T-CELLS IN MURINE LUPUS - PROPAGATION AND REGULATION OF DISEASE

MRL/Mp-lpr-/lpr mice develop a spontaneous lupus syndrome, including h ypergammaglobulinemia, autoantibodies, glomerulonephritis, and lymphad enopathy. To investigate the role of lymphocyte subsets in the pathoge nesis of disease, lupus-prone MRL mice deficient in alpha beta T cells , gamma delta T cells, or both were generated. Mice deficient in crp T cells developed a partially penetrant lupus syndrome, characterized b y lymphadenopathy, elevated levels of class-switched immunoglobulins, an increased incidence of antinuclear antibodies, and immune deposits in kidneys which progressed to renal insufficiency over time. In compa rison to wild type animals, gamma delta T cell-deficient animals devel oped an accelerated and exacerbated disease phenotype, characterized b y accelerated hypergammaglobulinemia and enhanced autoantibody product ion and mortality. Repertoire analysis of these latter animals identif ied polyclonal expansion (V beta) of alpha beta CD4+ B220-cens. Mice l acking both alpha beta and gamma 6 T cells failed to generate class-sw itched autoantibodies and immune complex renal disease. First, these f indings demonstrate that murine lupus in the setting of Fas-deficiency does not absolutely require the presence of alpha beta T cells, and t hey also suggest that a significant basis for MRL/lpr disease, includi ng renal disease, involves alpha beta T cell-independent, gamma delta T cell dependent, polyreactive B cell autoimmunity, upon which alpha b eta T cell-dependent mechanisms aggravate specific autoimmune response s. Second, these data indicate that gamma delta T cells partake in the regulation of systemic autoimmunity, presumably via their effects on alpha beta CD4+ B220-T cells that provide B cell help. Finally, these results demonstrate that MRL/lpr B cells, despite their intrinsic abno rmalities, cannot per se cause tissue injury without T cell help.