Progress has been made in several of the aims of the project, in particular on the role of TLR signaling in regulating proliferation and survival of fibroblasts and dendritic cells, on the regulation of cytokine production from human DC, on the role of plasmacytoid DC in regulating oral tolerance, on the effect of NK cells on Th1 differentiation in Toxoplasma Gondii infection, role of TNF, MyD88 and IL-18 in colitis-dependent carcinogenesis. Hepatic plasmacytoid dendritic cells contribute to orally induced CD8+ T cell tolerance (Immunity. 2008;9:464-75). The liver is thought to contribute to systemic T cell tolerance to orally absorbed antigens, although the precise mechanism of its tolerogenic effect is unclear. Here we show that the liver is a site of oral antigen presentation and that hepatic dendritic dells (DC) can tolerize mice to subsequent CD8+ T cell priming, in a model of hapten-specific contact sensitivity (CHS). The tolerogenic potential of liver DC is confined to plasmacytoid DC (pDC), is enhanced by exposure to hapten, and requires CD4+ T cells. Finally, in vivo depletion of pDC abrogated oral tolerance and restored hapten-specific CD8+ T cell and CHS responses. Thus, pDC are tolerogenic and play an essential role in oral tolerance. These studies are now being extended to analyze the role of liver pDC in other model of tolerance and in particular in testing whether pDC are require to induce TNBS tolerance in a model of colitis and carcinogenesis. We have generate a mouse expressing the human Dyptheria Toxin Receptor and the Green Fluorescent protein specifically on pDC. These mice can be used for the identication and in vivo depletion of pDC and they will be used in experiments aimed to identify and deplete pDCs in vivo. In addition to the models of oral tolerance we have established that TLR9-activated pDC in the intestinal lamina propria prevent the conversion of naive CD4 T cells in FoxP3+ Treg and we are estending our studies to other models in which pDCs are involved in immunoregulation. Toxoplasma gondii infected TAP1 deficient mice display impaired NK cell IFN-gamma production leading to defective CD4+ T cell priming and increased mortality (J Exp Med. 2007, 204:2591-602). To investigate if Transporter Associated with Antigen Processing (TAP)1 is required for CD8+ T cell mediated control of Toxoplasma gondii in vivo, we compared the resistance of TAP1-/-, CD8-/- and wild-type (WT) mice to infection with the parasite. Surprisingly TAP1-/- mice displayed greater susceptibility than either CD8-/- or WT mice to infection with an avirulent parasite strain. The decreased resistance of the TAP1-/- mice correlated with a reduction in the frequency of activated and IFN-gamma-producing CD4+ T cells. Interestingly, infected TAP1-/- mice showed a reduced frequency of IFN-gamma producing natural killer (NK) cells relative to that of WT controls, and after NK cell-depletion both CD8-/- and WT mice succumbed to infection with the same kinetics as TAP1-/- animals and displayed impaired CD4+T cell IFN-gamma responses. Together, these results reveal a previously unappreciated role for TAP1 in the induction of IFN-gamma producing NK cells and provide the first demonstration of the function of this cell population in the priming of CD4+ T lymphocyte responses to T. gondii infection. These studies are now being extended to understand the difference between the TAP1-/- and beta2microglobulin-/- in this function of NK cells and the possible role of NKT cells in the regulation of NK activity. Innate resistance and pro-inflammatory cytokines in carcinogenesis. A very extensive investigation has been initiated to study the role of inflammatory receptors and cytokines in skin and colon chemical carcinogenesis. Following our early observation that MyD88-/- are resistant to skin carcinogenesis, we have now showed that MyD88 expression is required both in radioresistant skin cells as well as in hematopoieitc cells and that MyD88-/- keratinocytes are very altered in their gene expression pattern after Ras transformation in vitro, suggesting that this altered pattern of gene expression may be responsible for the lack of polyps formation in response to chemical carcinogenesis. In the colon, MyD88 deficiency resulted in an increased susceptibility to DSS induced colitis that surprisingly was associated with a highly increased susceptibility to chemically induced carcinogenesis. The MyD88 phenotype was in part due to lack of signaling through the IL-18 receptor in the MyD88-/- cells. We also observed that TNF is required for colitis-dependent carcinogenesis but, interestingly, TNF produced by the enterocytes was required for carcinogenesis whereas T cells and macrophages produced TNF had an antitumor effect. These results indicate that TNF, a molecule described originally for its anti-tumor activity but then described as a required factor for carcinogenesis, has indeed a dual role and its anti-tumor and pro-tumor activity depend by which cells it is produced and probably by its temporal production by different cell types during the carcinogenesis processes.
| Perez-Chanona, Ernesto; Trinchieri, Giorgio (2016) The role of microbiota in cancer therapy. Curr Opin Immunol 39:75-81 |
| Bodogai, Monica; Moritoh, Kanako; Lee-Chang, Catalina et al. (2015) Immunosuppressive and Prometastatic Functions of Myeloid-Derived Suppressive Cells Rely upon Education from Tumor-Associated B Cells. Cancer Res 75:3456-65 |
| Trinchieri, Giorgio (2015) Cancer Immunity: Lessons From Infectious Diseases. J Infect Dis 212 Suppl 1:S67-73 |
| Dzutsev, Amiran; Trinchieri, Giorgio (2015) Proteus mirabilis: The Enemy Within. Immunity 42:602-4 |
| Ridnour, Lisa A; Cheng, Robert Y S; Weiss, Jonathan M et al. (2015) NOS Inhibition Modulates Immune Polarization and Improves Radiation-Induced Tumor Growth Delay. Cancer Res 75:2788-99 |
| Viaud, S; Daillère, R; Boneca, I G et al. (2015) Gut microbiome and anticancer immune response: really hot Sh*t! Cell Death Differ 22:199-214 |
| Levay, Agata; Brenneman, Randall; Hoinka, Jan et al. (2015) Identifying high-affinity aptamer ligands with defined cross-reactivity using high-throughput guided systematic evolution of ligands by exponential enrichment. Nucleic Acids Res 43:e82 |
| Dzutsev, Amiran; Goldszmid, Romina S; Viaud, Sophie et al. (2015) The role of the microbiota in inflammation, carcinogenesis, and cancer therapy. Eur J Immunol 45:17-31 |
| de Matos-Neto, Emidio M; Lima, Joanna D C C; de Pereira, Welbert O et al. (2015) Systemic Inflammation in Cachexia - Is Tumor Cytokine Expression Profile the Culprit? Front Immunol 6:629 |
| Cella, Marina; Trinchieri, Giorgio (2014) A new VEGF connection between two old neighbors. Nat Immunol 15:8-9 |
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