RESUMEN
Proteolytic shedding of ligands for the NK group 2D (NKG2D) receptor is a strategy used by tumors to modulate immune recognition by NK cells and cytotoxic T cells. A number of metalloproteases, especially those of the A disintegrin and metalloprotease (ADAM) family, can mediate NKG2D ligand cleavage and this process can be modulated by expression of the thiol isomerase ERp5. In this article, we describe that an increased shedding of the NKG2D ligand MICA is observed postinfection with several strains of human CMV due to an enhanced activity of ADAM17 (TNF-α converting enzyme) and matrix metalloprotease 14 caused by a reduction in the expression of the endogenous inhibitor of metalloproteases tissue inhibitors of metalloproteinase 3 (TIMP3). This decrease in TIMP3 expression correlates with increased expression of a cellular miRNA known to target TIMP3, and we also identify a human CMV-encoded microRNA able to modulate TIMP3 expression. These observations characterize a novel viral strategy to influence the shedding of cell-surface molecules involved in immune response modulation. They also provide an explanation for previous reports of increased levels of various ADAM17 substrates in the serum from patients with CMV disease. Consistent with this hypothesis, we detected soluble MICA in serum of transplant recipients with CMV disease. Finally, these data suggest that it might be worthwhile to prospectively study ADAM17 activity in a larger group of patients to assay whether this might be a useful biomarker to identify patients at risk for development of CMV disease.
Asunto(s)
Infecciones por Citomegalovirus/inmunología , Regulación hacia Abajo/inmunología , Regulación Viral de la Expresión Génica/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , MicroARNs/genética , Inhibidor Tisular de Metaloproteinasa-3/antagonistas & inhibidores , Inhibidor Tisular de Metaloproteinasa-3/biosíntesis , Línea Celular Tumoral , Citomegalovirus/genética , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/enzimología , Infecciones por Citomegalovirus/genética , Regulación hacia Abajo/genética , Antígenos de Histocompatibilidad Clase I/sangre , Humanos , Metaloproteinasa 14 de la Matriz/sangre , Metaloproteinasa 14 de la Matriz/metabolismo , MicroARNs/biosíntesis , Cultivo Primario de Células , Especificidad por Sustrato/genética , Especificidad por Sustrato/inmunología , Inhibidor Tisular de Metaloproteinasa-3/sangre , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunologíaRESUMEN
A tumor-supporting role for the TNF-like ligand APRIL has been suggested. Here we describe that 9- to 12-month-old APRIL transgenic mice develop lymphoid tumors that originate from expansion of the peritoneal B-1 B cell population. Aging APRIL transgenic mice develop progressive hyperplasia in mesenteric lymph nodes and Peyer's patches, disorganization of affected lymphoid tissues, mucosal and capsular infiltration, and eventual tumor cell infiltration into nonlymphoid tissues such as kidney and liver. We detected significantly increased APRIL levels in sera of B cell chronic lymphoid leukemia (B-CLL) patients, indicating that APRIL promotes onset of B-1-associated neoplasms and that APRIL antagonism may provide a therapeutic strategy to treat B-CLL patients.
Asunto(s)
Transformación Celular Neoplásica , Leucemia de Células B/metabolismo , Leucemia de Células B/patología , Proteínas de la Membrana/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Envejecimiento , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Hiperplasia/genética , Hiperplasia/metabolismo , Hiperplasia/patología , Riñón/metabolismo , Riñón/patología , Leucemia de Células B/sangre , Leucemia de Células B/genética , Tejido Linfoide/metabolismo , Tejido Linfoide/patología , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Nucleares/sangre , Bazo/crecimiento & desarrollo , Bazo/metabolismo , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
The TNF-like ligands APRIL and BLyS are close relatives and share the capacity to bind the receptors TACI and BCMA. BLyS has been shown to play an important role in B cell homeostasis and autoimmunity, but the biological role of APRIL remains less well defined. Analysis of T cells revealed an activation-dependent increase in APRIL mRNA expression. We therefore generated mice expressing APRIL as a transgene in T cells. These mice appeared normal and showed no signs of B cell hyperplasia. Transgenic T cells revealed a greatly enhanced survival in vitro as well as enhanced survival of staphylococcal enterotoxin B-reactive CD4+ T cells in vivo, which both directly correlate with elevated Bcl-2 levels. Analysis of humoral responses to T cell-dependent antigens in the transgenic mice indicated that APRIL affects only IgM but not IgG responses. In contrast, T cell-independent type 2 (TI-2) humoral response was enhanced in APRIL transgenic mice. As TACI was previously reported to be indispensable for TI-2 antibody formation, these results suggest a role for APRIL/TACI interactions in the generation of this response. Taken together, our data indicate that APRIL is involved in the induction and/or maintenance of T and B cell responses.
