AuthOr’s VIew OncoImmunology 1:7, 1211-1212; October 2012; © 2012 Landes Bioscience AuthOr’s VIew CD4 responses against IDO Mads h ald Andersen Center for Cancer Immune t herapy (CCIt ); Department of hematology; Copenhagen university hospital; herlev, Denmark Keywords: IDO, CD4, antigen, immune regulation, Th17, Th1 Natural indoleamine-2,3-dioxygenase (IDO)-reactive CD4+ t cells have been shown to release interferon γ (IFNγ), tumor necrosis factorα (t NFα), as well as interleukin 17 (IL-17). In some individuals, these cells also demonstrated the ability to suppress IL-10 production. IDO-specific CD4+ helper t cells among peripheral blood lymphocytes may participate in immunoregulatory networks by delaying the immune suppressive actions of IDO. h owever, IDO-specific CD4+ t cells may also have a regulatory phenotype, de facto exerting immunosuppressive functions. Natural Anti-IDO CD4+ T-cell Responses Indoleamine-2,3-dioxygenase (IDO) underpin a significant counter-regulatory mechanism induced by pro-inflamma- tory signals such as interferonγ (IFNγ). Recently, we described cytotoxic CD8+ T-cell reactivity toward IDO both in cancer patients as well as in healthy indi- viduals.1 We showed that the presence of such IDO-specific CD8+ T cells boosts T-cell immunity against viral as well as tumor-associated antigens by eliminating IDO+ suppressive cells, suggesting a role of such effector T cells in the regulation of immune responses. This made us scru- tinize CD4+ IDO-specific T cells. Indeed, the release of pro-inflammatory cytokines by CD4+ IDO-specific T cells may be important as a counter-response to IDO- induced immunosuppression. Hence, we first sat out to analyze if CD4+ T cells nat- urally recognize IDO. In this respect, we frequently observed detectable numbers of IDO-specific CD4+ T cells in cancer patients and, to a lesser extent, in healthy individuals.2 Thus, we identified a Class II-restricted IDO-derived CD4+ T-cell epi- tope in the vicinity of a previously described Class I-restricted IDO-epitope. We found that IDO-specific CD4+ T cells released IFNγ as well as tumor necrosisα (TNFα). The cancer relevance of these CD4+ T cells was further emphasized by the findings that IDO-specific T-cells reacted toward dendritic cells (DCs) pulsed with IDO+ tumor lysates. Interestingly, we detected a correlation between the presence of IDO-specific CD4+ cells and CD8+ T-cell responses against IDO, suggesting that MHC Class I- and Class II-restricted IDO responses co-develop (Fig. 1). In contrast to Th1 cytokines, we could not detect any release of inteleukin 4 (IL-4, a prototypic Th2 cytokine) in response to the IDO- derived CD4 epitope.2 Th17 Cells Since the release of IL-17 is mediated by a very specific subset of CD4+ T-helper cells (Th17 cells), IL-17 has recently been the focus of great interest. Upon stimulation with the IDO-derived CD4 epitope, we frequently detected IDO-specific CD4+ T cells that released IL-17. Th17 cells are thought to be particularly important in maintaining barrier immunity at muco- sal surfaces such as the gut and skin.3 Interestingly, IDO is expressed at high lev- els in the gastrointestinal tract, although its precise role in intestinal immunity is not well understood.4 One could speculate that a fraction of Th17 cells that are highly prevalent at the mucosal tissues of healthy individuals3 is recognizing IDO. Th17 cells might have been proposed to play a protective role against cancer. Tumor- infiltrating Th17 cells express other cyto- kines in addition to IL-17, which may be functionally relevant. These include Correspondence to: Mads Hald Andersen; Email: mads.hald.andersen@regionh.dk Submitted: 05/09/12; Accepted: 05/16/12 http://dx.doi.org/10.4161/onci.20687 IFNγ, TNFα as well as IL-2.5 IDO- specific Th17 cells appeared to exhibit a similar effector T-cell cytokine profile.2 Recently, a FOXP3+ T regulatory (Treg) cell lineage was described that could be redirected to become “Th17-like effector cells”.7 It was suggested that these CD4+ cells correspond to a pool of constitutively primed “first responder” cells capable of rapid suppression as well as of supply- ing help when redirected by the innate immune system.7 IDO may play a vital role in the conversion of such FOXP3+ Tregs to Th17-like effector cells and hence it could be speculated that IDO-specific T cells may be such constitutively primed “first responder” Th17-like T cells. Regulatory T Cells To examine if CD4+ IDO-specific T cells may also function as immune suppressive cells we examined IL-10 release in response to the IDO-derived CD4 epitope. IL-10 is mainly expressed by Tregs.6 In some individuals, we could indeed detect IL-10 responses. Thus, IDO-specific Tregs may enhance IDO-mediated immunosuppres- sion, thus protecting cancer cells from an immune attack. Along similar lines, spe- cific regulatory CD8+ T cells in cancer patients have been described to recognize another immunosuppressive molecule, heme oxygenase 1.8 Interestingly, in some instances, we detected background IL-10 release in vitro, by ELISPOT assays on cells www.landesbioscience.com OncoImmunology 1211