NATURAL-KILLER-CELL DEVELOPMENT IS BLOCKED IN THE CONTEXT OF ABERRANTT-LYMPHOCYTE ONTOGENY

Over-expression of human or mouse CD3-epsilon transgenes profoundly di sturbs T lymphocyte and natural killer (NK) cell development, One of t hese transgenic strains, termed tg epsilon 26, displays a very early b lock in T lymphocyte and NK cell development, We showed previously tha t the absence of early thymocyte progenitors results in an abnormal th ymic microenvironment, Due to this thymic defect, T cell development c ould not be restored by bone marrow (BM) transplantation in adult tg e psilon 26 mice but could in fetal tg epsilon 26 mice, Here we examine the effect of this abnormal thymic environment on NK cell development, We demonstrate that NK cell maturation in tg epsilon 26 mice was reco nstituted by BM derived from completely T cell-deficient mice, i,e, RA G-2(-/-) and TCR beta x delta(-/-), but not from wild-type mice, Moreo ver, tg epsilon 26 mice transplanted with BM from partially T cell-def icient mice, i,e, TCR alpha(-/-), TCR beta(-/-) and TCR delta(-/-) mic e, did not reconstitute their NK cell compartment. We conclude from th ese studies that the thymic environment is not required for NK cell de velopment, but that aberrantly educated alpha beta or gamma delta T ly mphocytes can influence NK cell ontogeny, Furthermore, high serum leve ls of tumor necrosis factor (TNF) were detected in the vast majority o f tg epsilon 26 mice transplanted with BM cells derived from partially T cell-deficient mice, but never from tg epsilon 26 mice transplanted with BM cells derived from completely T cell-deficient mice, The high levels of TNF may play an important role in the observed inhibition o f NK cell development, since in vivo treatment with an anti-TNF antibo dy restored NK cell development.