{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:16:48Z","timestamp":1790173008369,"version":"4.1.0"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2013,5,1]],"date-time":"2013-05-01T00:00:00Z","timestamp":1367366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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, \u223c10% of CD8 CD44hi 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\u2013intrinsic 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\u20134-1BB\u2013treated melanoma patients. Remarkably, the absence of GITR in mice almost completely abrogates cellular expansions, splenomegaly, and liver inflammation associated with anti\u20134-1BB 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\u20134-1BB in unimmunized mice.<\/jats:p>","DOI":"10.4049\/jimmunol.1201854","type":"journal-article","created":{"date-parts":[[2013,3,27]],"date-time":"2013-03-27T23:58:14Z","timestamp":1364428694000},"page":"4627-4639","source":"Crossref","is-referenced-by-count":36,"title":["GITR-Dependent Regulation of 4-1BB Expression: Implications for T Cell Memory and Anti\u20134-1BB\u2013Induced Pathology"],"prefix":"10.1093","volume":"190","author":[{"given":"Gloria H Y","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M","family":"Snell","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E","family":"Wortzman","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek L","family":"Clouthier","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania H","family":"Watts","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,5,1]]},"reference":[{"key":"2025032406575848400_r1","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1084\/jem.20020369","article-title":"Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells","volume":"195","author":"Becker","year":"2002","journal-title":"J. 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