Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Abstract

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 Role for Monocyte Chemoattractant Protein-1 in the Generation and Function of Memory CD8+ T Cells

“…The CD8 ϩ 1B2 ϩ 2C cells generated in immunized murine recipients were confirmed to be memory T cells because 2C cells derived from lymph nodes were mainly CD44 high and CD62L high , a T CM phenotype, while 2C cells derived from liver tissues were mainly CD44 high and CD62L low , a T EM phenotype (Fig. 1B), as also described previously (6,47,48). It is noteworthy that very few 2C memory cells were detected in the bone marrow cells of immunized mice in our allogeneic murine system (our unpublished observation).…”

“…CD8 ϩ T cell memory phenotype was further confirmed by staining with anti-CD62L-APC or anti-CD44-APC (BD Pharmingen) as described previously (6). To purify memory CD8 ϩ T cells for adoptive transfer experiments or in vitro studies, central memory CD8 ϩ T cells (1B2 ϩ CD8 ϩ CD44 high CD62L high ) were isolated from spleens and lymph nodes by FACSAria cell sorting after the four-color staining, while effector memory CD8 ϩ T cells (1B2 ϩ CD8 ϩ CD44 high CD62L low ) were purified from blood, livers, and kidneys (6,12,47) via the same four-color cell sorting. The purity of sorted 2C memory cells was typically Ͼ96%.…”

In vivo metabolism of tryptophan in meningiomas is mediated by indoleamine 2,3-dioxygenase 1

“…[37][38][39] Moreover, IDO has an important role in the activation of regulatory T cells. [40][41][42][43] In fact, IDO expression has been demonstrated in a number of tumor types and shown to be associated with immunosuppression, thereby facilitating tumor growth.…”

A Novel Cancer Therapy by Skin Delivery of Indoleamine 2,3-Dioxygenase siRNA

“…The establishment of tolerance may be mediated through either localized depletion of tryptophan or accumulation of toxic metabolites. Tryptophan catabolism also affects naBve T cell proliferation and memory CD8 T cell generation (10). IDO also plays an important role in immune escape in cancer (5, 11 -13).…”