NFAT and NFκB Activation in T Lymphocytes: A Model of Differential Activation of Gene Expression

Abstract

Mathematical models for the regulation of the Ca²⁺-dependent transcription factors NFAT and NFκB that are involved in the activation of the immune and inflammatory responses in T lymphocytes have been developed. These pathways are important targets for drugs, which act as powerful immunosuppressants by suppressing activation of NFAT and NFκB in T cells. The models simulate activation and deactivation over physiological concentrations of Ca²⁺, diacyl glycerol (DAG), and PKCθ using single and periodic step increases. The model suggests the following: (1) the activation NFAT does not occur at low frequencies as NFAT requires calcineurin activated by Ca²⁺ to remain dephosphorylated and in the nucleus; (2) NFκB is activated at lower Ca²⁺ oscillation frequencies than NFAT as IκB is degraded in response to elevations in Ca²⁺ allowing free NFκB to translocate into the nucleus; and (3) the degradation of IκB is essential for efficient translocation of NFκB to the nucleus. Through sensitivity analysis, the model also suggests that the largest controlling factor for NFAT activation is the dissociation/reassociation rate of the NFAT:calcineurin complex and the translocation rate of the complex into the nucleus and for NFκB is the degradation/resynthesis rate of IκB and the import rate of IκB into the nucleus.