RESUMEN
CD4+ CD8+ double-positive thymocytes give rise to both conventional TCRαß+ T cells and invariant natural killer T cells (iNKT cells), but these two kinds of cells display different characteristics. The molecular mechanism underlying iNKT cell lineage development and function acquisition remain to be elucidated. We show that the loss of chromatin assembly factor 1B (CHAF1b) maintains the normal development of conventional TCRαß+ T cells but severely impairs early development of iNKT cells. This dysregulation is accompanied by the impairment in chromatin activation and gene transcription at Vα14-Jα18 locus. Notably, ectopic expression of a Vα14-Jα18 TCR rescues Chaf1b-deficient iNKT cell developmental defects. Moreover, cytokine secretion and antitumor activity are substantially maintained in Vα14-Jα18 TCR transgene-rescued Chaf1b-deficient iNKT cells. Our study identifies CHAF1b as a critical factor that controls the early development but not function acquisition of iNKT cells via lineage- and stage-specific regulation.
Asunto(s)
Factor 1 de Ensamblaje de la Cromatina/inmunología , Células T Asesinas Naturales/inmunología , Animales , Diferenciación Celular/inmunología , Línea Celular Tumoral , Linaje de la Célula/inmunología , Ensamble y Desensamble de Cromatina/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Timocitos/inmunologíaRESUMEN
The largest gene families in eukaryotes are subject to allelic exclusion, but mechanisms underpinning single allele selection and inheritance remain unclear. Here, we describe a protein complex sustaining variant surface glycoprotein (VSG) allelic exclusion and antigenic variation in Trypanosoma brucei parasites. The VSG-exclusion-1 (VEX1) protein binds both telomeric VSG-associated chromatin and VEX2, an ortholog of nonsense-mediated-decay helicase, UPF1. VEX1 and VEX2 assemble in an RNA polymerase-I transcription-dependent manner and sustain the active, subtelomeric VSG-associated transcription compartment. VSG transcripts and VSG coats become highly heterogeneous when VEX proteins are depleted. Further, the DNA replication-associated chromatin assembly factor, CAF-1, binds to and specifically maintains VEX1 compartmentalisation following DNA replication. Thus, the VEX-complex controls VSG-exclusion, while CAF-1 sustains VEX-complex inheritance in association with the active-VSG. Notably, the VEX2-orthologue and CAF-1 in mammals are also implicated in exclusion and inheritance functions. In trypanosomes, these factors sustain a highly effective and paradigmatic immune evasion strategy.
Asunto(s)
Variación Antigénica/genética , Epigénesis Genética/inmunología , Proteínas Protozoarias/genética , Trypanosoma brucei brucei/genética , Glicoproteínas Variantes de Superficie de Trypanosoma/genética , Alelos , Animales , Variación Antigénica/inmunología , Línea Celular , Factor 1 de Ensamblaje de la Cromatina/inmunología , Factor 1 de Ensamblaje de la Cromatina/metabolismo , Replicación del ADN/inmunología , Regulación de la Expresión Génica/inmunología , Interacciones Huésped-Parásitos/genética , Interacciones Huésped-Parásitos/inmunología , Evasión Inmune , Proteínas Protozoarias/inmunología , Transcripción Genética/inmunología , Trypanosoma brucei brucei/inmunología , Tripanosomiasis Africana/inmunología , Tripanosomiasis Africana/parasitología , Glicoproteínas Variantes de Superficie de Trypanosoma/inmunología , Glicoproteínas Variantes de Superficie de Trypanosoma/metabolismoRESUMEN
Autoantibodies to proliferating cell nuclear antigen (PCNA) are specifically, if rarely, present in systemic lupus erythematosus (SLE) patient sera. Even SLE patients lacking PCNA reactivity often show reaction to PCNA-binding protein. Here, immunoreactivity to chromatin assembly factor-1 (CAF-1), an essential molecule for DNA replication and a PCNA-binding protein, was compared for the sera of SLE patients, normal healthy controls (NHCs) and other disease controls, and in autoimmune sera reactive to standard autoantigens, by enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence, and immunoblotting. CAF1 and IRF1 expression in SLE and NHC peripheral mononuclear cells were compared by quantitative real-time polymerase chain reaction. Serum interferon-γ-inducing protein-10 and anti-double-stranded (ds)DNA antibody levels were measured by ELISA. Increased CAF-1 autoimmune reactivity was recognized in SLE or serum anti-dsDNA antibody-positive patients. Significantly greater central nervous system (CNS) involvement (aseptic meningitis) and serum anti-dsDNA antibody titers were present more often in anti-CAF-1 antibody-positive than antibody-negative SLE patients. IFN-γ positively regulated CAF-1 expression in vitro and was associated with anti-CAF-1 antibody production in SLE. Thus, a novel anti-CAF-1 autoantibody is frequently found in patients with SLE and is a useful biomarker for diagnosis, especially in cases with CNS involvement. Aberrant IFN-γ regulation appears to play an important role in anti-CAF-1 antibody production in SLE.