Journal
LEUKEMIA
Volume 26, Issue 1, Pages 127-138Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2011.324
Keywords
thymus; Notch; gammadelta T-cell
Categories
Funding
- Fund for Scientific Research, Flanders (Fonds voor Wetenschappelijk Onderzoek Vlaanderen, FWO)
- geconcerteerde onderzoeksactiviteiten (GOA of the Ghent University)
- Belgian Science Policy
- Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen, IWT
- FWO Vlaanderen
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In wild-type mice, T-cell receptor (TCR) gamma delta(+) cells differentiate along a CD4 CD8 double-negative (DN) pathway whereas TCR alpha beta(+) cells differentiate along the double-positive (DP) pathway. In the human postnatal thymus (PNT), DN, DP and single-positive (SP) TCR gamma delta(+) populations are present. Here, the precursor-progeny relationship of the various PNT TCR gamma delta(+) populations was studied and the role of the DP TCR gamma delta(+) population during T-cell differentiation was elucidated. We demonstrate that human TCR gamma delta(+) cells differentiate along two pathways downstream from an immature CD1(+) DN TCR gamma delta(+) precursor: a Notch-independent DN pathway generating mature DN and CD8 alpha alpha SP TCR gamma delta(+) cells, and a Notch-dependent, highly proliferative DP pathway generating immature CD4 SP and subsequently DP TCR gamma delta(+) populations. DP TCR gamma delta(+) cells are actively rearranging the TCR alpha locus, and differentiate to TCR- DP cells, to CD8 alpha beta SP TCR gamma delta(+) cells and to TCR alpha beta(+) cells. Finally, we show that the gamma delta 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 TCR gamma delta(+) thymocytes induce proliferation and differentiation along the DP pathway in vivo. Leukemia (2012) 26, 127-138; doi:10.1038/leu.2011.324; published online 4 November 2011
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