Computer simulation of the role of SOCS family protein in helper T cell differentiation

The T_h1/T_h2 balance determines the nature of an immune response, and particular cytokines, IL-4 and IL-12, determine the direction at the initial stage of activation through TCRs. To investigate how cytokine networks and related signaling pathways impact upon the T_h1/T_h2 balance, we have developed a computer model for the simulation of T_h differentiation. The model includes the IL-4, IL-12 and IFN-γ signal transduction pathways, a positive and negative feedback mechanism for cytokine signaling and cytokine-induced negative regulators such as suppressors of cytokine signaling (SOCS)1, SOCS3 and SOCS5. In the present study, we propose a 'T_h0 model', in which naive T cells differentiate neither into T_h1 nor into T_h2 states in unskewed cytokine conditions. The model was found to be consistent with experimental results in BALB/c mice. The results of in silico analysis in the condition with SOCS- and signal transducer and activator of transcription (STAT) family-deficient and transgenic states were well fitted to ex vivo experimental results for T_h1 and T_h2 differentiation profiles in the deficient and transgenic mice. The T_h0 model suggested the possibility that dominant T_h1 differentiation in STAT4/STAT6 double-deficient mice may be due to a positive feedback effect of initial IFN-γ production from T cells. The in silico assessment of beneficial effects of inhibitory drugs by simulation analysis with our T_h0 model indicated that Janus kinase 3-specific inhibitors might be suitable candidates for the modification of T_h2-dominant immune responses. Our results demonstrate that models for the simulation of signaling network, such as our T_h0 model, are useful tools for the in silico evaluation of novel drug candidates.