RESUMEN
New members of the extended MHC class I-like family were identified based on their ability to bind human cytomegalovirus glycoprotein UL16 and/or their mutual homology. Soluble UL16 binding proteins (ULBP) competed with each other for binding to NK cells. Treatment of human and mouse NK cells with ULBP led to increased production of cytokines/chemokines, proliferation, cytotoxic activity and up-regulation of activation-associated surface molecules. The presence of ULBP during the stimulation phase of the CTL assay caused increased cytotoxic activity. Addition of soluble recombinant UL16 protein inhibited the biological activities mediated by ULBP, suggesting the existence of a novel mechanism utilized by CMV to evade elimination by the host immune system.
Asunto(s)
Proteínas Portadoras/metabolismo , Citomegalovirus/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Proteínas del Envoltorio Viral/metabolismo , Animales , Unión Competitiva , Proteínas Portadoras/antagonistas & inhibidores , División Celular/efectos de los fármacos , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Citomegalovirus/inmunología , Citotoxicidad Inmunológica , Citometría de Flujo , Proteínas Ligadas a GPI , Humanos , Inmunoglobulina G/inmunología , Péptidos y Proteínas de Señalización Intercelular , Interleucina-15/inmunología , Péptidos y Proteínas de Señalización Intracelular , Células Asesinas Naturales/citología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Activación de Linfocitos/efectos de los fármacos , Recuento de Linfocitos , Proteínas de la Membrana , Ratones , Ratones SCID , Unión Proteica , Solubilidad , Bazo/citología , Linfocitos T Citotóxicos/inmunología , Proteínas del Envoltorio Viral/farmacologíaRESUMEN
The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation. Cross-linking of 4-1BB and the T cell receptor (TCR) on activated T cells has been shown to deliver a costimulatory signal to T cells. Here, we expand upon previously published studies by demonstrating that CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB. In comparison, CD28-mediated costimulatory signals appear to function in a reciprocal manner to those induced through 4-1BB costimulation. In vivo examination of the effects of anti-4-1BB monoclonal antibodies (mAbs) on antigen-induced T cell activation have shown that the administration of epitope-specific anti-4-1BB mAbs amplified the generation of H-2d-specific cytotoxic T cells in a murine model of acute graft versus host disease (GVHD) and enhanced the rapidity of cardiac allograft or skin transplant rejection in mice. Cytokine analysis of in vitro activated CD4+ and CD8+ T cells revealed that anti-4-1BB costimulation markedly enhanced interferon-gamma production by CD8+ T cells and that anti-4-1BB mediated proliferation of CD8+ T cells appears to be IL-2 independent. The results of these studies suggest that regulatory signals delivered by the 4-1BB receptor play an important role in the regulation of cytotoxic T cells in cellular immune responses to antigen.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Inmunidad Celular , Activación de Linfocitos/inmunología , Receptores de Factor de Crecimiento Nervioso/inmunología , Receptores del Factor de Necrosis Tumoral/inmunología , Animales , Antígenos CD , Linfocitos T CD8-positivos/citología , División Celular/inmunología , Ratones , Ratones Endogámicos BALB C , Receptores de Factor de Crecimiento Nervioso/biosíntesis , Receptores del Factor de Necrosis Tumoral/biosíntesis , Transducción de Señal/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis TumoralRESUMEN
We report that the cytoplasmic domains of the T-lymphocyte glycoproteins CD4 and CD8 alpha contain short related amino acid sequences that are involved in binding the amino-terminal domain of the intracellular tyrosine protein kinase, p56lck. Transfer of as few as six amino acid residues from the cytoplasmic domain of the CD8 alpha protein to the cytoplasmic domain of an unrelated protein conferred p56lck binding to the hybrid protein in HeLa cells. The common sequence motif shared by CD4 and CD8 alpha contains two cysteines, and mutation of either cysteine in the CD4 sequence eliminated binding of p56lck.p56lck also contains two cysteine residues within its CD4-CD8 alpha-binding domain, and both are critical to the interaction with CD4 or CD8 alpha. Because the interaction does not involve disulfide bond formation, a metal ion could stabilize the complex.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/metabolismo , Antígenos CD4/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Antígenos CD8 , Cisteína/fisiología , Citoplasma/metabolismo , Análisis Mutacional de ADN , Humanos , Técnicas In Vitro , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito , Datos de Secuencia Molecular , Unión Proteica , Transducción de Señal , Relación Estructura-ActividadRESUMEN
The response to a novel set of T cell mitogens has been analysed and compared to the response to Mls locus differences. These polyclonal T cell activators, staphylococcal enterotoxins A and B, stimulate T cells in a way that requires an antigen-presenting cell bearing class II MHC products and involves the CD4:T cell receptor complex. However, the specificity of MHC recognition by the T cell receptor is lost in this response. Thus, these mitogens produce a response with characteristics similar to that induced by Mls locus differences. These mitogens can be used to analyse the immunobiology of this response, and may help in understanding and identifying the Mls locus product as well.