NZB mice exhibit a primary T cell defect in fetal thymic organ culture

Defects in T cell development have been suggested to be a factor in the dev elopment of systemic autoimmunity in NZB mice. However, the suggestion of a primary T cell defect has often been by extrapolation, and few direct obse rvations of T cell precursors in NZB mice have been performed. Moreover, th e capacity of NZB bone marrow T cell precursors to colonize the thymus and the ability of the NZB thymic microenvironment to support T lymphopoiesis h ave not been analyzed, To address this important issue, we employed the fet al thymic organ culture system to examine NZB T cell development. Our data demonstrated that NZB bone marrow cells were less efficient at colonizing f etal thymic lobes than those of control BALB/c or C57BL/6 mice. In addition , NZB bone marrow cells did not differentiate into mature T cells as effici ently as bone marrow cells from BALB/c or C57BL/6 mice. Further analysis re vealed that this defect resulted from an intrinsic deficiency in the NZB Li n(-)Sca-1(+)c-kit(+) bone marrow stem cell pool to differentiate into T cel ls in fetal thymic organ culture. Taken together, the data document heretof ore unappreciated deficiencies in T cell development that may contribute to the development of the autoimmune phenotype in NZB mice.