Transgenic mice will be produced which express human Thy-1 under the control of the murine IFN-gamma promoter and murine Thy-1.1 under the control of the murine IL-4 promoter. These transgenes will be introduced into a number of strains which are murine Thy-1.2+. Because of the promoters used, human Thy-1 will be expressed in TH 1 T cells expressing IFN-gamma and murine Thy-1.1 will be expressed in TH2 cells expressing IL- 4. It is possible that both human Thy-1 and murine Thy-1.1 will be expressed in THO cells. This double positivity will then be a marker for the THO subset. Utilizing the appropriate monoclonal antibodies, these transgenic mice will provide unique cell surface markers for the detection of the TH1, THO and TH2 T cell subsets.(monoclonal antibodies for CD8 and NK1 will be required to detect the expected small number of CD8+ T cells and NK cells which also express IFN-gamma). These reporter gene transgenes will then be introduced into the BALB/c, B10.D2, NOD, NOD.A-beta-d, NOD.A-beta-g7.PD, B10.PL, NZB. MRL inbred strain backgrounds. The transgenes will also be introduced into three T cell receptor transgenic lines expressing T cell receptor specific for a myelin basic protein peptide and two influenza hemagglutinin peptides recognized by a CD4 and a CD8 T cell receptor. The presence of the reporter gene transgenes in these inbred strains will permit an analysis of the role of the TH1, THO, and TH2 T cell subsets in the normal immune response in a variety of immunizing conditions, and in the autoimmunity seen in the NOD mouse, in experimental allergic encephalomyelitis (EAE) in the (B10.PL x SJL)F1 mouse, and in the autoimmune syndromes seen in the NZB x NZW mouse and the MRL-lpr/lpr mouse. In a similar manner, the transgenes will permit the analysis of TH1 and TH2 T cell subsets in transgenic mice injected with the peptide for which the T cell receptor is transgenic and will permit a study of the relative inducibility of apoptosis anergy and deletion in the TH l and TH2 cell subsets. In addition, these reporter gene/transgenic mouse lines will permit an analysis of the role of T cells subsets in a wide variety of immune conditions and will be made available to other investigators in this program project as well as to other investigators in this and other institutions. Ultimately, these transgenic mice offer the possibility of validating the very productive paradigm for T cell subset differentiation initially proposed by Coffmann and Mossmann.
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