Macrophages secrete the immunoregulatory peptide somatostatin (SOM) that inhibits IFN-gamma release by splenocytes and granuloma cells of schistosome-infected mice. In this report we demonstrate that granuloma cells express mRNA for the SOM receptor SSTR2 but not the other four SSTR subtypes. Blocking SSTR2 activity with anti-SSTR2 antiserum prevents SOM inhibition of T cell IFN-gamma production. This demonstrates that SOM regulates T cell function via SSTR2. Two isoforms of SSTR2 exist due to alternative RNA splicing. We developed sensitive and specific competitive PCR assays to quantify total SSTR2, SSTR2A and SSTR2B mRNA levels. The SSTR2A isoform accounts for 99% of inflammatory cell SSTR2 mRNA and does not appear to be regulated at the transcripitonal level. B cells and macrophage cell lines also express SSTR2 mRNA which raises the possibility that SOM influences T cell IFN-gamma release by regulating accessory cell function. We show that SOM acts directly on T cells to inhibit TCR-stimulated IFN-gamma release. Thus, SOM may directly regulate T cell IFN-gamma release at inflammatory sites.