Mice homozygous for the gene Ipr develop a spectrum of autoantibodies closely resembling that of human SLE. Previous work has shown that the lpr defect must be expressed in the T cells that hyperproliferate and in the B cells that produce autoantibodies. Although autoantibody production in lpr mice requires T cells, it is not known whether these need to be lpr T cells. To ask whether normal (+/+) T cells can help lpr B cells produce autoantibodies, we have constructed chimeras containing mixtures of lpr-derived and normal-derived lymphoid cells, and have selectively eliminated the lpr-derived T cells by in vivo treatment with monoclonal anti-Thy-1 of the appropriate allotype. A mixture of T cell-depleted bone marrow from congenic strains of normal and lpr mice differentially marked by Ig H chain allotype and Thy-1 alleles was transferred into lethally irradiated lpr mice. The mice received weekly injections of either anti-Thy-1.2 to deplete specifically lpr T cells or an isotype-matched irrelevant control mAb. Absence of lpr-derived T cells in the experimental group was documented by immunofluorescence. In mice treated with control antibody, autoantibodies of Ipr origin were present in high titers, as determined by allotype-specific ELISA. In contrast, mice depleted of lpr-derived T cells had greatly reduced titers of antichromatin and rheumatoid factor. These mice also had increased levels of serum total IgM and IgG2a of +/+ origin. Parallel experiments were performed using a combination of two lpr marrow sources, also differentially marked by Ig H chain allotype and Thy-1 expression. Mice depleted of Thy-1.2-bearing T cells produced autoantibodies of both allotypes due to the presence of Thy-1.1-bearing T cells of Ipr origin. These data indicate that autoantibody production in lpr mice requires expression of the lpr gene in those T cells that provide help.