Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators

Abstract

Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in normal and pathologic settings. Here, we describe that spontaneous cytotoxic T-cell reactivity against IDO exists not only in patients with cancer but also in healthy persons. We show that the presence of such IDO-specific CD8 ؉ T cells boosted T-cell immunity against viral or tumor-associated antigens by eliminating IDO ؉ suppressive cells. This had profound effects on the balance between interleukin-17 (IL-17)-producing CD4 ؉ T cells and regulatory T cells. Furthermore, this caused an increase in the production of the proinflammatory cytokines IL-6 and tumor necrosis factor-␣ while decreasing the IL-10 production. Finally, the addition of IDO-inducing agents (ie, the TLR9 ligand cytosinephosphate-guanosine, soluble cytotoxic T lymphocyte-associated antigen 4, or interferon ␥) induced IDO-specific T cells among peripheral blood mononuclear cells from patients with cancer as well as healthy donors. In the clinical setting, IDO may serve as an important and widely applicable target for immunotherapeutic strategies in which IDO plays a significant regulatory role. We describe for the first time effector T cells with a general regulatory function that may play a vital role for the mounting or maintaining of an effective adaptive immune response. We suggest terming such effector T cells "supporter T cells." (Blood. 2011;117(7): 2200-2210) IntroductionInduction of tolerance, which is a central mechanism counteracting tumor-specific immunity and preventing effective anticancer immune therapy, requires a specific environment in which tolerogenic dendritic cells (DCs) play an essential role deviating the immune response away from effective immunity. It was recently shown that IDO provides a potential mechanism for the development of DC-mediated T-cell tolerance. IDO ϩ DCs inhibit T-cell proliferation because of tryptophan depletion and accumulation of toxic tryptophan metabolites. 1,2 IDO ϩ DCs have been shown to induce T-cell anergy or generation of regulatory T cells (Tregs). In patients with cancer, IDO elevation occurs in a subset of plasmacytoid DCs in tumor-draining lymph nodes. 3 In addition, most human tumors overexpress IDO. 4 Activation of IDO in either tumor cells or nodal regulatory DCs each appears to be sufficient to facilitate tumoral immune escape. 2 IDO may help in tilting the tumor microenvironment from hostile to supportive for tumor cells and also may elaborate a peripheral mechanism of immune escape that could facilitate tumor progression. 5,6 Tregs have been defined as a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens. 7,8 Subsequently, they are additionally termed suppressor T cells. Tregs exist to down-regulate immune responses in various inflammatory circumstances and ultimately assure peripheral T-cell tolerance. The best-characterized subset of these immune sup...

Long-lasting Disease Stabilization in the Absence of Toxicity in Metastatic Lung Cancer Patients Vaccinated with an Epitope Derived from Indoleamine 2,3 Dioxygenase

“…Noteworthy, we found a trend toward higher pretreatment levels of IDO-specific T cells in the SDþPR patients compared with the PD patients. Thus, our data indicate that the SDþPR patients had a higher level of T cells primed for an IDO response, which is in accordance with previously suggested IDO immunity (7). In addition, we utilized the MHC peptide tetramer technology to directly visualize IDO-specific T cells.…”

“…We recently described that IDO-reactive T cells are able to recognize and kill tumor cells as well as IDO-expressing dendritic cells, that is, one of the major immune-suppressive cell populations (6,7). Consequently, IDO may serve as an important and widely applicable target for anticancer immunotherapeutic strategies.…”

Spontaneous Cytotoxic T-Cell Reactivity against Indoleamine 2,3-Dioxygenase-2

“…Hence, it is still a question how IDO2-specific T cells are activated in healthy individuals in vivo and what, if any, potential role such IDO2-specific T cells play in immune regulation. It may be possible that the sizable reactivity to this antigen in normal individuals contributes to immune surveillance against cancer as we have recently shown that IDO1-specific T cells isolated from healthy individuals were cytotoxic toward IDO1-expressing cells in a similar manner as IDO1-specific T cells isolated from cancer patients (20). However, it still needs to be verified that the IDO2-specific class I-restricted lymphocytes in peripheral blood of healthy subjects are indeed cytolytic for IDO2-expressing cells in vivo.…”

Response to Comment on “Myeloid-Derived Suppressor Cells Suppress Antitumor Immune Responses through IDO Expression and Correlate with Lymph Node Metastasis in Patients with Breast Cancer”

“…Therefore, it is questionable whether current IDO inhibitors are optimal candidates for clinical application, and more therapeutic strategies targeting IDO are needed. As reported in your study (7), the strategy of inducing endogenic cytotoxic immune cells, such as "supporter T cells," to suppress IDO 1 cells provides new insights into clinical regulation of IDO. In addition, targeting the signaling pathway mediating IDO expression is also a promising strategy that attracts considerable…”