title: Notch induces human T-cell receptor γδ+ thymocytes to differentiate along a parallel, highly proliferative and bipotent CD4 CD8 double-positive pathway.
abstract: In wild-type mice, T-cell receptor (TCR) γδ(+) cells differentiate along a CD4 CD8 double-negative (DN) pathway whereas TCRαβ(+) cells differentiate along the double-positive (DP) pathway. In the human postnatal thymus (PNT), DN, DP and single-positive (SP) TCRγδ(+) populations are present. Here, the precursor-progeny relationship of the various PNT TCRγδ(+) populations was studied and the role of the DP TCRγδ(+) population during T-cell differentiation was elucidated. We demonstrate that human TCRγδ(+) cells differentiate along two pathways downstream from an immature CD1(+) DN TCRγδ(+) precursor: a Notch-independent DN pathway generating mature DN and CD8αα SP TCRγδ(+) cells, and a Notch-dependent, highly proliferative DP pathway generating immature CD4 SP and subsequently DP TCRγδ(+) populations. DP TCRγδ(+) cells are actively rearranging the TCRα locus, and differentiate to TCR(-) DP cells, to CD8αβ SP TCRγδ(+) cells and to TCRαβ(+) cells. Finally, we show that the γδ subset of T-cell acute lymphoblastic leukemias (T-ALL) consists mainly of CD4 SP or DP phenotypes carrying significantly more activating Notch mutations than DN T-ALL. The latter suggests that activating Notch mutations in TCRγδ(+) thymocytes induce proliferation and differentiation along the DP pathway in vivo.
authors: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent University Hospital, Ghent, Belgium.
authors: S
authors: S
authors: Van Coppernolle
authors: S
authors: S
authors: Vanhee
authors: G
authors: G
authors: Verstichel
authors: S
authors: S
authors: Snauwaert
authors: A
authors: A
authors: van der Spek
authors: I
authors: I
authors: Velghe
authors: M
authors: M
authors: Sinnesael
authors: M H
authors: MH
authors: Heemskerk
authors: T
authors: T
authors: Taghon
authors: G
authors: G
authors: Leclercq
authors: J
authors: J
authors: Plum
authors: A W
authors: AW
authors: Langerak
authors: T
authors: T
authors: Kerre
authors: B
authors: B
authors: Vandekerckhove
mesh_terms: D001483:Base Sequence; D015704:CD4 Antigens / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D018920:Coculture Techniques; D017931:DNA Primers; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D051880:Receptors, Notch / Q000502:physiology*; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D017931:DNA Primers; D016692:Receptors, Antigen, T-Cell, gamma-delta; D051880:Receptors, Notch