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Differentiation and role of Natural Killer cell subsets

NK cells are innate lymphocytes that play a role in the early response against intracellular pathogens and against tumors. Several NK cell subsets have been described in peripheral organs that correspond to discrete stages of in v... ver más

31/12/2017

INSERM

1M€

Presupuesto del proyecto: 1M€

Líder del proyecto

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHER... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

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Financiación concedida El organismo FP7 notifico la concesión del proyecto el día 2017-12-31 No tenemos la información de la convocatoria

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Líder del proyecto

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHER... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 1M€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto NK cells are innate lymphocytes that play a role in the early response against intracellular pathogens and against tumors. Several NK cell subsets have been described in peripheral organs that correspond to discrete stages of in vivo maturation. How NK cells differentiate from early precursors and what are the specific functions of each NK cell subset are unresolved issues. Here, we propose a three-aim program to address these questions. First, we want to revisit the partition of the NK cell population that is currently based on surface markers of undefined function by looking at the expression of transcription factors (TF) essential for NK cell development and maturation, such as T-bet and Eomes, using novel TF reporter mice. This strategy should also allow us to identify very early steps of NK cell development (NK cell progenitors) that remain ill defined. Second, we will try and identify molecular mechanisms that induce transition between NK cell maturation stages. For this we will take advantage of a previous gene profiling analysis that pointed at several pathways and TF that were highly regulated during NK cell maturation. The role of these pathways and TF in the differentiation of NK cells will be measured using a novel Cre/lox system allowing NK-specific gene deletion. Detailed analysis of mouse mutants will be used to delineate the role of selected genes and pathways in NK cell differentiation. Third, we will compare patterns of migration, cytokine secretion, in vivo cytotoxicity and global gene expression by individual NK cell subsets during an airway infection by Influenza to get insight on the specific functions of NK cell subsets during immune responses. Altogether, the results of this study should provide developmental, molecular and functional evidences to support the physiological relevance of NK cell subsets. This may improve strategies that aim at manipulating NK cell function for the benefit of patients with cancer or chronic infectious diseases

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