How instruction and feedback can select the appropriate T helper response

The decision of the immune system to trigger immune responses that are, respectively, induced by Th1 or Th2 effectors is a critical one, because it profoundly influences disease outcome. We have recently constructed a mathematical model of Th1-Th2-pathogen interactions that shows that the major decisional events can often be successfully determined by the intrinsic behaviour of the T helper system itself. For certain dangerous types of pathogens, however, which replicate rapidly or have developed strategies to evade the immune response, additional stimuli may be necessary. As a possible mechanism for the decision-making process innate immune recognition has been proposed. Here we present an enlarged version of our model, which incorporates signals created from the innate immune system after pathogen recognition. The model analysis suggests that there is 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, if timing is unimportant then Th2 signals are superfluous since the intrinsic T helper dynamics provide an automatic switch to Th2 if Th1 effectors fail to control the pathogen. Th2 signals may, however, be required to accelerate the onset of the Th2 response. 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.