Peroxisome proliferator-activated receptor-gamma (PPAR gamma) controls adipogenesis and glucose metabolism. It was reported recently that PPAR gamma activation by its agonistic ligands modifies lymphocyte function. Since synthetic ligands are known to exert their effect via PPAR gamma-dependent and -independent pathways, we examined the physiological role of PPAR gamma in lymphocytes by using heterozygote mutant mice in which one allele of PPAR gamma is deleted (PPAR gamma(+/-)). In contrast to T cells, which did not exhibit a significant difference, B cells from PPAR gamma(+/-) showed an enhanced proliferative response to stimulation by either lipopolysaccharide or cross-linking of antigen receptors. Dysregulation of the NF-kappa B pathway in B cells from PPAR gamma(+/-) was indicated by spontaneous NF-kappa B activation, as well as increased I kappa B alpha phosphorylation and gel-shift activity following LPS stimulation. Mice primed with either ovalbumin or methylated BSA also showed enhanced antigen-specific immune response of both T and B cells, an immunological abnormality that exacerbated antigen-induced arthritis. These findings indicate that PPAR gamma plays a critical role in the control of B cell response and imply a role in diseases in which B cell hyperreactivity is involved, such as arthritis and autoimmunity.