RETARDED THYMIC INVOLUTION AND MASSIVE GERMINAL CENTER FORMATION IN NF-ATP-DEFICIENT MICE

NF-ATp and NF-ATc are the most prominent nuclear NF-AT transcription f actors in peripheral T lymphocytes. After T cell activation both facto rs bind to and control the promoters and enhancers of numerous lymphok ine and receptor ligand genes. In order to define a specific role for NF-ATP in vivo we have inactivated the NF-ATp gene by gene targeting i n mice. We show that NF-ATp deficiency leads to the accumulation of pe ripheral T cells with a ''preactivated'' phenotype, enhanced immune re sponses of T cells after secondary stimulation in vitro and severe def ects in the proper termination of antigen responses, as shown by a red uced deletion of superantigen-reactive CD4(+) T cells. These alteratio ns in the function of the immune system are correlated with drastic ch anges in the morphology of lymphoid organs. Approximately 25 % of NF-A Tp-deficient mice older than 6 months develop large germinal centers i n the spleen and peripheral lymph nodes. In addition, they exhibit a p ronounced retardation in the involution of the thymus. The thymus of t hese NF-ATp-deficient mice exhibits large cortical areas typical for n ewborn mice and a massive infiltration of IgM(+)/IgD(+) B lymphocytes. Contrary to the T lymphocytes from IL-2-deficient mice which develop a phenotype similar to the NF-ATp(-/-) mice, NF-ATp(-/-) T cells do no t show obvious defects in Fas-mediated apoptosis. This might indicate defects in other types of programmed cell death which are controlled b y the activity of NF-ATp.