Notch activity influences the alpha beta versus gamma delta T cell lineage decision

The choice between the alpha beta or gamma delta T cell fates is influenced by the production of functional, in-frame rearrangements of the TCR genes, but the mechanism that controls the lineage choice is not known. Here, we show that T cells that are heterozygous for a mutation of the Notch1 gene are more likely to develop as gamma delta T cells than as alpha beta T cells, implying that reduced Notch activity favors the ya T cell fate over the alpha beta T cell fate. A constitutively activated form of Notch produces a reciprocal phenotype and induces thymocytes that have functional gamma delta TCR gene rearrangements to adopt the alpha beta T cell fate. Our data indicate that Notch acts together with the newly formed T cell antigen receptor to direct the alpha beta versus gamma delta T cell lineage decision.