title: Dynamics of antigen presentation to transgene product-specific CD4+T cells and of Treg induction upon hepatic AAV gene transfer.
abstract: The tolerogenic hepatic microenvironment impedes clearance of viral infections but is an advantage in viral vector gene transfer, which often results in immune tolerance induction to transgene products. Although the underlying tolerance mechanism has been extensively studied, our understanding of antigen presentation to transgene product-specific CD4+T cells remains limited. To address this, we administered hepatotropic adeno-associated virus (AAV8) vector expressing cytoplasmic ovalbumin (OVA) intowtmice followed by adoptive transfer of transgenic OVA-specific T cells. We find that that the liver-draining lymph nodes (celiac and portal) are the major sites of MHC II presentation of the virally encoded antigen, as judged byin vivoproliferation of DO11.10 CD4+T cells (requiring professional antigen-presenting cells,e.g., macrophages) and CD4+CD25+FoxP3+Treg induction. Antigen presentation in the liver itself contributes to activation of CD4+T cells egressing from the liver. Hepatic-induced Treg rapidly disseminate through the systemic circulation. By contrast, a secreted OVA transgene product is presented in multiple organs, and OVA-specific Treg emerge in both the thymus and periphery. In summary, liver draining lymph nodes play an integral role in hepatic antigen presentation and peripheral Treg induction, which results in systemic regulation of the response to viral gene products.
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Perrin
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Zolotukhin
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sherman
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA.
authors.forename: Moanaro
authors.initials: M
authors.lastname: Biswas
authors.affiliation: Division of Gastroenterology and Hepatology, Weill Cornell Medicine , New York, New York, USA.
authors.forename: Ype P
authors.initials: YP
authors.lastname: de Jong
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, Massachusetts, USA.
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital , Memphis, Tennessee, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA.
authors.forename: Roland W
authors.initials: RW
authors.lastname: Herzog