A Potential Role of Indoleamine 2,3-Dioxygenase–Specific T cells in Leishmania Vaccination

To the Editor—In a recent issue of the Journal, Makala and colleagues elegantly describe that indoleamine 2,3dioxygenase (IDO) is increased in lymph nodes in cutaneous Leishmania major infection [1]. IDO is implicated in suppressing T-cell immunity to parasite antigens, and IDO inhibition reduced local inflammation and parasite burdens. IDO is an immunoregulatory enzyme implicated in immunity under normal and pathological settings [2], and provides a potential mechanism for the development of dendritic cell (DC)–mediated T-cell tolerance [3]. IDO DCs inhibit T-cell proliferation due to tryptophan depletion and accumulation of toxic tryptophan metabolites [2]. IDO may be relevant to the outcome of immunotherapy as an inflammation-induced counter-regulatory mechanism, and may be induced by both type I and II interferons, which are found at sites of immune activation and inflammation [4]. Counter-regulatory responses are important as they help to limit the intensity and extent of immune responses, which otherwise could cause dangerous damage to the host. However, with regard to vaccination, counter-regulatory responses antagonize the ability to create an intense immune response against the target. The findings by Makala et al support a counter-regulatory role for IDO that benefits the pathogen, not the host. In this regard, an interesting aspect of IDO is that systemic inactivation at the organism level, either pharmacologically or genetically, does not appear to cause autoimmunity [5]. IDO may not be involved in tolerance to self, but rather in tolerance to nonself antigens, where immune non-responsiveness may be important, for example, fetal antigens [5]. Induction of IDO tolerogenic DCs occurs during infection of DCs with viruses and intracellular pathogens, such as Listeria monocytogenes. We have described that peptides comprised in the IDO protein sequence are spontaneously recognized by cytotoxic T cells in cancer patients [6] and healthy individuals [7]. IDO-reactive T cells recognized and killed IDO-expressing cells, for example, tumor cells or regulatory DCs. Importantly, the presence of such IDO-specific CD8 T cells boosted T-cell immunity against viral or tumor-associated antigens by eliminating IDO suppressive cells, thereby directly targeting the IDO-dependent counterregulatory pathway. The direct killing of IDO-expressing cells diminished IDOmediated suppression of effector T cells and decreased the local Treg suppression by reprogramming Tregs to acquire a proinflammatory Th17-like phenotype under influence of increased interleukin-6 production. It was recently described that Treg cells can undergo rapid reprogramming into activated T-helper cells after vaccination in combination with toll-like receptor 9 [8]. The conversion of the Tregs was suppressed by tumor-induced IDO expression. The pharmacologic inhibition of IDO restored Treg cell reprogramming, vaccine efficacy, and antitumor CD8 T-cell responses. Thus, reprogramming of