Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development

Autor: Pieter-Jan Volders, Marieke Lavaert, Kaat Durinck, Anne-Catherine Dolens, Bart Vandekerckhove, Pieter Van Vlierberghe, Tessa Kerre, Karin Weening, Pieter Mestdagh, Juliette Roels, Franki Speleman, Joni Van der Meulen, Jo Vandesompele, Katleen De Preter, Imke Velghe, Jelle De Medts, Tom Taghon, Katrien De Mulder, Georges Leclercq
Rok vydání: 2020
Předmět:
Zdroj: EMBO Rep
ISSN: 1469-3178
1469-221X
Popis: γδ and αβ T cells have unique roles in immunity and both originate in the thymus from T‐lineage committed precursors through distinct but unclear mechanisms. Here, we show that Notch1 activation is more stringently required for human γδ development compared to αβ‐lineage differentiation and performed paired mRNA and miRNA profiling across 11 discrete developmental stages of human T cell development in an effort to identify the potential Notch1 downstream mechanism. Our data suggest that the miR‐17–92 cluster is a Notch1 target in immature thymocytes and that miR‐17 can restrict BCL11B expression in these Notch‐dependent T cell precursors. We show that enforced miR‐17 expression promotes human γδ T cell development and, consistently, that BCL11B is absolutely required for αβ but less for γδ T cell development. This study suggests that human γδ T cell development is mediated by a stage‐specific Notch‐driven negative feedback loop through which miR‐17 temporally restricts BCL11B expression and provides functional insights into the developmental role of the disease‐associated genes BCL11B and the miR‐17–92 cluster in a human context.
Databáze: OpenAIRE
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