Abnormal development of T cells in the thymus is thought to be related to autoimmune disease and the expansion of the unusual CD4-CD8-B220+ peripheral T cel subset that results in lymphadenopathy in MRL-lpr/lpr mice. Although we and others have previously shown that rearranged TCR-transgenes alter T cell development in the thymus and abrogate lymphoproliferative disease in lpr mice, the origin and developmental pathway of the LN CD4-CD8-B220+ T cells has not been fully elucidated. We therefore undertook the systematic analysis of the effect of a TCR-beta transgene on the production and differentiation of (lymph node) LN T cells and the production, differentiation, and release of thymocyte T cell populations. In nontransgenic mice, there was increased proliferation of CD4-CD8-B220+ T cells in the LN of adult MRL-lpr/lpr mice compared to MRL(-)+/+ mice, as measured by in vivo BrdU labeling. These proliferating LN T cells were greatly reduced by thymectomy of adult MRL-lpr/lpr mice 1 wk before bromodeoxyuridine labeling, indicating that recent thymic emigrants or factors were required to sustain proliferation. In the thymus, there was increased production and accumulation of CD4+CD8+TCRdull thymocytes in nontransgenic MRL-lpr/lpr compared to MRL(-)+/+ mice. As the rate of maturation from CD4+CD8+TCRdull to CD4+CD8+TCRbright was the same (6%) in both MRL-lpr/lpr and MRL(-)+/+ mice, the accumulation of the immature population in the MRL-lpr/lpr mice could not be due to a maturation defect. However, there was a decrease in apoptosis and intrathymic death of CD4+CD8+TCRdull thymocytes in MRL-lpr/lpr compared to MRL(-)+/+ mice. Introduction of the TCR-beta transgene into lpr/lpr mice normalized the proliferation of T cells in the LN. In the thymus, the TCR-beta transgene resulted in a dramatic increase in maturation efficiency and a reduction in apoptosis in MRL(-)+/+ mice. These data suggest that the TCR transgene inhibits lymphoproliferation by reducing the production of "neglected" CD4+CD8+TCRdull thymocytes that will undergo Fas Ag-mediated apoptosis. They further suggest that in lpr mice, which express a mutated Fas Ag, the "neglected" thymocytes are able to continually escape to the periphery, where they proliferate.