In the BXSB autoimmune disease-prone mouse strain, male mice develop severe lupus-like symptoms and die early in life (4-6 mo), whereas females do not. We have previously demonstrated that profound phenotypic and functional changes occur with age in CD4+ cells from BXSB males. CD4+ cells from males (4 mo old) were predominantly CD44high, CD45RBlow, and MEL-14low (activated/memory phenotypes), while the reciprocal phenotypes characteristic of naive cells were prevalent in age-matched females and young adult males (2 mo old). CD4+ cells from older males proliferated less and produced less IL-2 and IFN-gamma than cells from either females or young males in response to immobilized anti-CD3 mAb. We tested the effect of CTLA4Ig treatment on the progression of disease in BXSB males. CD4+ cells from CTLA4Ig-treated mice at 4 mo of age were predominantly CD44low, CD45RBhigh, and MEL-14high phenotypes that were identical with those observed in CD4+ cells from young (3-mo-old) females. In contrast, control male mice treated with IgG2a accumulated the CD4+ memory phenotype. CD4+ cells from 4-mo-old male CTLA4Ig-treated mice proliferated and produced IL-2 at levels similar to those of cells from females in response to immobilized anti-CD3 mAb. Furthermore, in contrast to IgG2a-treated mice, female and CTLA4Ig-treated male mice at 4 mo of age produced no anti-chromatin Abs. Three of four male mice injected with CTLA4Ig until 6 mo of age appeared healthy at 8 mo of age, whereas all five of IgG2a-treated control males died by 6 mo of age. These 8-mo-old CTLA4Ig-treated males showed variable resistance to autoimmunity as well as function and phenotype marker expression, and a less striking glomerulonephritis than 4-mo-old untreated males. The results of this study demonstrate that the rampant T cell activation and T cell dysfunction that occur in male BXSB mice by 4 mo of age are abrogated by blocking the CTLA4-dependent costimulatory signal(s). They also show that treatment with CTLA4Ig can suppress the pathogenesis of disease and increase longevity.