T lymphocytes cultured under the low-shear stress environment of modeled microgravity demonstrate an inhibition of activation in response to T-cell receptor (TCR)–mediated signaling. Modeled microgravity culture-induced inhibition mimics the inhibition observed during spaceflight. This work investigates the molecular signaling events of interleukin 2 transcription activation in modeled microgravity as generated with clinorotation. Under normal conditions, NFAT (nuclear factor of activated T cells) is dephosphorylated and activated with sustained calcium (Ca ) influx and calcineurin activity, whereas AP-1 is activated by protein kinase C (PKC) and Ras-mediated pathways. Purified human T lymphocytes are shown to exhibit differential inhibition of transcription factor activation in modeled microgravity. Activation of AP-1 is blocked with clinorotation, whereas NFAT dephosphorylation occurs. This work supports the theory that modeled microgravity differentially blocks the activation of distinct signaling mechanism.