Characterization of cytomegalovirus-induced adaptive NK cells and the role of CD94/NKG2C receptor
Human cytomegalovirus (HCMV) infection induces a persistent reconfiguration of the NK cell compartment in some individuals, promoting the development of a mature NK cell subset, hallmarked by high expression levels of the CD94/NKG2C activating receptor (NKG2Cbright), together with additional phenoty...
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| Tipo de documento: | tese |
| Estado: | Versão publicada |
| Data de publicação: | 2017 |
| País: | España |
| Recursos: | CBUC, CESCA |
| Repositório: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/565635 |
| Acesso em linha: | http://hdl.handle.net/10803/565635 |
| Access Level: | Acceso aberto |
| Palavra-chave: | NK cells Cytomegalovirus NKG2C FcRγ TNF-α HLA-E UL40 Células NK Citomegalovirus 576 |
| Resumo: | Human cytomegalovirus (HCMV) infection induces a persistent reconfiguration of the NK cell compartment in some individuals, promoting the development of a mature NK cell subset, hallmarked by high expression levels of the CD94/NKG2C activating receptor (NKG2Cbright), together with additional phenotypic and functional features. The mechanisms underlying the adaptive differentiation and expansion of NKG2C+ NK cells remain unknown. In the present work we addressed the relationship between adaptive NKG2C+ NK cells and down-regulation of FcεRγ (FcRγ) expression, a phenotypic trait also associated with HCMV infection. Our results showed that expansions of adaptive NKG2Cbright and detection of FcRγ– NK cells largely coincided in a subgroup of HCMV+ individuals, presumably representing events related with a common virus-host interaction pattern. In addition, the existence of adaptive FcRγ-defective NK cells lacking NKG2C and activating KIRs supported the existence of alternative activation pathways promoting their differentiation. Finally, we disclose an association between NKG2C copy number and the distribution pattern of adaptive NK cell subsets. Several observations indirectly support the involvement in this process of a cognate interaction of CD94/NKG2C with ligand(s) displayed by HCMV-infected cells. To approach this issue, we developed a sensitive reporter system stably expressing CD94/NKG2C and DAP12 in the human Jurkat leukemia T cell line, segregated from other NK cell receptors involved in theinteraction with HCMV-infected cells. Signalling was detected by transfection of a reporter plasmid encoding Luciferase under NFAT/AP1-dependent promoter. Although Jurkat-NKG2C+ cells were activated by anti-CD94/NKG2C mAbs and HLA-E+ 721.221 cells, no response was detected to fibroblasts infected with AD169 or Towne HCMV strains, regardless of their ability to preserve surface HLA-E expression. On the other hand, infection with clinical isolates or with the endotheliotropic TB40/E strain triggered Jurkat-NKG2C+ activation; yet, this response was not inhibited by blocking mAbs and was independent of CD94/NKG2C expression. These results are discussed in the framework of previous observations supporting the hypothetical existence of specific ligand(s) for CD94/NKG2C in HCMV-infected cells. |
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