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

Abstract

Chronic infection of anogenital epithelium with human papillomavirus (HPV) promotes development of cancer. Many pathogens evoke immunosuppressive mechanisms to enable persistent infection. We have previously shown that grafted skin expressing HPV16 E7 oncoprotein from a keratin-14 promoter (K14E7) is not rejected by a syngeneic, immunocompetent host. In this study we show that indoleamine 2, 3-dioxygenase (IDO) 1, an IFN-γ inducible immunoregulatory molecule, is more highly expressed by langerin−ve dermal dendritic cells from K14E7 skin than nontransgenic control skin. Furthermore, inhibiting IDO activity using 1-D/L-methyl tryptophan promotes K14E7 skin graft rejection. Increased IDO1 expression and activity in K14E7 skin requires IFN-γ and iNKT cells, both of which have been shown to negatively regulate T-cell effector function and suppress K14E7 graft rejection. Further, dendritic cells from K14E7 skin express higher level of IFN-γ receptor (IFN-γR) than dendritic cells from control skin. K14E7 transgenic skin recruits significantly higher number of dendritic cells, independent of IFN-γ and IFN-γR expression. Consistent with these observations in a murine model, we found higher expression of IDO1 and IFN-γ but not IDO2 in the cervical epithelium of patients with HPV-associated cervical intraepithelial neoplasia (CIN) 2/3. Our data support a hypothesis that induction of IDO1 in HPV infected skin contributes to evasion of host immunity.

Human Papillomavirus E7 Oncoprotein Transgenic Skin Develops an Enhanced Inflammatory Response to 2,4-Dinitrochlorobenzene by an Arginase-1-Dependent Mechanism

“…We have previously shown that skin grafts expressing HPV16.E7 oncoprotein are not spontaneously rejected when transplanted onto syngeneic animals, but are rejected when certain components of the innate immune system are unavailable, confirming that expression of HPV16.E7 in the epithelium results in the establishment of a local suppressive environment and the subversion of antigen specific T cells (Mattarollo et al , 2010; Mittal et al , 2013). Therefore, successful strategies targeting HPV-associated cancer need to circumvent or disrupt the local suppressive environment.…”

IL-17 Suppresses Immune Effector Functions in Human Papillomavirus-Associated Epithelial Hyperplasia

“…These can develop into myeloid-derived suppressor cells (MDSC) at the tumor site and suppress T cell responses (42). Infiltrates of myeloid cells were also observed in HPV16 E7-driven hyperplastic skin (25), suggesting an IL-17-associated recruitment of myeloid cells and their subsequent development into MDSC as a possible mechanism responsible for impaired host effector T cell responses to K14E7 skin grafts, particularly as IDO expression is elevated in CIN2/3 lesions, and in K14E7 skin, and contributes to local immune regulation (43). However, numbers of CD11b + Gr-1 int MDSC were similar in K14E7 and E7 + IL-17 −/− grafts (Supplemental Figure 3), indicating that recruitment of MDSC into E7 + skin is IL-17-independent.…”

Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

“…In recent years, great advances have been made in understanding the role of amino acid metabolism of Arg and Trp during development of the immune response (49 -51). Hence, amino acid catabolic enzymes arginase and indoleamine 2,3-dioxygenase have been shown to have important immunoregulatory functions (52,53). BCATc is another amino acid catabolic enzyme that is described here as a novel immunoregulatory enzyme and indicates a role for Leu metabolism in the regulation of T cell metabolic reprograming.…”