Liao, GongxianO’Keeffe, Michael S.Wang, Guoxingvan Driel, Boazde Waal Malefyt, ReneReinecker, Hans-ChristianHerzog, Roland W.Terhorst, Cox2014-03-112014Liao, Gongxian, Michael S. O’Keeffe, Guoxing Wang, Boaz van Driel, Rene de Waal Malefyt, Hans-Christian Reinecker, Roland W. Herzog, and Cox Terhorst. 2014. “Glucocorticoid-Induced TNF Receptor Family-Related Protein Ligand is Requisite for Optimal Functioning of Regulatory CD4+ T Cells.” Frontiers in Immunology 5 (1): 35. doi:10.3389/fimmu.2014.00035. http://dx.doi.org/10.3389/fimmu.2014.00035.1664-3224http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879918Glucocorticoid-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.en-USGITR-LTNFSF18Flt3LTregCX3CR1Journal Article2014-03-1110.3389/fimmu.2014.00035