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Immune Suppression'' Indoleamine 2,3-Dioxygenase-Dependent T Comment on ''Reduced Cytotoxic Function of Effector CD8 + T Cells Is Responsible for Indoleamine 2,3-Dioxygenase-Dependent Immune Suppression'' This information is current as of September 25, 2021. Rikke Bæk Sørensen, Per thor Straten and Mads Hald Andersen J Immunol 2009; 183:6040; ; doi: 10.4049/jimmunol.0990093 http://www.jimmunol.org/content/183/10/6040 Downloaded from References This article cites 1 articles, 1 of which you can access for free at: http://www.jimmunol.org/content/183/10/6040.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. 6040 LETTERS TO THE EDITOR than data from studies in which the function of 12/15-LOX is impaired by either gene deletion or inhibitors. Studies analyzing the role of 12/15-LOX in allergic disease are confounded by the complex involvement of this enzyme in eicosanoid pathways. Indeed, gene deletion of 12/15-LOX in mice induces compensatory substrate feedback mechanisms that influence the levels of cysteinyl leukotrienes (5, 6). While Mabalirajan et al. show that the 12/15-LOX inhibitor esculetin concomitantly inhibits allergic responses and 12/15-LOX (7), the use of this inhibitor in drawing any conclusion for the role of 12(S)- HETE in allergic disease is seriously undermined by the observa- tion that esculin is also a potent inhibitor of 5-LOX and leukotri- ene synthesis and promotes prostaglandin synthesis (8, 9). While the correspondence from Mabalirajan et al. suggests that we should exercise caution in translating in vitro observa- tions to in vivo correlates, we consider extrapolating findings from protein-protein interaction studies and in vitro cell culture systems to the proof of principle experiment showing that al- Downloaded from lergic mice treated with exogenous 12(S)-HETE develop atten- uated disease to be a logical and reasonable process. Dianne C. Webb John Curtin School of Medical Research http://www.jimmunol.org/ Australian National University Canberra, Australia References FIGURE 1. A, Example of increase in specific CD8ϩ T cell immunity 1. Cai, Y., R. K. Kumar, J. Zhou, P. S. Foster, and D. C. Webb. 2009. Ym1/2 promotes Th2 cytokine expression by inhibiting 12/15(S)-lipoxygenase: identification of a novel by L-1MT against viral epitopes (CMVpp65495–503, EBVbmlf1280–288, and ␥ 6 pathway for regulating allergic inflammation. J. Immunol. 182: 5393–5399. FLUmatrix p58–66) using IFN- ELISPOT. Top row,10 PBMC per well; 2. Mabalirajan, U. J. Aich, G. D. Leishangthem, S. K. Sharma, A. K. Dinda, and B. bottom row,5ϫ 105 PBMC per well. B, PBMC from cancer patients (n ϭ Ghosh. Effects of vitamin E on mitochondrial dysfunction and asthma features in an 19; ⅷ) and healthy donors (n ϭ 6; ⅜). experimental allergic murine model. J. Appl. Physiol. In press. 3. Webb, D. C., A. N. McKenzie, and P. S. Foster. 2001. Expression of the Ym2 lectin by guest on September 25, 2021 binding protein is dependent on interleukin (IL)-4 and IL-13 signal transduction: iden- cell function can be restored using the IDO blocker L-1-methyl- tification of a novel allergy-associated protein. J. Biol. Chem. 276: 41969–41976. 4. Spector, A. A., J. A. Gordon, and S. A. Moore. 1988. Hydroxyeicosatetraenoic acids tryptophan (L-1MT). We have extrapolated these very impor- (HETEs). Prog. Lipid Res. 27: 271–323. tant data from a rat model to the human system by showing that 5. Sun, D., and C. D. Funk. 1996. Disruption of 12/15-lipoxygenase expression in peri- the addition of L-1MT to human PBMC increases the specific toneal macrophages: enhanced utilization of the 5-lipoxygenase pathway and dimin- ϩ ished oxidation of low density lipoprotein. J. Biol. Chem. 271: 24055–24062. immunity of human CD8 T cells. Hence, in PBMC from six 6. Hajek, A. R., A. R. Lindley, S. Favoreto, Jr., R. Carter, R. P. Schleimer, and D. A. of 25 examined individuals we observed a major increase in spe- Kuperman. 2008. 12/15-Lipoxygenase deficiency protects mice from allergic airways ϩ inflammation and increases secretory IgA levels. J. Allergy Clin. Immunol. 122: cific T cell reactivity against known viral CD8 epitopes by the 633–639. addition of L-1MT (Fig. 1). Importantly, a decrease in T cell 7. Mabalirajan, U., A. K. Dinda, S. K. Sharma, and B. Ghosh. 2009. Esculetin restores mitochondrial dysfunction and reduces allergic asthma features in experimental murine reactivity after the addition of L-1MT was not seen in any of the ϩ model. J. Immunol. 183: 2059–2967. examined individuals. The inhibition of CD8 T cell function 8. Neichi, T., Y. Koshihara, and S. Murota. 1983. Inhibitory effect of esculetin on 5-li- poxygenase and leukotriene biosynthesis. Biochim. Biophys. Acta 753: 130–132. by IDO makes the combination of IDO-blocking and anti- 9. Du, L., Z. Zhang, X. Luo, K. Chen, X. Shen, and H. Jiang. 2006. Binding investigation cancer immunotherapy very appealing. Hence, IDO inhibitor of human 5-lipoxygenase with its inhibitors by SPR technology correlating with mo- lecular docking simulation. J. Biochem. 139: 715–723. drugs might potentially enhance the efficacy of vaccine-induced immune responses in cancer like that of the viral responses de- www.jimmunol.org/cgi/doi/10.4049/jimmunol.0990092 scribed here. Liu et al. provide a very interesting model for fur- ther examination of the immune-suppressing actions of IDO. Comment on “Reduced Cytotoxic This inflammation-induced counter-regulatory mechanism may .Function of Effector CD8؉ T Cells be highly relevant to the outcome of immunotherapy of cancer Is Responsible for Indoleamine Rikke Bæk Sørensen, Per thor Straten, 2,3-Dioxygenase-Dependent and Mads Hald Andersen Immune Suppression” Herlev University Hospital Herlev, Denmark ndoleamine 2,3-dioxygenase exerts an immunosuppres- sive function in, e.g., cancer. Liu and colleagues show in an References 1. Liu, H., L. Liu, K. Liu, P. Bizargity, W. W. Hancock, and G. A. Visner. 2009. Reduced I elegant study in a rat model that an IDO-high environ- cytotoxic function of effector CD8ϩ T cells is responsible for indoleamine 2,3-dioxy- ment inhibits both proliferation and cytokine production as genase-dependent immune suppression. J. Immunol. 183: 1022–1031. ϩ ϩ well as the cytotoxicity of effector CD8 T cells (1). CD8 T www.jimmunol.org/cgi/doi/10.4049/jimmunol.0990093.
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