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.