{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T11:53:10Z","timestamp":1791114790707,"version":"4.1.0"},"reference-count":40,"publisher":"Rockefeller University Press","issue":"11","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2000,6,5]]},"abstract":"<jats:p>The mechanisms that determine whether receptor stimulation leads to lymphocyte tolerance versus activation remain poorly understood. We have used rat insulin promoter (RIP)-gp\/P14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic \u03b2-islet cells together with T cells expressing an LCMV-gp\u2013specific T cell receptor to assess the requirements for the induction of autoimmunity. Our studies have shown that administration of the gp peptide gp33 leads to the activation of P14-transgenic T cells, as measured by the upregulation of activation markers and the induction of effector cytotoxic activity. This treatment also leads to expansion and deletion of P14 T cells. Despite the induction of cytotoxic T lymphocyte activity, peptide administration is not sufficient to induce diabetes. However, the administration of gp peptide together with an activating anti-CD40 antibody rapidly induces diabetes. These findings suggest that the induction of tolerance versus autoimmunity is determined by resting versus activated antigen-presenting cells.<\/jats:p>","DOI":"10.1084\/jem.191.11.2021","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:48:33Z","timestamp":1027702113000},"page":"2021-2028","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":99,"title":["Role of Antigen-Presenting Cells in Mediating Tolerance and Autoimmunity"],"prefix":"10.1084","volume":"191","author":[{"given":"Kristine M.","family":"Garza","sequence":"first","affiliation":[{"name":"aDepartments of Medical Biophysics and Immunology, Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Chan","sequence":"additional","affiliation":[{"name":"aDepartments of Medical Biophysics and Immunology, Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Suri","sequence":"additional","affiliation":[{"name":"aDepartments of Medical Biophysics and Immunology, Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linh T.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"aDepartments of Medical Biophysics and Immunology, Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Odermatt","sequence":"additional","affiliation":[{"name":"bInstitute of Pathology, Department of Experimental Pathology, University Hospital, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen P.","family":"Schoenberger","sequence":"additional","affiliation":[{"name":"cDivision of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, California 92121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela S.","family":"Ohashi","sequence":"additional","affiliation":[{"name":"aDepartments of Medical Biophysics and Immunology, Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1999,6,6]]},"reference":[{"key":"2023072509021883600_R1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1084\/jem.184.1.1","article-title":"Models of T cell anergyis there a common molecular mechanism?","volume":"184","author":"Schwartz","year":"1996","journal-title":"J. Exp. Med."},{"key":"2023072509021883600_R2","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1111\/j.1600-065X.1996.tb00900.x","article-title":"Pancreatic islet allograft immunity and tolerancethe two-signal hypothesis revisited","volume":"149","author":"Gill","year":"1996","journal-title":"Immunol. Rev."},{"key":"2023072509021883600_R3","first-page":"130","article-title":"Dendritic cells and T lymphocytesdevelopmental and functional interactions","volume":"204","author":"Shortman","year":"1997","journal-title":"Ciba Found. Symp."},{"key":"2023072509021883600_R4","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/S0167-5699(98)01328-0","article-title":"The evolution of self-tolerancea new cell arises to meet the challenge of self-reactivity","volume":"19","author":"Fazekas de St. Groth","year":"1998","journal-title":"Immunol. Today."},{"key":"2023072509021883600_R5","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/32588","article-title":"Dendritic cells and the control of immunity","volume":"392","author":"Banchereau","year":"1998","journal-title":"Nature."},{"key":"2023072509021883600_R6","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1016\/0092-8674(90)90420-J","article-title":"Extrathymic tolerance of mature T cellsclonal elimination as a consequence of immunity","volume":"63","author":"Webb","year":"1990","journal-title":"Cell."},{"key":"2023072509021883600_R7","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1084\/jem.186.2.239","article-title":"Class I\u2013restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8+ T cells","volume":"186","author":"Kurts","year":"1997","journal-title":"J. Exp. Med."},{"key":"2023072509021883600_R8","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1084\/jem.184.2.485","article-title":"Role of antigen, CD8, and cytotoxic T lymphocyte (CTL) avidity in high dose antigen induction of apoptosis of effector CTL","volume":"184","author":"Alexander-Miller","year":"1996","journal-title":"J. Exp. Med."},{"key":"2023072509021883600_R9","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/0092-8674(91)90164-T","article-title":"Ablation of \u201ctolerance\u201d and induction of diabetes by virus infection in viral antigen transgenic mice","volume":"65","author":"Ohashi","year":"1991","journal-title":"Cell."},{"key":"2023072509021883600_R10","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1002\/eji.1830230834","article-title":"T cell immunity after a viral infection versus T cell tolerance induced by soluble viral peptides","volume":"8","author":"Kyburz","year":"1993","journal-title":"Eur. J. Immunol."},{"key":"2023072509021883600_R11","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/342559a0","article-title":"Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen","volume":"342","author":"Pircher","year":"1989","journal-title":"Nature."},{"key":"2023072509021883600_R12","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S1074-7613(00)80258-7","article-title":"the SCID but not the RAG-2 gene product is required for S mu-S epsilon heavy chain class switching","volume":"5","author":"Rolink","year":"1996","journal-title":"Immunity."},{"key":"2023072509021883600_R13","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1146\/annurev.immunol.16.1.111","article-title":"CD40 and CD154 in cell-mediated immunity","volume":"16","author":"Grewal","year":"1998","journal-title":"Annu. Rev. Immunol."},{"key":"2023072509021883600_R14","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1084\/jem.180.4.1263","article-title":"Activation of human dendritic cells through CD40 crosslinking","volume":"180","author":"Caux","year":"1994","journal-title":"J. Exp. Med."},{"key":"2023072509021883600_R15","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1084\/jem.184.2.747","article-title":"Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacityT-T help via APC activation","volume":"184","author":"Cella","year":"1996","journal-title":"J. Exp. Med."},{"key":"2023072509021883600_R16","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/30989","article-title":"A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell","volume":"393","author":"Ridge","year":"1998","journal-title":"Nature."},{"key":"2023072509021883600_R17","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1038\/30996","article-title":"Help for cytotoxic-T-cell responses is mediated by CD40 signalling","volume":"393","author":"Bennet","year":"1998","journal-title":"Nature."},{"key":"2023072509021883600_R18","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/31002","article-title":"T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions","volume":"393","author":"Schoenberger","year":"1998","journal-title":"Nature."},{"key":"2023072509021883600_R19","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1084\/jem.189.12.1981","article-title":"Interleukin 12\u2013dependent interferon \u03b3 production by CD8\u03b11 lymphoid dendritic cells","volume":"189","author":"Ohteki","year":"1999","journal-title":"J. Exp. Med."},{"key":"2023072509021883600_R20","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1126\/science.273.5283.1862","article-title":"CD40 ligand-dependent T cell acivationrequirement of B7-CD28 signaling through CD40","volume":"273","author":"Yang","year":"1996","journal-title":"Science."},{"key":"2023072509021883600_R21","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1126\/science.7688139","article-title":"Differential T cell costimulatory requirements in CD28-deficient mice","volume":"261","author":"Shahinian","year":"1993","journal-title":"Science."},{"key":"2023072509021883600_R22","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/0092-8674(93)90074-Z","article-title":"Transgenic mice that express a myelin basic protein specific T cell receptor develop spontaneous autoimmunity","volume":"72","author":"Goverman","year":"1993","journal-title":"Cell."},{"key":"2023072509021883600_R23","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/0092-8674(93)90730-E","article-title":"Following a diabetogenic T cell from genesis through pathogenesis","volume":"74","author":"Katz","year":"1993","journal-title":"Cell."},{"key":"2023072509021883600_R24","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/0092-8674(94)90419-7","article-title":"High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice","volume":"78","author":"Lafaille","year":"1994","journal-title":"Cell."},{"key":"2023072509021883600_R25","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1126\/science.286.5445.1732","article-title":"Arthritis provoked by linked T and B cell recognition of glycolytic enzyme","volume":"286","author":"Matsumoto","year":"2000","journal-title":"Science."},{"key":"2023072509021883600_R26","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1084\/jem.184.3.923","article-title":"Constitutive class I\u2013restricted exogenous presentation of self antigens in vivo","volume":"184","author":"Kurts","year":"1996","journal-title":"J. Exp. Med."},{"key":"2023072509021883600_R27","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/359079a0","article-title":"Infection breaks T-cell tolerance","volume":"359","author":"Rocken","year":"1992","journal-title":"Nature."},{"key":"2023072509021883600_R28","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1084\/jem.187.5.763","article-title":"Viral and bacterial infections interfere with peripheral tolerance induction and activate CD8+ T cells to cause immunopathology","volume":"187","author":"Ehl","year":"1998","journal-title":"J. Exp. Med."},{"key":"2023072509021883600_R29","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1084\/jem.137.3.740","article-title":"Termination of tolerance to human gamma globulin in mice by antigen and bacterial lipopolysaccharide (endotoxin)","volume":"137","author":"Chiller","year":"1973","journal-title":"J. Exp. Med."},{"key":"2023072509021883600_R30","doi-asserted-by":"crossref","first-page":"938","DOI":"10.4049\/jimmunol.126.3.938","article-title":"Bacterial lipopolysaccharide (endotoxin) interferes with the induction of tolerance and primes thymus-derived lymphocytes","volume":"126","author":"Parks","year":"1981","journal-title":"J. Immunol."},{"key":"2023072509021883600_R31","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/1074-7613(95)90050-0","article-title":"Lipopolysaccharide interferes with the induction of peripheral T cell death","volume":"2","author":"Vella","year":"1995","journal-title":"Immunity."},{"key":"2023072509021883600_R32","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1084\/jem.184.4.1413","article-title":"Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo","volume":"184","author":"De Smedt","year":"1996","journal-title":"J. Exp. Med."},{"key":"2023072509021883600_R33","doi-asserted-by":"crossref","first-page":"6552","DOI":"10.4049\/jimmunol.162.11.6552","article-title":"Analysis of adjuvant function by direct visualization of antigen presentation in vivoendotoxin promotes accumulation of antigen-bearing dendritic cells in the T cell areas of lymphoid tissue","volume":"162","author":"Sousa","year":"1999","journal-title":"J. Immunol."},{"key":"2023072509021883600_R34","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/10503","article-title":"Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40","volume":"5","author":"Sotomayor","year":"1999","journal-title":"Nat. Med."},{"key":"2023072509021883600_R35","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/10495","article-title":"CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy","volume":"5","author":"Diehl","year":"1999","journal-title":"Nat. Med."},{"key":"2023072509021883600_R36","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.4049\/jimmunol.162.4.2024","article-title":"CD40 activation boosts T cell immunity in vivo by enhancing T cell clonal expansion and delaying peripheral T cell deletion","volume":"162","author":"Maxwell","year":"1999","journal-title":"J. Immunol."},{"key":"2023072509021883600_R37","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1084\/jem.188.11.2075","article-title":"Prevention of peripheral tolerance by a dendritic cell growth factorFlt3 ligand as an adjuvant","volume":"11","author":"Bulendran","year":"1998","journal-title":"J. Exp. Med."},{"key":"2023072509021883600_R38","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1146\/annurev.iy.01.040183.001043","article-title":"Immunobiology of tissue transplantationa return to the passenger leukocyte concept","volume":"1","author":"Lafferty","year":"1983","journal-title":"Annu. Rev. Immunol."},{"key":"2023072509021883600_R39","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1146\/annurev.iy.12.040194.005015","article-title":"Tolerance, danger, and the extended family","volume":"12","author":"Matzinger","year":"1994","journal-title":"Annu. Rev. Immunol."},{"key":"2023072509021883600_R40","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/0167-5699(92)90198-G","article-title":"The immune system evolved to discriminate infectious nonself to noninfectious self","volume":"13","author":"Janeway","year":"1992","journal-title":"Immunol. Today."}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/191\/11\/2021\/1696600\/000067.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/191\/11\/2021\/1696600\/000067.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T10:13:24Z","timestamp":1690280004000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/191\/11\/2021\/20579\/Role-of-Antigen-Presenting-Cells-in-Mediating"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,6,6]]},"references-count":40,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2000,6,5]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.191.11.2021","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1999,6,6]]}}}