Notch Induces T Cell Receptor γδ Thymocytes to Differentiate along a Bipotent CD4 CD8 Double Positive Pathway (111.6)

Abstract

Abstract It is well documented that in wildtype mice TCRγδ+ cells differentiate along a double negative (DN) pathway whereas TCRαβ+ cells differentiate along the double positive (DP) pathway, suggesting that the TCR itself induces lineage differentiation. Under experimental conditions and in genetically modified mice, however, evidence was presented suggesting that rather than TCR itself, TCR signal strength and notch determine lineage choice. In the human thymus, a “chimeric” DP TCRγδ+ cell population is present and constitutes a sizeable fraction of the γδ population. We asked the question whether these cells belong to the αβ or γδ lineage or whether these cells are bipotent. We found that TCRγδ DP cells are bipotent cells since strong TCR signals induces differentiation to TCRγδ cells, whereas Notch activation induces TCRαβ lineage differentiation. We furthermore could show that Notch signaling diverts TCRγδ DN cells to the DP pathway and induces strong proliferation. In line with these findings, TCRγδ+ acute lymphoblastic leukemias (ALL) with activating Notch1 mutations follow the DP differentiation pathway, whereas the DN ALL cells are devoid of these activating Notch1 mutations. We were able to confirm that also in vivo TCRγδ DP have rearranged TCRβ chains, actively rearrange the TCRα locus and delete the TCRδ locus (αβ lineage). Using TCRα rearrangements as a lineage marker, we could show that a subpopulation of mature TCRγδ cells is derived from DP cells.