title: GITR-dependent regulation of 4-1BB expression: implications for T cell memory and anti-4-1BB-induced pathology.
abstract: The TNFR family member 4-1BB plays a key role in the survival of activated and memory CD8 T cells. However, the mechanisms that regulate 4-1BB re-expression on memory CD8 T cells after Ag clearance are unknown. In unimmunized mice, ∼10% of CD8 CD44(hi) memory T cells in the bone marrow (BM) and liver express 4-1BB, with minimal 4-1BB expression in spleen and lymph node. IL-2, IL-15, and IL-7 are collectively dispensable for 4-1BB expression on the memory CD8 T cells. Rather, T cell-intrinsic glucocorticoid-induced TNFR-related protein (GITR) contributes to 4-1BB expression on CD8 T cells upon their entry into the BM or liver. Consistent with its role in regulation of 4-1BB, GITR is required on memory CD8 T cells for their persistence in vivo. These findings reveal site-specific effects of the BM and liver microenvironment on CD8 memory T cells. Previous work has demonstrated that 4-1BB agonists given to unimmunized mice induce splenomegaly, hepatitis, and other immune system anomalies. Moreover, severe liver pathology has been observed in a subset of anti-4-1BB-treated melanoma patients. Remarkably, the absence of GITR in mice almost completely abrogates cellular expansions, splenomegaly, and liver inflammation associated with anti-4-1BB agonist treatment of unimmunized mice. In contrast, lack of CD8 T cells selectively improves liver pathology, but not splenomegaly in the mice. Thus, the regulation of 4-1BB expression by GITR on CD8 T cells, as well as on other cells, contributes to the pathological effects of anti-4-1BB in unimmunized mice.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Gloria H Y
authors.initials: GH
authors.lastname: Lin
authors.forename: Laura M
authors.initials: LM
authors.lastname: Snell
authors.forename: Michael E
authors.initials: ME
authors.lastname: Wortzman
authors.forename: Derek L
authors.initials: DL
authors.lastname: Clouthier
authors.forename: Tania H
authors.initials: TH
authors.lastname: Watts
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000276:immunology* / Q000378:metabolism*; D006505:Hepatitis / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology / Q000378:metabolism; D007156:Immunologic Memory / Q000276:immunology*; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013163:Splenomegaly / Q000276:immunology / Q000378:metabolism
chemical_list: D053330:4-1BB Ligand; D053450:Glucocorticoid-Induced TNFR-Related Protein; D018960:Hyaluronan Receptors; D007378:Interleukins; C106544:Tnfrsf18 protein, mouse