Influence of the NKG2C genotype in the development of adaptive NK cells and characterization of the antibody-mediated response to Epstein-Barr virus
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Document Version
Author
Director
López-Botet, M. (Miguel)
Muntasell i Castellví, Aura
Muntasell i Castellví, Aura
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157 p.
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Citation
López Montañés, M. Influence of the NKG2C genotype in the development of adaptive NK cells and characterization of the antibody-mediated response to Epstein-Barr virus. Universitat Pompeu Fabra; 2016. handle: http://hdl.handle.net/10803/543847
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Doctoral program
Programa de doctorat en Biomedicina
Abstract
El citomegalovirus humano (HCMV) promueve una redistribución del compartimento de células Natural Killer (NK) marcada por un incremento de las células NK maduras que expresan niveles elevados del receptor activador CD94/NKG2C. Los mecanismos subyacentes a la diferenciación/expansión de las células NK NKG2C+ y su implicación en la defensa anti-viral son cuestiones no resueltas. Analizamos la influencia de la deleción del gen NKG2C (KLRG2) en la reconfiguración del compartimento NK y en la función del receptor CD94/NKG2C. Los individuos NKG2C+/+ HCMV+ presentaron mayor porcentaje y número de células NKG2C+ comparados con los individuos hemicigotos, independientemente del dimorfismo de HLA-E. Además, la dosis génica de NKG2C influyó en la movilización de Ca2+, degranulación y en la proliferación dependiente de IL-15 tras la activación vía NKG2C. Estos resultados apoyan un papel activo del receptor CD94/NKG2C en el desarrollo de la respuesta NK adaptativa. Las células NKG2C+ presentan una respuesta eficaz contra células infectadas por HCMV en presencia de anticuerpos específicos. Caracterizamos la respuesta de las células NK mediada por anticuerpos específicos para el virus Epstein-Barr (EBV), evaluando la contribución de las células NKG2C+ adaptativas. Los sueros EBV+ promovieron una potente degranulación y secreción de citocinas (TNF-α e IFN-γ) por parte de las células NK contra células B infectadas en la fase de ciclo lítico, siendo la secreción de citocinas mediada por anticuerpos dominada por las células NKG2C+ adaptativas. La unión de vesículas liberadas por células infectadas por EBV, que contenían el antígeno viral gp350/220, a linfocitos B promovió la degranulación y secreción de TNF-α dependiente de anticuerpos, induciendo bajos niveles de IFN-γ y citotoxicidad. Estos resultados muestran el potencial de la respuesta mediada por anticuerpo de las células NK en el control de la infección por EBV, y sugieren que las vesículas gp350+ pueden desviar la maquinaria citotóxica, interfiriendo con la defensa anti-viral.
Human cytomegalovirus (HCMV) promotes to a variable degree a redistribution of the Natural Killer (NK) cell compartment hallmarked by increased proportions of mature NK cells displaying high expression levels of the CD94/NKG2C activating receptor. The mechanisms underlying the differentiation/expansion of NKG2C+ NK cells and their implication in the response to other pathogens are open issues. We analyzed the putative influence of NKG2C gene (KLRG2) deletion on the HCMV-induced NK cell repertoire reconfiguration and CD94/NKG2C receptor function. NKG2C+/+ HCMV+ individuals displayed increased proportions and absolute numbers of adaptive NKG2C+ NK cells as compared to hemizygous subjects, independently of HLA-E dimorphism. Moreover, NKG2C gene dose influenced early signaling events, degranulation and IL-15-dependent proliferation in response to CD94/NKG2C receptor engagement. These results further supported an active role of the CD94/NKG2C receptor in the adaptive NK cell response. NKG2Cbright NK cells display efficient antibody-dependent functions against HCMV-infected cells. We characterized the NK cell response triggered by serum antibodies specific for Epstein-Barr virus (EBV), evaluating the contribution of adaptive NKG2C+ NK cells. EBV+ sera triggered vigorous NK-cell degranulation and cytokine secretion (i.e. TNF-α and IFN-γ) in response to EBV-infected B cells in lytic viral cycle, as compared to direct NK cell activation. The EBV-specific antibody-driven cytokine response was dominated by adaptive NKG2C+ NK cells. Binding of gp350/220 viral antigen-containing vesicles, released by EBV-infected cells, to B lymphocytes triggered antibody-dependent degranulation and TNF-α production, but induced low levels of IFN-γ secretion and target cell damage. These results evidenced the potential of antibody-driven NK cell activation in the control of EBV infection suggesting that gp350+ vesicles may divert the cytotoxic machinery, potentially favoring viral immune evasion.
Human cytomegalovirus (HCMV) promotes to a variable degree a redistribution of the Natural Killer (NK) cell compartment hallmarked by increased proportions of mature NK cells displaying high expression levels of the CD94/NKG2C activating receptor. The mechanisms underlying the differentiation/expansion of NKG2C+ NK cells and their implication in the response to other pathogens are open issues. We analyzed the putative influence of NKG2C gene (KLRG2) deletion on the HCMV-induced NK cell repertoire reconfiguration and CD94/NKG2C receptor function. NKG2C+/+ HCMV+ individuals displayed increased proportions and absolute numbers of adaptive NKG2C+ NK cells as compared to hemizygous subjects, independently of HLA-E dimorphism. Moreover, NKG2C gene dose influenced early signaling events, degranulation and IL-15-dependent proliferation in response to CD94/NKG2C receptor engagement. These results further supported an active role of the CD94/NKG2C receptor in the adaptive NK cell response. NKG2Cbright NK cells display efficient antibody-dependent functions against HCMV-infected cells. We characterized the NK cell response triggered by serum antibodies specific for Epstein-Barr virus (EBV), evaluating the contribution of adaptive NKG2C+ NK cells. EBV+ sera triggered vigorous NK-cell degranulation and cytokine secretion (i.e. TNF-α and IFN-γ) in response to EBV-infected B cells in lytic viral cycle, as compared to direct NK cell activation. The EBV-specific antibody-driven cytokine response was dominated by adaptive NKG2C+ NK cells. Binding of gp350/220 viral antigen-containing vesicles, released by EBV-infected cells, to B lymphocytes triggered antibody-dependent degranulation and TNF-α production, but induced low levels of IFN-γ secretion and target cell damage. These results evidenced the potential of antibody-driven NK cell activation in the control of EBV infection suggesting that gp350+ vesicles may divert the cytotoxic machinery, potentially favoring viral immune evasion.
Keywords
Cytomegalovirus, Epstein-Barr virus, CD94/NKG2C receptor, Antibody, Anticuerpo, Células natural killer, Natural killer cell, Virus Epstein-Barr
Subjects
578 - Virology
Publisher
Universitat Pompeu Fabra
