Helper T (Th) cells are a crucial component of the adaptive immune system and are of fundamental importance in orchestrating the appropriate response to pathogenic challenge. They fall into two broad categories defined by the cytokines each produces. Th1 cells are required for effective immunity to intracellular bacteria, viruses and protozoa whereas Th2 are required for optimal antibody production to T dependent antigens. A great deal of experimental data on the regulation of Th1 and Th2 differentiation have been obtained but many essential features of this complex system are still not understood. Here we present a mathematical model of Th1/Th2 regulation in presence of a constant antigenic stimulus. We include Fas-mediated activation-induced cell death (AICD) as this process has been identified as an important mechanism for limiting clonal expansion and resolving T cell responses. We see that the strengths of the activation signals for each T helper cell subset, which are dependent on the antigen dose, co-stimulatory signals and the cytokine environment, critically determine the dominant helper subset. In addition we show that the occurence of switches from Th1- to Th2-dominance is based on the antigen dose-dependence of T helper differentiation and can arise from differential susceptibility for AICD of T helper subsets, and asymmetries in the nature of the cross-suppressive cytokine interactions. In a second step we model interactions between the T helper system and a replicating pathogen and propose a possible default selection mechanism for the appropriate T helper response against a particular pathogen. The decision of a naive T cell to differentiate into Th1 or Th2 is crucial, since it profoundly influences disease outcome. Here we show that the internal behaviour of the T-helper system, which emerges from regulatory mechanisms `built-in' into the T-helper system, itself can usually select the appropriate T-helper response. This phenomenon arises from an initial Th1 bias together with the induction of Th1 -> Th2 switches when Th1 effectors do not lead to efficient antigen clearance. For certain dangerous types of pathogens that replicate rapidly or have developed strategies to evade the immune response, however, this default selection mechanism fails and additional stimuli may be necessary. As an additional mechanism for the decision-making process innate immune recognition has been proposed. Mainly Th1-promoting APC-derived signals have been experimentally described until now. Here we present an extended version of our model, which suggests that this is due to low fault-tolerance of the T-helper system to incorrect Th1-signals. In the presence of incorrect Th1-stimuli an initial Th1 response is shifted to the correct Th2 dominated response owing to the intrinsic T helper dynamics. By contrast, according to our model there is no fault-tolerance for incorrect Th2-signals. In fact, Th2-signals are superfluous since the intrinsic T helper dynamics provide an automatic switch to Th2 if Th1 effectors fail to control the pathogen. Additionally, we discuss the role of feedback where successful pathogen destruction leads to up-regulation of activation of the effective T helper type. As one possibility we examine the role of CpG motifs as indicators for successful pathogen destruction. Differences between instructive and feedback mechanisms are highlighted.     «

Helper T (Th) cells are a crucial component of the adaptive immune system and are of fundamental importance in orchestrating the appropriate response to pathogenic challenge. They fall into two broad categories defined by the cytokines each produces. Th1 cells are required for effective immunity to intracellular bacteria, viruses and protozoa whereas Th2 are required for optimal antibody production to T dependent antigens. A great deal of experimental data on the regulation of Th1 and Th2 differ...     »