title: Glucocorticoid-Induced TNF Receptor Family-Related Protein Ligand is Requisite for Optimal Functioning of Regulatory CD4(+) T Cells.
abstract: Glucocorticoid-induced tumor necrosis factor receptor family-related protein (TNFRSF18, CD357) is constitutively expressed on regulatory T cells (Tregs) and is inducible on effector T cells. In this report, we examine the role of glucocorticoid-induced TNF receptor family-related protein ligand (GITR-L), which is expressed by antigen presenting cells, on the development and expansion of Tregs. We found that GITR-L is dispensable for the development of naturally occurring FoxP3(+) Treg cells in the thymus. However, the expansion of Treg in GITR-L (-/-) mice is impaired after injection of the dendritic cells (DCs) inducing factor Flt3 ligand. Furthermore, DCs from the liver of GITR-L (-/-) mice were less efficient in inducing proliferation of antigen-specific Treg cells in vitro than the same cells from WT littermates. Upon gene transfer of ovalbumin into hepatocytes of GITR-L (-/-)FoxP3(GFP) reporter mice using adeno-associated virus (AAV8-OVA) the number of antigen-specific Treg in liver and spleen is reduced. The reduced number of Tregs resulted in an increase in the number of ovalbumin specific CD8(+) T effector cells. This is highly significant because proliferation of antigen-specific CD8(+) cells itself is dependent on the presence of GITR-L, as shown by in vitro experiments and by adoptive transfers into GITR-L (-/-) Rag (-/-) and Rag (-/-) mice that had received AAV8-OVA. Surprisingly, administering αCD3 significantly reduced the numbers of FoxP3(+) Treg cells in the liver and spleen of GITR-L (-/-) but not WT mice. Because soluble Fc-GITR-L partially rescues αCD3 induced in vitro depletion of the CD103(+) subset of FoxP3(+)CD4(+) Treg cells, we conclude that expression of GITR-L by antigen presenting cells is requisite for optimal Treg-mediated regulation of immune responses including those in response during gene transfer.
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA.
authors.forename: Gongxian
authors.initials: G
authors.lastname: Liao
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: O'Keeffe
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA.
authors.forename: Guoxing
authors.initials: G
authors.lastname: Wang
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA.
authors.forename: Boaz
authors.initials: B
authors.lastname: van Driel
authors.affiliation: Biologics Discovery, Merck Research Laboratories , Palo Alto, CA , USA.
authors.forename: Rene
authors.initials: R
authors.lastname: de Waal Malefyt
authors.affiliation: Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Department of Medicine, Massachusetts General Hospital, Harvard Medical School , Boston, MA , USA.
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Reinecker
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, FL , USA.
authors.forename: Roland W
authors.initials: RW
authors.lastname: Herzog
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA , USA.
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
keywords: CX3CR1; Flt3L; GITR-L; TNFSF18; Treg