RESUMEN
Cancer development is often associated with the lack of specific and efficient recognition of tumor cells by the immune system. Natural killer (NK) cells are lymphocytes of the innate immune system that participate in the elimination of tumors. We report the identification of a tumor cell surface molecule that binds NKp30, a human receptor which triggers antitumor NK cell cytotoxicity and cytokine secretion. This previously unannotated gene belongs to the B7 family and, hence, was designated B7-H6. B7-H6 triggers NKp30-mediated activation of human NK cells. B7-H6 was not detected in normal human tissues but was expressed on human tumor cells, emphasizing that the expression of stress-induced self-molecules associated with cell transformation serves as a mode of cell recognition in innate immunity.
Asunto(s)
Antígenos CD/inmunología , Antígeno B7-1/inmunología , Células Asesinas Naturales/inmunología , Ligandos , Activación de Linfocitos , Receptor 3 Gatillante de la Citotoxidad Natural/inmunología , Secuencia de Aminoácidos , Animales , Antígenos CD/genética , Antígenos de Superficie/inmunología , Antígenos B7 , Antígeno B7-1/genética , Línea Celular Tumoral/inmunología , Femenino , Humanos , Inmunidad Innata/inmunología , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/inmunología , Células K562 , Células Asesinas Naturales/citología , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Receptor 3 Gatillante de la Citotoxidad Natural/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunologíaRESUMEN
MOTIVATION: Gene finding remains an open problem well after the sequencing of the human genome. The low gene sensitivity of current methods is a problem for divergent protein families, because fairly accurate exon assemblies are required before sensitive fold recognition algorithms can be applied. This paper presents a new genomic threading algorithm which integrates the gene finding and fold recognition steps into a single process. The method is applicable to evolutionarily divergent protein families that have retained some trace of their common ancestry, number and phase of introns, sizes of exons and placement of structural elements on specific exons. Such conserved structural signals may be visible despite dramatic evolution of protein sequence. RESULTS: The method is evaluated on the family of helical cytokines by cross-validation sensitivity analysis. The method has also been applied to all intergenic regions of the human genome, and an expression and cloning approach has been coupled with the predictions of the method. Two genes discovered by this method are discussed. SUPPLEMENTARY INFORMATION: All data used and the results obtained in the cross-validation analysis are available at http://www.soi.city.ac.uk/~conklin/papers/GT/
Asunto(s)
Algoritmos , Mapeo Cromosómico/métodos , Citocinas/química , Citocinas/genética , Exones/genética , Genoma Humano , Análisis de Secuencia de ADN/métodos , Humanos , Conformación Proteica , Pliegue de Proteína , Relación Estructura-ActividadRESUMEN
Cytokines play a critical role in modulating the innate and adaptive immune systems. Here, we have identified from the human genomic sequence a family of three cytokines, designated interleukin 28A (IL-28A), IL-28B and IL-29, that are distantly related to type I interferons (IFNs) and the IL-10 family. We found that like type I IFNs, IL-28 and IL-29 were induced by viral infection and showed antiviral activity. However, IL-28 and IL-29 interacted with a heterodimeric class II cytokine receptor that consisted of IL-10 receptor beta (IL-10Rbeta) and an orphan class II receptor chain, designated IL-28Ralpha. This newly described cytokine family may serve as an alternative to type I IFNs in providing immunity to viral infection.