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Polymorphisme du gène NCR3/NKp30 et variabilité de la fonction des cellules Natural Killer humaines

Abstract : Natural Killer (NK) cells are not just invaluable cytotoxic effectors of innate immune response against tumors and infections but also important immunoregulators. They are activated by an intricate balance between signals provided by their inhibitory and activating receptors. Among activating receptors, NCR3 can mediate tumor lysis and dendritic cell maturation making it a crucial receptor in NK cell function. Furthermore, a recent study showed that alternative splicing of NCR3 can affect NK cell function and patient responses to treatment. In order to characterize interindividual variability of NK cell response and to set up a reference for future investigations in pathologies, we investigated 43 healthy donors and studied correlations between NK cell functional variability in response to NKp30 triggering with NKp30 transcript and membrane expression in light of genomic polymorphism. We showed a tight correlation between membrane expression of NKp30 and NKp46 with the cytotoxic NK cell response but not with cytokine secretion. In addtion, we identified a new variant influencing T1 NCR3 transcripts, rs11575836, which is associated with NKp30-induced cytotoxicity. This study pointed out the specifity of pathways underlying NK cell function and the complexity of gene networks involved in their regulation. NCR3 genetic variability was also assessed in myasthenia gravis, an autoimmune disease where NK cells seem to be implicated. NCR3 re-sequencing did not shown any association with common polymorphisms but disclosed two rare nonsense mutations that were found only in patients. One of them, L19R, a non-conservative amino acid change, is of particular interest because it is located in a highly-conserved region across phylogeny. Although numerous issues remain to be clarified, our results indicate that it should be possible to integrate information of DNA polymorphism, with that of transcript and membrane protein expression to identify functional patterns in NK cell response
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Submitted on : Monday, February 18, 2013 - 11:42:37 AM
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  • HAL Id : tel-00789417, version 1


Nathalie Germaud. Polymorphisme du gène NCR3/NKp30 et variabilité de la fonction des cellules Natural Killer humaines. Médecine humaine et pathologie. Université René Descartes - Paris V, 2012. Français. ⟨NNT : 2012PA05T046⟩. ⟨tel-00789417⟩



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