DELINEATION OF T-PROGENITOR CELL-ACTIVITY WITHIN THE CD34(+) COMPARTMENT OF ADULT BONE-MARROW

T-cell production is largely dependent on the presence of a thymus gland where CD34(+) precursors mature into T lymphocytes. Prethymic stages of T-cell development are less defined. Therefore, this study aims to delineate T-progenitor cell potential within the CD34(+) Lineage- (Lin(-)) cell compartment of adult bone marrow (ABM). Fractionation of CD34(+) Lin(-) ABM cells with CD45RA, Thy-1, CD38, and HLA-DR failed to absolutely segregate T-cell reconstituting ability, indicating broad distribution of T-progenitor cell potential. Titration experiments showed that low numbers of CD34(+) Lin(-) CD45RA(+) (RA(+)) cells had greater thymus repopulating ability than CD34(+) Lin(-) CD45RA(-) cells (RA(-)). The great majority (>95%) of RA(+) cells expressed CD38, HLA-DR and 70% to 90% of RA(+) cells lacked Thy-1 surface expression. RA(+) cells contained colony-forming unit granulocyte-macrophage (CFU-GM) progenitor cells but were depleted of erythroid potential, did not provide hematopoietic reconstitution of human bone fragments implanted into SCID mice, and did not efficiently maintain CD34(+) cells with secondary clonogenic potential in bone marrow cultures. Thus, RA(+) cells are oligopotent (nonprimitive) CD34(+) progenitors with T-cell reconstituting ability. In contrast, these same assays indicated that CD34(+) Lin(-) CD45RA(-) cells (RA(-) cells) comprised hematopoietic stem cells (HSC) with primitive multilineage (T, B, myeloid, and erythroid) hematopoietic potential. It was confirmed that HSC-containing populations, such as CD34(+) Lin(-) CD45RA(-) Thy-1(+) cells had thymus repopulating ability. Culture of RA- cells on murine bone marrow stromal cells in the presence of interleukin (IL)-3, IL-6, and leukemia inhibitory factor (LIF) generated CD34(+) CD45RA(+) progeny engrafting in a secondary severe combined immunodeficiency (SCID)-hu thymus assay. Altogether, our results underscore the fact that T-cell reconstituting potential can be dissociated from HSC activity. Furthermore, we speculate that HSC might develop into the T lineage indirectly, via differentiation into an intermediate oligopotent CD34(+) CD45RA(+) stage. Finally, T-progenitor cells can be cultured in vitro. (C) 1995 by The American Society of Hematology.