One of the fundamental questions of modern T-cell biology is the control of helper T-cell differentiation into subsets with discrete effector functions. Of particular interest is the control of expression of Interleukin-4, expressed by """"""""Th2"""""""" cells and Interleukin-2, expressed by """"""""Th1"""""""" cells. Several genes involved in Interleukin-4 transcription in Th2 cells have recently been identified, but it is still unclear how the differentiation occurs, and to what extent it is reversible. In order to examine the kinetics, reversibility, and long-term persistence of the Th1 or Th2 phenotype, we have adopted a fate mapping system. In one strain of mouse, there is a transgenic reporter construct, that is not expressed until properly triggered, at which point it is expressed constitutively. In another strain of mouse, the triggering gene is expressed, under the control of the Interleukin-4 promoter. The two are mated, and any cell that expresses Interleukin-4 will activate, irreversibly, the reporter construct. This will then allow a number of experiments. First, reporter expressing cells, which at one point must have been of a Th2 phenotype, can be induced to become Th1 cells, and express Interleukin-2. Failure indicates that the process is irreversible. By exposing the animal to various pathogens and examining reporter positive cells over a time course, the kinetics of the response can be accurately determined. Finally, over a long time course, the animals will be examined for the persistence of antigen-specific reporter positive cells. In this fashion, an estimate can be made as to the length of the memory response.
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