Indoleamine 2,3 -Dioxygenase Activity Suppresses T Ceil Responses

Abstract

Cells expressing indoleamine 2,3-dioxygenasc (IDO) inhibit proliferation of human T cells in vitro and protect murine fetuses from lethal attack by maternal T cells in vivo. This work investigates the hypothesis that IDO activity suppresses T cell responses. To test the prediction that pharmacological inhibition o f IDO enhances murine T cell responses in vivo, splenocytes from H-2Kb-specific T cell receptor transgenic (BM3) mice were injected into H-2Kb-expressing (CBK) recipients. As predicted, CD8+ T cell responses were augmented by 1-methyl-Dx-tryptophan (1-MeTrp) treatment o f recipient CBK mice, but only when BM3 donor T cells were derived from male mice. To further evaluate the prediction that IDO-expressing antigen presenting cells (APCs) inhibit antigen-specific T cell responses, we prepared IDO- and vectortransfected murine tumor cells expressing H-2Kb. BM3 T cell proliferation was diminished in co-cultures with IDO-transfected MCS7G cells, relative to vcctortransfected MCS7G cells. Furthermore, IDO-transfected MCS7G cells failed to prime H-2b-specific recall responses in allogeneic CBA mice unless co-administered with 1-MeTrp or endotoxin adjuvant. These results show that IDO-expressing APCs inhibit murine T cell responses in vitro and in vivo, and demonstrate the efficacy o f 1-MeTrp treatment in reversing the effects o f murine IDO-mediated T cell suppression in vivo.