thymus, Notch, gammadelta T-cell, Science & Technology, Life Sciences & Biomedicine, Oncology, Hematology, ACUTE LYMPHOBLASTIC-LEUKEMIA, ALPHA-BETA/GAMMA-DELTA, FUNCTIONAL MATURATION, LINEAGE COMMITMENT, BETA-LINEAGE, FATE, EXPRESSION, IMMUNOGLOBULIN, REARRANGEMENTS, ACTIVATION, Base Sequence, CD4 Antigens, CD8 Antigens, Cell Differentiation, Cell Proliferation, Coculture Techniques, DNA Primers, Humans, Real-Time Polymerase Chain Reaction, Receptors, Antigen, T-Cell, gamma-delta, Receptors, Notch, Thymocytes, Antigens, CD4, Antigens, CD8, Immunology, 1103 Clinical Sciences, 1112 Oncology and Carcinogenesis
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.