GITR-dependent regulation of 4-1BB expression: implications for T cell memory and anti-4-1BB-induced pathology

• Published in: The Journal of immunology (1950) 2013-05, Vol.190 (9), p.4627-4639
• Main Authors: Lin, Gloria H Y, Snell, Laura M, Wortzman, Michael E, Clouthier, Derek L, Watts, Tania H
• Format: Article
• Language: English
• Subjects: 4-1BB Ligand - immunology; 4-1BB Ligand - metabolism; Animals; Bone Marrow - immunology; Bone Marrow - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Glucocorticoid-Induced TNFR-Related Protein - immunology; Glucocorticoid-Induced TNFR-Related Protein - metabolism; Hepatitis - immunology; Hepatitis - metabolism; Humans; Hyaluronan Receptors - immunology; Hyaluronan Receptors - metabolism; Immunologic Memory - immunology; Interleukins - immunology; Interleukins - metabolism; Liver - immunology; Liver - metabolism; Lymph Nodes - immunology; Lymph Nodes - metabolism; Melanoma - immunology; Melanoma - metabolism; Mice; Mice, Inbred C57BL; Spleen - immunology; Spleen - metabolism; Splenomegaly - immunology; Splenomegaly - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1201854

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.