We searched for clonable committed T cell progenitors in the adult mouse bone marrow and isolated rare (Ϸ0.05%) cells with the Thy-1 hi CD2 ؊ CD16 ؉ CD44 hi CD25 ؊ Lin ؊ phenotype. In vivo experiments showed that these cells were progenitors committed only to reconstituting the T cell lineage of irradiated Ly5 congenic hosts. Reconstitution of the thymus was minimal compared with that of the bone marrow, spleen, and lymph nodes. At limiting dilutions, donor T cell reconstitution of the spleen frequently occurred without detectable donor cells in the thymus. Progenitors were capable of rapidly reconstituting athymic hosts. In conclusion, the clonable bone marrow progenitors were capable of T cell reconstitution predominantly by means of an extrathymic pathway.T cell progenitor ͉ extrathymic maturation ͉ T cell reconstitution ͉ thymus

We identified committed T cell progenitors (CTPs) in the mouse bone marrow that have not rearranged the TCRβ gene; express a variety of genes associated with commitment to the T cell lineage, including GATA-3, T cell-specific factor-1, Cβ, and Id2; and show a surface marker pattern (CD44+CD25−CD24+CD5−) that is similar to the earliest T cell progenitors in the thymus. More mature committed intermediate progenitors in the marrow have rearranged the TCR gene loci, express Vα and Vβ genes as well as CD3ε, but do not express surface TCR or CD3 receptors. CTPs, but not progenitors from the thymus, reconstituted the αβ T cells in the lymphoid tissues of athymic nu/nu mice. These reconstituted T cells vigorously secreted IFN-γ after stimulation in vitro, and protected the mice against lethal infection with murine CMV. In conclusion, CTPs in wild-type bone marrow can generate functional T cells via an extrathymic pathway in athymic nu/nu mice.

nu/nu mice fail to develop a thymus and mature T cells due to a defect in the whn gene encoding a transcription factor necessary for terminal epithelial cell differentiation. We investigated whether early T cell progenitor development in the nu/nu bone marrow is also defective. We demonstrated a maturation arrest of nu/nu marrow T cell progenitors associated with a lack of pTα gene expression and a failure to give rise to mature T cells in adoptive euthymic hosts. Wild-type hemopoietic stem cells rapidly matured into functional T cell progenitors in the marrow of euthymic or thymectomized but not nu/nu hosts. We show that defects in bone marrow prethymic T cell development can also contribute to T cell deficiency in nu/nu mice.