Figure 1. u pregulation of indoleamine-2,3-dioxygenase expression is an early event in antigen- presenting cells, since it is induced by pro-inflammatory signals. Indoleamine-2,3-dioxygenase (IDO) protein is processed and IDO-derived peptides are presented on the cell surface of antigen- presenting cells (APCs) by Class II h LA molecules, from where they are recognized by CD4+ t cells. t he release of pro-inflammatory cytokines by CD4+ IDO-specific t cells may be important as a counter-response to IDO-induced immunosuppression. t hese CD4+ t cells may indeed help overcoming the immunosuppressive effects of IDO in the early phases of inflammatory responses. Moreover, IDO-specific CD4+ t cells may promote CD8 + cytotoxic t -cell responses, including anti-CMV and anti-IDO responses. IDO-specific CD8+ t cells may further boost t -cell immunity by eliminating IDO+ suppressive cells, for instance by releasing granzyme B (GrB) and perforins. from pre-stimulated subjects. This enabled us to recognize that stimulation with the IDO-derived peptide in two healthy donors triggered an overall suppression of IL-10. In this regard, we have previously observed a decrease in IL-10 when IDO- specific CD8+ T cells were present.1 Thus, the role of IDO-specific CD4+ T cells in immunoregulatory networks may be a complex balance between activation and inhibition, with a predominant role played by the local microenvironment. Correlation with Cytomegalovirus Immunity Cytomegalovirus (CMV) is the most immunodominant antigen to be encoun- tered by the human immune system.9 The CD8+ T-cell response to CMV typically consists of a sizeable percentage of the total CD8+ T-cell repertoire in CMV- seropositive individuals. Monocytes are major CMV target cells in vivo, and CMV has been shown to induce IDO expres- sion in these cells. Such an expression of IDO is believed to confer an advantage to CMV-infected monocytes, de facto facili- tating their escape from T-cell responses.10 We observed that the presence of IDO- specific CD4+ T-cell responses corre- lated with the presence of CMV-directed responses.2 In light of this, it could well be possible that the observed IDO-specific T cell responses have developed as a sup- port for constitutive anti-CMV T-cell responses in the individuals. Conclusions In conclusion, we have described the pres- ence of naturally occurring IDO-specific CD4+ T-helper cells. Many questions remain unanswered, however, regarding the basic properties of IDO-specific T cells and the potential role of these cells in the regulation of immune responses. We suggest that the activation of such CD4+ cells could help overcoming the immu- nosuppressive actions of IDO, which oth- erwise result from the early expression of IDO in maturing antigen-presenting cells. However, since IDO-specific CD4+ T cells may also secrete immunoregulatory cyto- kines, the balance between immune acti- vation and inhibition may depend largely on the local microenvironment. References 1. Sørensen RB, Hadrup SR, Svane IM, Hjortsø MC, Thor Straten P, Andersen MH. Indoleamine-2,3- dioxygenase specific, cytotoxic T cells as immune regu- lators. Blood 2011; 117:2200-10; PMID:21079151. 2. Munir S, Larsen SK, Iversen TZ, Donia M, Klausen TW, Svane IM, et al. Natural CD4(+) T-Cell Responses against Indoleamine-2,3-Dioxygenase. PLoS One 2012; 7:34568; PMID:22539948. 3. O’Quinn DB, Palmer MT, Lee YK, Weaver CT. Emergence of the Th17 pathway and its role in host defense. Adv Immunol 2008; 99:115-63. 4. Cherayil BJ. Indoleamine-2,3-dioxygenase in intestinal immunity and inflammation. Inflamm Bowel Dis 2009; 15:1391-6; PMID:19322906. 5. Martin-Orozco N, Muranski P, Chung Y, Yang XO, Yamazaki T, Lu S, et al. T helper 17 cells promote cyto- toxic T cell activation in tumor immunity. Immunity 2009; 31:787-98; PMID:19879162. 6. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005; 6:345-52; PMID:15785760. 7. Sharma MD, Hou DY, Baban B, Koni PA, He Y, Chandler PR, et al. Reprogrammed foxp3(+) regula- tory T cells provide essential help to support cross- presentation and CD8(+) T cell priming in naive mice. Immunity 2010; 33:942-54; PMID:21145762. 8. Andersen MH, Sørensen RB, Brimnes MK, Svane IM, Becker JC, thor Straten P. Identification of heme oxygenase-1-specific regulatory CD8+ T cells in cancer patients. J Clin Invest 2009; 119:2245-56; PMID:19662679. 9. Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al. Broadly targeted human cyto- megalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 2005; 202:673-85; PMID:16147978. 10. Furset G, Fløisand Y, Sioud M. Impaired expres- sion of indoleamine-2,3-dioxygenase in monocyte- derived dendritic cells in response to Toll-like recep- tor-7/8 ligands. Immunology 2008; 123:263-71; PMID:17725606. 1212 OncoImmunology Volume 1 Issue 7