RESUMEN
The caliber and magnitude of T cell responses are regulated by costimulatory molecules following the engagement of TCRs and MHC molecules. B7-DC has the highest homology with B7-H1 in the B7 family, and both of them bind an immunoregulatory molecule, programmed death 1. Previous studies have demonstrated that B7-DC stimulates T cell proliferation and CTL generation, which sharply contrasts the inhibitory role of B7-H1. Th2 cytokines prompt B7-DC expression, which in turn enhances Th1 responses. In this study, we used an intestinal nematode, Nippostrongylus brasiliensis, to induce strong Th2 responses and to evaluate B7-DC function under Th2-polarizing conditions in vivo. By either blocking B7-DC expression during N. brasiliensis infection or by examining N. brasiliensis-infected B7-DC knockout mice, we observed enhanced eosinophilia, the overproduction of serum IgE, and increased Th2 cytokine production along with decreased Th1 cytokine production (particularly IFN-gamma production), indicating that B7-DC inhibits Th2 responses. Our results further demonstrate that the inhibition of Th2 responses by B7-DC occurs independently of programmed death 1 but conceivably acts through an as yet unknown alternative receptor that enhances Th1 responses. Although the deficiency of B7-DC expression that enhanced the production of IL-13 paradoxically resulted in better protection against N. brasiliensis infection, our results show that B7-DC plays an important role in bolstering a robust Th1 response that is required for effective antiviral and anticancer immunity, even under a strong Th2-polarizing environment induced by N. brasiliensis infection.
Asunto(s)
Antígeno B7-1/fisiología , Nippostrongylus/inmunología , Infecciones por Strongylida/inmunología , Células Th2/inmunología , Animales , Antígeno B7-1/genética , Células Cultivadas , Eosinofilia/inmunología , Eosinofilia/parasitología , Retroalimentación Fisiológica , Inmunoglobulina E/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Proteína 2 Ligando de Muerte Celular Programada 1 , Células Th2/metabolismo , Células Th2/parasitologíaRESUMEN
Ligation of CD40 on B cells increases their ability to present Ag and to activate MHC class II (MHC-II)-restricted T cells. How this occurs is not entirely clear. In this study we demonstrate that CD40 ligation on Ag-presenting B cells (APC) for a short period between 30 min and 3 h has a rapid, augmenting effect on the ability of a B cell line and normal B cells to activate T cells. This is not due to alterations in Ag processing or to an increase in surface expression of CD80, CD86, ICAM-1, or MHC-II. This effect is particularly evident with naive, resting T lymphocytes and appears to be more pronounced under limiting Ag concentrations. Shortly after CD40 ligation on a B cell line, MHC-II and CD80 progressively accumulated in cholesterol-enriched microdomains on the cell surface, which correlated with an initial enhancement in their Ag presentation ability. Moreover, CD40 ligation induced a second, late, more sustained enhancement of Ag presentation, which correlates with a significant increase in CD80 expression by APC. Thus, CD40 signaling enhances the efficiency with which APC activate T cells by at least two related, but distinct, mechanisms: an early stage characterized by aggregation of MHC-II and CD80 clusters, and a late stage in which a significant increase in CD80 expression is observed. These results raise the possibility that one important role of CD40 is to contribute to the formation of the immunological synapse on the APC side.
Asunto(s)
Adyuvantes Inmunológicos/fisiología , Presentación de Antígeno/inmunología , Antígeno B7-1/metabolismo , Antígenos CD40/fisiología , Antígenos de Histocompatibilidad Clase II/metabolismo , Microdominios de Membrana/inmunología , Microdominios de Membrana/metabolismo , Adyuvantes Inmunológicos/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Antígeno B7-1/fisiología , Linfocitos T CD4-Positivos/inmunología , Antígenos CD40/inmunología , Antígenos CD40/metabolismo , Bovinos , Línea Celular , Colesterol/metabolismo , Antígenos de Histocompatibilidad Clase II/fisiología , Hibridomas , Interfase/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C3H , Ratones Transgénicos , Esfingolípidos/metabolismo , Factores de TiempoRESUMEN
The ICOS-B7RP-1-mediated T cell costimulatory pathway has been implicated crucial for T cell activation and differentiation. In this study, we investigated the role of this costimulation in the regulation of immune responses to parasitic infections by using blocking antibody against B7RP-1 as well as ICOS-deficient mice. The administration of anti-B7RP-1 monoclonal antibody (mAb) significantly suppressed the footpad swelling in susceptible BALB/c mice upon Leishmania major infection. The observation was consistent not only with the significant suppression of IL-4, IL-5 and IL-10 secretion from lymph node cells, which were derived from L. major-infected mice, but also with the significant reduction of total serum IgE and IgG(1) in anti-B7RP-1 mAb-treated BALB/c mice. Infection of ICOS-deficient mice with L. major also suggested the impaired Th2 immune responses in the absence of this costimulation. The immunological function of ICOS-B7RP-1 costimulatory pathway in infection was further confirmed by infecting anti-B7RP-1 mAb-treated wild type or ICOS-deficient mice with Nippostrongylus brasiliensis. The characteristic elevation of total serum IgE and eosinophilia upon N. brasiliensis infection was suppressed by blocking this costimulation. Moreover, the protection to N. brasiliensis adult worms was suppressed in anti-B7RP-1 mAb-treated wild type or ICOS-deficient mice. These results suggest the crucial role of this costimulatory pathway in the regulation of Th2-biased T cell differentiation and in host immune responses against L. major and N. brasiliensis infections.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/fisiología , Antígeno B7-1/fisiología , Sistema Inmunológico/fisiología , Leishmaniasis Cutánea/inmunología , Infecciones por Strongylida/inmunología , Animales , Antígenos de Diferenciación de Linfocitos T/inmunología , Antígeno B7-1/inmunología , Sistema Inmunológico/inmunología , Ligando Coestimulador de Linfocitos T Inducibles , Proteína Coestimuladora de Linfocitos T Inducibles , Leishmania major/inmunología , Ratones , Ratones Endogámicos BALB C , Nippostrongylus/inmunología , Células Th2/inmunología , Células Th2/fisiologíaRESUMEN
Glucuronoxylomannan (GXM), the major capsular polysaccharide of Cryptococcus neoformans, is the most important virulence factor of this fungus. We analyzed the molecular events related to protective immune responses against a non-encapsulated strain of C. neoformans, mediated by murine splenic CD4(+) T lymphocytes in vitro, and the impact of GXM addition upon these events. Both the lymphoproliferation of CD4(+) T cells and the control of fungus growth were dependent on B7 co-stimulation. Addition of GXM did not modify CD4(+) T cell proliferation, but exacerbated infection in cultures obtained from normal and infected hosts. GXM enhanced the secretion of IL-10 and IL-4, while it reduced the production of pro-inflammatory cytokines TNF-alpha and IFN-gamma. The blockade of IL-10 activity with neutralizing antibodies increased TNF-alpha production and reduced yeast cell growth. The findings suggest that GXM exacerbates infection by down-regulating cell-mediated protective immune response and that IL-10 is implicated in yeast evasion.
Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Cryptococcus neoformans/inmunología , Interleucina-10/fisiología , Polisacáridos/toxicidad , Levaduras/crecimiento & desarrollo , Animales , Antígeno B7-1/fisiología , Linfocitos T CD4-Positivos/inmunología , Interferón gamma/biosíntesis , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos BALB C , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Th2 immune responses to a number of infectious pathogens are dependent on B7-1/B7-2 costimulatory molecule interactions. We have now examined the Th2 immune response to Nippostrongylus brasiliensis (Nb) in B7-1/B7-2(-/-) mice and show that Th2 effector cells develop that can mediate worm expulsion and produce substantial Th2 cytokines comparable with wild-type infected mice; however, in marked contrast, B cell Ag-specific Ab production is abrogated after B7 blockade. To examine the mechanism of T cell activation, OVA-specific DO11.10 T cells were transferred to recipient mice, which were then immunized with a combination of Nb plus OVA or either alone. Only the combination of Nb plus OVA triggered T cell differentiation to OVA-specific Th2 cells, suggesting that Nb acts as an adjuvant to stimulate Ag-specific naive T cells to differentiate to effector Th2 cells. Furthermore, using the DO11.10 TCR-transgenic T cell adoptive transfer model, we show that blocking B7-1/B7-2 interactions does not impair nonparasite Ag-specific DO11.10 Th2 cell differentiation; however, DO11.10 T cell cycle progression and migration to the B cell zone are inhibited.
Asunto(s)
Antígenos CD/fisiología , Antígeno B7-1/fisiología , Epítopos de Linfocito T/fisiología , Inmunoconjugados , Interleucina-4/biosíntesis , Interfase/inmunología , Glicoproteínas de Membrana/fisiología , Nippostrongylus/inmunología , Subgrupos de Linfocitos T/inmunología , Células Th2/inmunología , Abatacept , Secuencia de Aminoácidos , Animales , Anticuerpos Antihelmínticos/biosíntesis , Anticuerpos Antihelmínticos/sangre , Antígenos CD/genética , Antígenos de Diferenciación/administración & dosificación , Linfocitos B/citología , Linfocitos B/inmunología , Antígeno B7-1/genética , Antígeno B7-1/inmunología , Antígeno B7-2 , Antígeno CTLA-4 , Ciclo Celular/genética , Ciclo Celular/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Inhibición de Migración Celular , Células Cultivadas , Inhibidores de Crecimiento/administración & dosificación , Inmunosupresores/administración & dosificación , Inyecciones Subcutáneas , Interfase/genética , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitología , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Datos de Secuencia Molecular , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología , Infecciones por Strongylida/genética , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/prevención & control , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/parasitología , Subgrupos de Linfocitos T/trasplante , Células Th2/citología , Células Th2/metabolismo , Células Th2/parasitologíaRESUMEN
Infection of BALB/c mice with Leishmania chagasi results in progressive increase of parasite burden in spleen, in spite of extensive T cell activation in situ. Explanted splenic CD4+ T cells showed decreased proliferation to anti-CD3, compared with controls, and no response to L. chagasi recombinant antigen Lcr1. Blockade of the negative costimulatory receptor CTLA-4 restored responses to anti-CD3 and induced vigorous responses to Lcr1. Blockade of B7-1, but not B7-2, also enhanced T cell responsiveness. CTLA-4 blockade completely restored activation-induced interleukin-2 secretion and increased interferon-gamma production. The effect, however, was not restricted to Th1 responses, since CTLA-4 blockade also enhanced antigen-induced interleukin-4 secretion. CTLA-4 blockade induced almost complete elimination of parasite burden in splenocyte cultures activated with anti-CD3 or Lcr1. These results indicate that CTLA-4 engagement by B7-1 plays an important role in maintaining unresponsiveness in CD4+ T cells in this model of chronic visceral leishmaniasis.