viruses.