The ‘instructive’ model hypothesized that all fates could be adopted by every naïve cell. By now, the ‘instructive’ model has been validated by showing that cells that had been partially differentiated towards

the Th2 phenotype could be re-educated to become Th1 cells [91, 106]. Many different signals have been described as being potentially instructive for Th cells, and much study has gone into which signals induce which phenotype. But how does the adaptive immune response choose a correct phenotype? The adaptive immune system of B and T lymphocytes is built on top of the so-called innate immune system composed of intracellular responses, neutrophils, granulocytes and natural killer cells. The members of the innate immune system

detect the presence of pathogens by evolutionary conserved signals that are usually called pathogen-associated molecular patterns (PAMPs) [107]. One important class of cellular find protocol receptors that can detect the presence of PAMPs are the Toll-like receptors (TLR), which discriminate between bacterial, viral and several other types of PAMPs [1, 108]. The innate system therefore uses evolutionary conserved information and is probably selected to mount an appropriate immune response buy Dabrafenib to particular pathogens. Because innate cells and infected cells secrete cytokines, these cytokines provide a key to the developing Th0 cells to adopt a particular phenotype [99]. Thus, the local

context of cytokines created by the innate immune GNA12 responses can instruct helper T cells to make an appropriate decision. One notorious example of Th decision-making is the priming with formalin-inactivated and alum-adjuvated RSV vaccine (FI-RSV). In the 1960s, a trial with this vaccine failed because it predisposed for enhanced disease rather than preventing it [109]. This was attributed to the generation of Th2 responses rather than the more appropriate Th1 response. Subsequent mouse studies into RSV have shown that immunization with the RSV fusion protein (F) or the RSV attachment protein (G) induces Th1 or Th2 responses when challenged with RSV [110]. Again the Th2 type response was associated with enhanced disease, including a marked eosinophilia reminiscent of that seen in FI-RSV-primed mice. Induction of these skewed Th2 responses can be abrogated by the insertion of a CD8 epitope derived from the RSV M2 protein into the G protein or by simultaneous priming of mice with G and M2 proteins prior to RSV infection [111]. This demonstrates that the presence or absence of a CD8+ T-cell epitope could play a role in determining the type of immune response against a pathogen. The absence of a CD8+ epitope appears to predispose for the formation of Th2 immunity. Conversely, in the presence of a CD8+ T-cell response, the CD4 T cells adopt a Th1 phenotype.