Liu Zhiwei, Dai Hehua, Wan Ni, Wang Tao, Bertera Suzanne, Trucco Massimo, Dai Zhenhua
Center for Biomedical Research, University of Texas Health Center at Tyler, Tyler, TX 75708, USA.
J Immunol. 2007 Apr 1;178(7):4260-6. doi: 10.4049/jimmunol.178.7.4260.
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.
树突状细胞衍生的吲哚胺2,3-双加氧酶（IDO）通过催化色氨酸来抑制初始T细胞增殖并诱导其凋亡，因此对于维持外周免疫耐受至关重要。然而，尚不清楚记忆T细胞是否受IDO介导的色氨酸分解代谢的调控，因为记忆T细胞比其初始对应细胞反应更快、更强烈，并且对传统的共刺激阻断具有抗性。在本研究中，我们提供证据表明记忆性CD8+T细胞易受IDO介导的色氨酸分解代谢的影响。我们发现，体内IDO的过表达减弱了中枢记忆性CD8+T细胞（T(CM)）和效应记忆性CD8+T细胞（T(EM)）的生成，而抑制IDO活性则促进它们的生成。此外，IDO过表达抑制了T(CM)细胞的效应功能或T(CM)细胞介导的同种异体移植排斥反应以及它们在体内的增殖。有趣的是，T(CM)细胞对色氨酸分解代谢诱导的凋亡具有抗性。然而，IDO过表达并未抑制T(EM)细胞的效应功能或T(EM)细胞介导的同种异体移植排斥反应，这表明与T(CM)细胞不同，T(EM)细胞一旦生成，其效应功能就不需要色氨酸。本研究为记忆T细胞反应性差异调节的潜在机制提供了见解，并对疫苗接种或耐受诱导具有临床意义。
