RESUMEN
Human cytomegalovirus infection in transplant recipients has been associated with adverse renal allograft outcome and with a large γδ T-cell response, but whether both mechanisms are connected is unknown. We previously showed that most expanded circulating cytomegalovirus-responsive γδ T cells express the Fcγ-receptor CD16, suggesting that γδ T cells may participate in allograft lesions mediated by donor-specific antibodies through antibody-dependent cellular cytotoxicity. Here, we show that cytomegalovirus-specific CD16(pos) γδ T cells can perform antibody-dependent cellular cytotoxicity against stromal cells coated with donor-specific antibodies in vitro. In vivo, graft-infiltrating γδ T cells localized in close contact with endothelial cells only in patients who experienced cytomegalovirus infection and were more frequent within peritubular capillaries and glomeruli from antibody-mediated acute rejections than within those from T cell-mediated acute rejections. Finally, a persistently increased percentage of circulating cytomegalovirus-induced γδ T cells correlated inversely with the 1-year eGFR only in kidney recipients with donor-specific antibodies. Collectively, these data support the conclusion that cytomegalovirus-induced γδ T cells are involved in, and may serve as a clinical biomarker of, antibody-mediated lesions of kidney transplants. Moreover, these findings offer a new physiopathologic link between cytomegalovirus infection and allograft dysfunction in recipients with donor-specific antibodies.
Asunto(s)
Infecciones por Citomegalovirus/inmunología , Rechazo de Injerto/inmunología , Isoanticuerpos/inmunología , Trasplante de Riñón/efectos adversos , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Adolescente , Adulto , Anciano , Línea Celular Transformada , Infecciones por Citomegalovirus/patología , Endotelio Vascular/citología , Endotelio Vascular/inmunología , Femenino , Fibroblastos/citología , Fibroblastos/inmunología , Proteínas Ligadas a GPI/inmunología , Prueba de Histocompatibilidad , Células Endoteliales de la Vena Umbilical Humana , Humanos , Células Asesinas Naturales/inmunología , Masculino , Microcirculación/inmunología , Persona de Mediana Edad , Perforina , Proteínas Citotóxicas Formadoras de Poros/inmunología , Receptores de IgG/inmunología , Trasplante Homólogo , Adulto JovenRESUMEN
Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in transplant recipients. Long-term protective immunity against HCMV requires both sustained specific T-cell response and neutralizing IgG production, but the interplay between these effector arms remains poorly defined. We previously demonstrated that γδ T cells play a substantial role as anti-HCMV T-cell effectors. The observation that CD16 (FcγRIIIA) was specifically expressed by the majority of HCMV-induced γδ T cells prompted us to investigate their cooperation with anti-HCMV IgG. We found that CD16 could stimulate γδ T cells independently of T-cell receptor (TCR) engagement and provide them with an intrinsic antibody-dependent cell-mediated cytotoxic (ADCC) potential. Although CD16(+)γδ T cells did not mediate ADCC against HCMV-infected cells, in accordance with the low level of anti-HCMV IgGs recognizing infected cells, they produced IFNγ when incubated with IgG-opsonized virions. This CD16-induced IFNγ production was greatly enhanced by IL12 and IFNα, 2 cytokines produced during HCMV infection, and conferred to γδ T cells the ability to inhibit HCMV multiplication in vitro. Taken together, these data identify a new antiviral function for γδ T cells through cooperation with anti-HCMV IgG that could contribute to surveillance of HCMV reactivation in transplant recipients.