Development of T lymphocytes from committed T cell progenitors in the bone marrow of adult mice.

摘要

T cell development is characterized by the colonization of the thymus by marrow-derived progenitors, which mature into TCRαβ+ T cells. We demonstrate that cultures of T cell-depleted marrow generate CD4+ and CD8+ T cells, developing through a CD4+CD8+ intermediate, and undergoing both positive and negative selection events. Furthermore, mature T cells inhibit T cell maturation in these cultures.; We identified two candidate progenitors populations in the marrow: a Thy1.2hiLin−CD2− and a Thy1.2hiLin−CD2+ population. Phenotypic examination shows that Thy1.2hiLin −CD2− cells express CD5, CD16, CD24, and CD44, but lack CD25, a phenotype previously shown in T cell progenitors. Molecular analysis shows that both populations express TCF-1, GATA-3, IL7Rα, and TCRC_β, indicative of their commitment to the T cell lineage. However, they differ in their expression of Rag-1, Rag-2 and preTα: Thy1.2hiLin−CD2− cells express these genes whereas the CD2+ population does not. Thy1.2hiLin−CD2− cells have not rearranged their TCRV_β genes while CD2 + cells show rearrangement of these genes. This gene expression pattern suggests that Thy1.2hiLin−CD2− cells are committed T cell progenitors (CTP), responsible for T cell maturation in marrow cultures. The data also implies that T cell lineage commitment occurs prior to migration to the thymus.; CTP are capable of generating T cells both in vitro and in vivo, progressing via a Thy1.2+TCRαβ −CD2+ intermediate without generation of cells from other lineages. Besides generating T cells in euthymic hosts, CTP mature in thymectomized and athymic hosts, illustrating their capacity for extrathymic differentiation.; Functionally, CTP-derived T cells produce low levels of IL-2, IL-4 and IL-10, and high levels of IFN-γ, a cytokine secretion pattern different from conventional T cells. Also, CTP-derived T cells do not induce GVHD when transplanted in allogeneic hosts, provide a low but detectable level of help to B cells in the antibody response against SRBC, and protect against mCMV infection.; In conclusion, these studies have provided a model to study extrathymic T cell differentiation from a clonable committed T cell progenitor found in the bone marrow, and suggest that commitment to the T cell lineage occurs prior to entry in the thymus.