REDUCTION OF EARLY B-LYMPHOCYTE PRECURSORS IN TRANSGENIC MICE OVEREXPRESSING THE MURINE HEAT-STABLE ANTIGEN

To study the role of the murine heat-stable Ag (HSA) in lymphocyte mat uration, we generated transgenic mice in which the HSA cDNA was under the transcriptional control of the TCR V beta promoter and Ig mu enhan cer. The HSA transgene was expressed during all stages of B lymphocyte maturation, Expression was first detected in the earliest lymphoid-co mmitted progenitors, which normally do not express HSA, and subsequent ly reached the highest levels in pro- and pre-B cells, In bone marrow, the number of IL-7-responsive clonogenic progenitors was <4% of norma l, whereas the frequency of earlier B lymphocyte-restricted precursors , detectable as Whitlock-Witte culture-initiating cells, was normal, P ro- and pre-B cells detected by flow cytometry were reduced by approxi mately 50% relative to controls, Mature splenic B cells were also redu ced but to a lesser extent than in marrow, and their response to LPS s timulation was impaired. Reconstitution of SCID and BALB/c-nu/nu mice with HSA transgenic marrow indicated that the perturbations in B lymph opoiesis were not caused by a defective marrow microenvironment or by abnormal T cells, Our previous studies showed elevated HSA expression throughout thymocyte development, which resulted in a profound depleti on of CD4(+)CD8(+) double-positive and single-positive thymocytes. Tog ether, these results indicate that HSA levels can determine the capaci ty of early T and B lymphoid progenitors to proliferate and survive, T herefore, HSA could serve as an important regulator during the early s tages of B and T lymphopoiesis.