Interplay of human adaptative NKG2C+ NK cells with specific antibodies and T cells in the response to cytomegalovirus infection
Human cytomegalovirus (HCMV) infection induces persistent changes in the host immune system, namely a sustained expansion of effector memory and cytotoxic specific T lymphocytes, the production of antibodies (Ab) and, in some individuals, associates with the differentiation of a functionally compete...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2018 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/664431 |
| Acceso en línea: | http://hdl.handle.net/10803/664431 |
| Access Level: | acceso abierto |
| Palabra clave: | NK cells HCMV Antibodies NKG2C T lymphocytes Células NK Anticuerpos Linfocitos T 576 |
| Sumario: | Human cytomegalovirus (HCMV) infection induces persistent changes in the host immune system, namely a sustained expansion of effector memory and cytotoxic specific T lymphocytes, the production of antibodies (Ab) and, in some individuals, associates with the differentiation of a functionally competent Natural Killer (NK) cell subset with adaptive features, identified by the elevated expression of the activating receptor CD94/NKG2C. NK cells are considered important players in the defence against HCMV, yet the exact mechanisms by which these cells contribute to primary infection and viral reactivation control remain partially understood. In the present study, we have characterized three distinct mechanisms by which NK cells could participate in the defence to HCMV infection. On one hand, we have shown that NK cell direct sensing of HCMV particles leads to the priming of their anti-viral effector functions by mechanisms involving TLR2 and type I IFN. We have also shown that NK cells cooperate with specific antibodies in the recognition of HCMV-infected cells, overriding viral immunoevasion strategies from early to late stages of the lytic cycle. Of note, adaptive NKG2C+ NK cells were highly responsive to Ab-driven activation, being particularly efficient in the production of antiviral cytokines. Finally, we have also shown that the increased expression of HLA class II molecules in circulating adaptive NKG2C+ NK cells endows them with the capacity to present HCMV-derived antigens to specific CD4+ T cells. Remarkably, CD4+ T cells activated in response to HLA-DR+ NK cells displayed an effector memory phenotype, lacked the co-stimulatory molecule CD28 and showed a cytotoxic and Th1 functional profile. Altogether, these results support that the interplay of human NK cells, particularly the adaptive NKG2C+ subset, with specific antibodies and T cells contributes to the defence against HCMV infection. |
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