MRL/Mp-lpr/lpr mice develop a systemic lupus erythematosus (SLE) like disease similar to human SLE and develop an age dependent lymphoproliferative disease characterized by massive accumulation of an abnormal subset of T lymphocytes. The abnormal lpr T cells are unresponsive to many mitogenic stimuli. Phenotypically normal CD4+ T cells, which account for only 5 to 10 percent of the lymphocytes in lpr mice, also play an important role in the pathogenesis of autoimmune disease. These CD4 bearing cells may recognize self Ia antigens or some processed self peptides bound to Ia. Interaction of these autoreactive T cells with B cells may result in production of autoantibodies. T cells and self-antigens may, therefore, be the cause of autoimmune diseases in these mice. T cell hybridomas were generated by fusing CD4+ lpr T cells with BW5147. These hybridomas will be used to investigate the T cell receptor repertoire of the autoreactive T cells. T cell hybridomas or their supernatants will be cultured with B cells to determine if they can activate B cells to produce antibodies. The isotype and specificities of antibodies produced will be determined. B cells from lpr mice may possess some intrinsic features which render them more stimulatory in activating autoreactive T cells. While it is clear that CD4+ T cells are essential for the development of lymphoproliferation in lpr mice, the relationship between CD4+ T cells and abnormal T cells is not clear. CD4+ T cells may be the precursors of the abnormal T cells. Lymphocytes infiltrate the kidneys and salivary glands in lpr mice. The majority of the infiltrating lymphocytes are CD4+ T cells. T cell clones and T cell hybridomas will be generated from infiltrating lymphocytes obtained from the kidneys and salivary glands of lpr mice. The T cell receptor (TCR) repertoire of these T cell clones and hybridomas will be characterized. Antigen presenting cells in the kidneys and salivary glands of lpr mice will also be isolated and their ability to activate the T cell clones or hybridomas will be determined. These studies should provide new insights into the relationship between autoreactive T cells, abnormal T cells and lymphocytes infiltrating inflamed organs in lpr mice.
