Systemic lupus erythematosus (SLE), which spontaneously develops in (NZB (New Zealand Black) x NZW (New Zealand White)) F1 mice, is strictly dependent on CD4+ T cells. We found that in these mice with overt SLE, CD4+ T cells expressing CD69 molecules, an early activation Ag, are dramatically increased in peripheral lymphoid tissues and inflammatory infiltrates in the kidney and lung, but not in peripheral blood, while CD8+ and NK1.1+ T cells were virtually CD69-. Various adhesion molecules, including LFA-1, ICAM-1, CD43, CD44, P-selectin, and E-selectin, were up-regulated. Analysis of the TCR repertoire showed no skewed TCR Vbeta usage. Studies on in vitro cytokine production of spleen cells on TCR cross-linking indicated that compared with findings in young mice, the aged mice showed severely impaired production of IL-2, IL-3, and IL-4, whereas the levels of IL-10 and IFN-gamma remained relatively intact. FACS-sorted CD69-CD4+ T cells from aged mice produced substantial amounts of these cytokines, including IL-2, IL-3, and IL-4, whereas CD69+CD4+ T cells were poor producers. Intriguingly, when cocultured, CD69+CD4+ T cells significantly inhibited the production of IL-2 by CD69-CD4+ T cells. IL-2 production by spleen cells from young mice was also markedly inhibited in the presence of CD69+CD4+ T cells obtained from aged mice. We propose that CD69+CD4+ T cells that are continuously activated by self peptides bound to MHC class II molecules in (NZB x NZW)F1 mice may be involved in the pathogenesis of SLE through abnormal regulatory effects on cytokine balance.