{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:05:28Z","timestamp":1791443128404,"version":"4.3.3"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2011,9,1]],"date-time":"2011-09-01T00:00:00Z","timestamp":1314835200000},"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":[[2011,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Ag-specific tolerance is a highly desired therapy for immune-mediated diseases. Intravenous infusion of protein\/peptide Ags linked to syngeneic splenic leukocytes with ethylene carbodiimide (Ag-coupled splenocytes [Ag-SP]) has been demonstrated to be a highly efficient method for inducing peripheral, Ag-specific T cell tolerance for treatment of autoimmune disease. However, little is understood about the mechanisms underlying this therapy. In this study, we show that apoptotic Ag-SP accumulate in the splenic marginal zone, where their uptake by F4\/80+ macrophages induces production of IL-10, which upregulates the expression of the immunomodulatory costimulatory molecule PD-L1 that is essential for Ag-SP tolerance induction. Ag-SP infusion also induces T regulatory cells that are dispensable for tolerance induction but required for long-term tolerance maintenance. Collectively, these results indicate that Ag-SP tolerance recapitulates how tolerance is normally maintained in the hematopoietic compartment and highlight the interplay between the innate and adaptive immune systems in the induction of Ag-SP tolerance. To our knowledge, we show for the first time that tolerance results from the synergistic effects of two distinct mechanisms, PD-L1\u2013dependent T cell-intrinsic unresponsiveness and the activation of T regulatory cells. These findings are particularly relevant as this tolerance protocol is currently being tested in a Phase I\/IIa clinical trial in new-onset relapsing-remitting multiple sclerosis.<\/jats:p>","DOI":"10.4049\/jimmunol.1004175","type":"journal-article","created":{"date-parts":[[2011,8,6]],"date-time":"2011-08-06T02:32:44Z","timestamp":1312597964000},"page":"2405-2417","source":"Crossref","is-referenced-by-count":186,"title":["Tolerance Induced by Apoptotic Antigen-Coupled Leukocytes Is Induced by PD-L1+ and IL-10\u2013Producing Splenic Macrophages and Maintained by T Regulatory Cells"],"prefix":"10.1093","volume":"187","author":[{"given":"Daniel R","family":"Getts","sequence":"first","affiliation":[{"name":"Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle M","family":"Turley","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra E","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher T","family":"Harp","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derrick","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma M","family":"Feeney","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghann Teague","family":"Getts","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron J","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xunrong","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael L","family":"Terry","sequence":"additional","affiliation":[{"name":"Discipline of Pathology, School of Medical Sciences, Bosch Institute, University of Sydney , Sydney, New South Wales 2006 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J C","family":"King","sequence":"additional","affiliation":[{"name":"Discipline of Pathology, School of Medical Sciences, Bosch Institute, University of Sydney , Sydney, New South Wales 2006 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,9,1]]},"reference":[{"key":"2025032410312630800_r1","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/nri2134","article-title":"CD3-specific antibodies: a portal to the treatment of autoimmunity","volume":"7","author":"Chatenoud","year":"2007","journal-title":"Nat. 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