Notch induces human T-cell receptor [gamma][delta]+ thymocytes to differentiate along a parallel, highly proliferative and bipotent CD4 CD8 double-positive pathway

• Published in: Leukemia Vol. 26; no. 1; p. 127
• Main Authors: Van Coppernolle, S, Vanhee, S, Verstichel, G, Snauwaert, S, Van Der Spek, A, Velghe, I, Sinnesael, M, Heemskerk, M H, Taghon, T, Leclercq, G, Plum, J, Langerak, A W, Kerre, T, Vandekerckhove, B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.01.2012
• Subjects: Blood & organ donations; Genotype & phenotype; Immunology; Leukemia; Mutation; Thymus gland; Netherlands; Belgium; United States > US; Germany
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2011.324

In wild-type mice, T-cell receptor (TCR) γδ(+) cells differentiate along a CD4 CD8 double-negative (DN) pathway whereas TCRα[beta](+) 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 CD8α[beta] SP TCRγδ(+) cells and to TCRα[beta](+) 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.