In CD8+ T cell-deficient lpr/lpr mice, CD4+B220+ and CD4+B220- T cells replace B220+ double-negative T cells as the predominant populations in enlarged lymph nodes.

Mice homozygous for lpr or gld develop autoimmunity and progressive lymphoproliferative disease characterized by the accumulation of two unusual populations of B220+ TCR-alpha beta+ T cells, a predominant CD4-CD8- double-negative (DN) subset and a minor CD4dull+ subset. B220+ DN T cells appear to be derived from negatively selected thymocytes, but their immediate precursors have not been identified conclusively, and their relationship to CD4+B220+ T cells is unclear. Our previous studies of lpr and gld mice treated chronically with anti-CD8 mAb provided evidence that the majority of B220+ DN T cells are unrelated to CD4+B220+ T cells and may be descended from peripheral thymus-derived CD8+ T cells. To investigate the contributions of MHC class I-selected thymus-derived T cells to the production of B220+ DN T cells and to the accumulation of CD4+ T cell subsets, we studied C3H-lpr and -gld mice rendered deficient in CD8+ T cells by the introduction of disrupted beta 2-microglobulin (beta 2-m) genes. These CD8+ T cell-deficient mice developed massively enlarged lymph nodes, in which CD4+B220+ T cells and CD4+ T cells replaced B220+ DN T cells as the dominant T cell subsets. As a population, the CD4+B220+ T cells were depleted of autoreactive populations specific for endogenous retroviral superantigens and were enriched for V beta 8.3+ T cells. The deficiency of CD8+ T cells in beta 2-m(-/-)-lpr mice had no effects on the accumulation of primed CD4+ T cells or autoreactive B cells. The selective reduction in B220+ DN T cells and corresponding accumulation of CD4+B220+ T cells in beta 2-m(-/-)-lpr mice provide strong evidence that 1) the majority of B220+ DN T cells are unrelated to CD4+ T cells and their development and/or accumulation is dependent on MHC class I expression; and 2) CD4+B220+ T cells are a remarkably similar, but separate, lineage of cells that develop independently of thymus-derived CD8+ T cells and class I MHC expression.