Substance P (SP) enhances antigen-dependent, T cell IFN production. It was determined if a T cell NK-1R was critical for IFN regulation. T cells from schistosome-infected mice were mixed with splenocytes from uninfected NK-1R KO animals. Thus, only the schistosome egg antigen-specific T cells expressed NK-1R. The cells were cultured 18h, with or without SP. SP enhanced antigen-induced IFN production 4-fold without affecting IL4 or IL5 secretion. NK-1R inhibitor blocked this stimulation. Neither purified T cells nor naïve KO splenocytes cultured alone responded to antigen. To further define the importance of T cell NK-1R, we developed a T cell selective NK-1R KO mouse by reconstituting T cell deficient Rag mice with NK-1R KO T cells. These mice challanged with schistosomiasis developed abnormal liver granulomas. Granuloma size was smaller in T cell-selective NK-1R KO mice compared to granulomas in Rags reconstituted with normal T cells. Splenocytes and granuloma cells from NK-1R KO mice made less IFN. The mice also made less IgG2a. Thus, T cell NK-1R is important for IFN regulation.