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* Center for Biomedical Research, University of Texas Health Center at Tyler, TX 75708; and
Division of Immunogenetics, Department of Pediatrics, Rangos Research Center, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213
Dendritic cell-derived indoleamine 2,3-dioxygenase (IDO) suppresses naive T cell proliferation and induces their apoptosis by catalyzing tryptophan, and hence is essential for the maintenance of peripheral tolerance. However, it is not known whether memory T cells are subject to the regulation by IDO-mediated tryptophan catabolism, as memory T cells respond more rapidly and vigorously than their naive counterparts and are resistant to conventional costimulatory blockade. In this study, we present the evidence that memory CD8+ T cells are susceptible to tryptophan catabolism mediated by IDO. We found that overexpression of IDO in vivo attenuated the generation of both central memory CD8+ T cells (TCM) and effector memory CD8+ T cells (TEM) while suppressing IDO activity promoted their generation. Moreover, IDO overexpression suppressed the effector function of TCM cells or TCM cell-mediated allograft rejection as well as their proliferation in vivo. Interestingly, TCM cells were resistant to apoptosis induced by tryptophan catabolism. However, IDO overexpression did not suppress the effector function of TEM cells or TEM cell-mediated allograft rejection, suggesting that TEM cells, unlike TCM cells, do not require tryptophan for their effector function once they are generated. This study provides insight into the mechanisms underlying the differential regulation of memory T cell responsiveness and has clinical implications for vaccination or tolerance induction.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by research grants from the Juvenile Diabetes Research Foundation International and a research award from the American Diabetes Association.
2 Address correspondence and reprint requests to Dr. Zhenhua Dai, Center for Biomedical Research, University of Texas Health Center, 11937 U.S. Highway 271, Tyler, TX 75708. E-mail address: zhenhua.dai{at}uthct.edu
3 Abbreviations used in this paper: IDO, indoleamine 2,3-dioxygenase; TCM, central memory CD8+ T cells; TEM, effector memory CD8+ T cells; Ad-IDO, adenoviral vector coding IDO; mLN, mesenteric lymph node; CD62L, CD62 ligand; MOI, multiplicity of infection.
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