Indoleamine 2,3-Dioxygenase Activity Contributes to Local Immune Suppression in the Skin Expressing Human Papillomavirus Oncoprotein E7 Deepak Mittal,

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Indoleamine 2,3-Dioxygenase Activity Contributes to Local Immune Suppression in the Skin Expressing Human Papillomavirus Oncoprotein E7 Deepak Mittal, Andrew J. Kassianos, Lee S. Tran, Anne-Sophie Bergot, Christine Gosmann, Janin Hofmann, Antje Blumenthal, Graham R. Leggatt, Ian H. Frazer Journal of Investigative Dermatology Volume 133, Issue 12, Pages 2686-2694 (December 2013) DOI: 10.1038/jid.2013.222 Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Inhibition of indoleamine 2,3-dioxygenase (IDO) activity promotes K14E7 graft rejection. (a) Schematic representation of the administration of 2mgml−1 1-methyl-dl-tryptophan (1-D/L-MT) in the drinking water of donor (C57Bl/6 and K14E7) and recipient C57Bl/6 (C57) mice before and after grafting. (b) Kaplan–Meier survival curves of C57, K14E7, and K14E7 grafts deficient in CD1d (CD1d−/−E7) on immunocompetent C57 recipient mice. C57 and K14E7 grafts were treated or not with 1-D/L-MT before and after the grafting. Median graft survival: K14E7+1-D/L-MT=47 days; C57+1-D/L-MT=undefined (P=0.02, log-rank test; n=8 mice per group for K14E7 and C57 grafts; n=4 for CD1d−/−E7 grafts). (c) IDO activity (kynurenine/tryptophan (Kyn/Trp)) from the serum of C57 mice transplanted with K14E7 grafts treated or not with 1-D/L-MT for 28 days after grafting. Journal of Investigative Dermatology 2013 133, 2686-2694DOI: (10.1038/jid.2013.222) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Indoleamine 2,3-dioxygenase (IDO1) expression in K14E7 skin is dependent on IFN-γ and invariant natural killer T (iNKT) cells. Expression of mRNA for (a) IDO1, (b) IDO2, and (d) tryptophan 2,3-dioxygenase (TDO) relative to RPL32 (L32) determined by real-time PCR in the ear skin of K14E7 and nontransgenic C57 mice. (c) IDO activity as measured by HPLC from the ear skin lysates of K14E7 and C57 mice. (n=10 for K14E7; n=7 for C57.) Expression of mRNA for (e) IDO1 and (f) IDO2 relative to L32 by real-time PCR in the ear skin of C57, K14E7, and K14E7 mice deficient in Jα18 (Jα18−/−E7), CD1d (CD1d−/−E7), IFN-γ (IFN-γ−/−E7), or IFN-γ receptor (IFN-γR−/−E7). IDO activity as measured by HPLC from (g) ear skin lysates and (h) serum of C57, K14E7, Jα18−/−E7, CD1d−/−E7, IFN-γ−/−E7, and IFN-γR−/−E7. Kyn/Trp, kynurenine/tryptophan; NS, not significant. n=14 for K14E7 and n=10 for C57; n≥4 for other mice. Journal of Investigative Dermatology 2013 133, 2686-2694DOI: (10.1038/jid.2013.222) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Skin dendritic cells (DCs) in K14E7 mice express high levels of IFN-γR. (a) Histogram plots showing flow cytometry staining for surface IFN-γ receptor (IFN-γR; unfilled black histograms) and isotype controls (filled gray histograms) in the ear skin of C57 (top), K14E7 (middle), and IFN-γ−/−E7 (bottom) mice. (b) Bar graph shows surface levels of IFN-γR expression on DCs from ear skin of C57 (white), K14E7 (black), and IFN-γ−/−E7 (gray) mice shown as δMFI (mean fluorescence intensity; δMFI=MFI of IFN-γR mAb-MFI of isotype control mAb). IFNγR−/−E7 mice (line bar) were used as a negative control for IFNγR staining. Mean+SEM; n=4 mice per group for K14E7 and IFN-γ−/−E7; n=6 for C57 mice, data pooled from two independent experiments. Journal of Investigative Dermatology 2013 133, 2686-2694DOI: (10.1038/jid.2013.222) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Dendritic cell (DC) infiltrates in K14E7 skin express indoleamine 2,3-dioxygenase 1 (IDO1) that is dependent on IFN-γR on DCs. (a) Flow cytometry plot showing CD3 and CD11c staining (left) on the skin cells pregated on CD45+ live cells. Histogram plot showing intracellular staining for IDO1 (filled black histogram) and isotype controls (filled gray histogram) in CD3+ lymphocytes and CD11c+ cells from K14E7, C57, and IFN-γR−/−E7 mice. (b) Bar graph shows representative FACS data as the percentage of IDO1-positive DCs in the skin of C57, K14E7, and IFN-γR−/−E7 mice. Mean+SEM; n=4 mice per group for K14E7 and IFN-γ−/−E7; n=6 for C57 mice. (c) FACS plot showing gating strategy for sorting resident (CD11c+MHCint) and migratory (CD11c+MHChi) DCs. MHC, major histocompatibility complex. (d) mRNA expression of IDO1 relative to RPL32 by real-time PCR in the resident (res) and migratory (mig) DCs sorted from the skin-draining lymph nodes of K14E7 mice. ND, not detectable. (e) Bar graph shows absolute number of MHCII+CD11c+ DCs (representative of FACS data) in the ear skin of C57, K14E7, IFN-γ−/−E7, and IFN-γR−/−E7 mice. Journal of Investigative Dermatology 2013 133, 2686-2694DOI: (10.1038/jid.2013.222) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Indoleamine 2,3-dioxygenase 1 (IDO1) is expressed by langerin−ve dendritic cells (DCs). (a) Dot plot shows classical dermal DCs (CD11b+CD207−), Langerhans cells (CD207+CD103−), and CD207+CD103+ DCs in the skin of K14E7 mice gated on live CD45+CD11c+MHCII+ cells. MHC, major histocompatibility complex. Absolute number of (b) classical dermal DC, (c) Langerhans cells, and (d) CD103+ dermal DCs subsets in the ear skin of C57 and K14E7 mice (mean+SEM; n=4 mice per group for K14E7 and n=6 for C57 mice). (e) Isotype control and (f) real staining for IDO1 and CD207, pregated on CD11c+MHCII+ cells, in the ear skin of K14E7 mice. (g) Proliferation of splenic CD8 cells cultured with splenic DCs (DC/T/irradiated feeder cells 1:5:5) from K14E7 and IFN-γR−/−E7 mice with or without 1-MT (1mM) and IFN-γ (10ngml−1). Results are expressed as mean counts per minute (c.p.m.)±SEM of triplicate wells. Journal of Investigative Dermatology 2013 133, 2686-2694DOI: (10.1038/jid.2013.222) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Elevated indoleamine 2,3-dioxygenase 1 (IDO1) and IFN-γ mRNA expression in cervical intraepithelial neoplasia (CIN) lesions. (a) mRNA expression of human IDO1, (b) IDO2, and (c) IFN-γ relative to HPRT by real-time PCR in biopsies of normal (NT) cervical epithelium and CIN 2/3 (CIN) tissue. Mean+SEM; n=7. IDO2 expression was not detectable in most of the samples analyzed. Journal of Investigative Dermatology 2013 133, 2686-2694DOI: (10.1038/jid.2013.222) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions