Suppression of memory CD8 T cell generation and function by tryptophan catabolism.
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 (T(CM)) and effector memory CD8+ T cells (T(EM)) while suppressing IDO activity promoted their generation. Moreover, IDO overexpression suppressed the effector function of T(CM) cells or T(CM) cell-mediated allograft rejection as well as their proliferation in vivo. Interestingly, T(CM) cells were resistant to apoptosis induced by tryptophan catabolism. However, IDO overexpression did not suppress the effector function of T(EM) cells or T(EM) cell-mediated allograft rejection, suggesting that T(EM) cells, unlike T(CM) 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.
Liu
Zhiwei
Z
Center for Biomedical Research, University of Texas Health Center at Tyler, Tyler, TX 75708, USA.
Dai
Hehua
H
Wan
Ni
N
Wang
Tao
T
Bertera
Suzanne
S
Trucco
Massimo
M
Dai
Zhenhua
Z
D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000502:physiology*; D018655:Lymphocyte Count; D051379:Mice; D008822:Mice, Transgenic; D014364:Tryptophan / Q000378:metabolism*; D015854:Up-Regulation
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan