Activation of T lymphocytes and their ensuing elaboration of proinflammatory cytokines, such as interferon (IFN)-γ, represent a critical step in atherogenesis and arteriosclerosis. IFNγ pathways also appear integral to the development of transplantation-associated arteriosclerosis (Tx-AA), limiting long-term cardiac allograft survival. Although disruption of these IFNγ signaling pathways limits atherosclerosis and Tx-AA in animals, little is known about inhibitory regulation of proinflammatory cytokine production in humans. The present study investigated whether activators of peroxisome proliferator-activated receptor (PPAR)α and PPARγ, with their known antiinflammatory effects, might regulate the expression of proinflammatory cytokines in human CD4-positive T cells. Isolated human CD4-positive T cells express PPARα and PPARγ mRNA and protein. Activation of CD4-positive T cells by anti-CD3 monoclonal antibodies significantly increased IFNγ protein secretion from 0 to 504±168 pg/mL, as determined by ELISA. Pretreatment of cells with well-established PPARα (WY14643 or fenofibrate) or PPARγ (BRL49653/rosiglitazone or pioglitazone) activators reduced anti-CD3-induced IFNγ secretion in a concentration-dependent manner. PPAR activators also inhibited TNFα and interleukin-2 protein expression. In addition, PPAR activators markedly reduced cytokine mRNA expression in these cells. Such antiinflammatory actions were also evident in cell-cell interactions with medium conditioned by PPAR activator-treated T cells attenuating human monocyte CD64 expression and human endothelial cell major histocompatibility complex class II induction. Thus, activation of PPARα and PPARγ in human CD4-positive T cells limits the expression of proinflammatory cytokines, such as IFNγ, yielding potential therapeutic benefits in pathological processes, such as atherosclerosis and Tx-AA.