{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T17:22:50Z","timestamp":1770744170310,"version":"3.49.0"},"reference-count":61,"publisher":"Rockefeller University Press","issue":"4","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1997,2,17]]},"abstract":"<jats:p>Multiple sclerosis is an autoimmune disease thought to be mediated by CD4+ T helper cells (Th). Experimental autoimmune encephalomyelitis is a rodent model of multiple sclerosis and has been used extensively to explore a variety of immunotherapies using soluble protein or peptide antigens. The underlying mechanisms of such therapy have been attributed to induction of T cell anergy, a switch in Th1 to Th2 responses, or peripheral deletion of autoreactive T cells. In this study, we have developed transgenic mice expressing a T cell receptor (TCR) specific for the NH2-terminal peptide Ac1-11 of the autoantigen myelin basic protein to explore the mechanism of soluble peptide therapy. T cells from these mice are highly skewed toward the CD4 population and have an abnormal thymic architecture, a phenomenon found in other TCR transgenic mice that exhibit a highly skewed CD4\/CD8 ratio. Soluble Ac1-11 or the analogues Ac1-11[4A] or Ac1-11[4Y] (which bind to the major histocompatibility complex [MHC] class II molecule I-Au with increasing affinities) given intravenously activates T cells, rendering cells hyperresponsive in vitro for at least two days after injection. Concomitantly, T cells apoptose in the periphery, the degree of which correlates with the affinity of the peptide for the MHC. In addition, a shift in the T helper phenotype of the surviving T cells occurs such that the low affinity peptide, Ac1-11, induces primarily a Th1 response, whereas the highest affinity peptide, Ac1-11[4Y], induces primarily a Th2 type response. These data show that both the nature and the presumed number of the peptide\u2013MHC complexes formed during specific peptide therapy affect both the degree of peripheral programmed cell death as well as the outcome of the T helper subset response in vivo, leading to amelioration of disease.<\/jats:p>","DOI":"10.1084\/jem.185.4.583","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:49:30Z","timestamp":1027702170000},"page":"583-600","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":54,"title":["Induction of Apoptosis and T Helper 2 (Th2) Responses Correlates with Peptide Affinity for the Major Histocompatibility Complex in Self-reactive T Cell Receptor Transgenic Mice"],"prefix":"10.1084","volume":"185","author":[{"given":"C.I.","family":"Pearson","sequence":"first","affiliation":[{"name":"From the *Department of Microbiology and Immunology, Stanford University Medical Center, Stanford, California 94305; and \u2021Department of Immunology, Erasmus Universiteit Rotterdam, Postbus 1738, 3000 DR Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W.","family":"van Ewijk","sequence":"additional","affiliation":[{"name":"From the *Department of Microbiology and Immunology, Stanford University Medical Center, Stanford, California 94305; and \u2021Department of Immunology, Erasmus Universiteit Rotterdam, Postbus 1738, 3000 DR Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.O.","family":"McDevitt","sequence":"additional","affiliation":[{"name":"From the *Department of Microbiology and Immunology, Stanford University Medical Center, Stanford, California 94305; and \u2021Department of Immunology, Erasmus Universiteit Rotterdam, Postbus 1738, 3000 DR Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[1997,2,17]]},"reference":[{"key":"2023072507111247000_B1","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/0952-7915(94)90128-7","article-title":"Role of cytokines in determining T-lymphocyte function","volume":"6","author":"O'Garra","year":"1994","journal-title":"Curr Opin Immunol"},{"key":"2023072507111247000_B2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1146\/annurev.iy.11.040193.000333","article-title":"Differential regulation of murine T lymphocyte subsets","volume":"11","author":"Fitch","year":"1993","journal-title":"Annu Rev Immunol"},{"key":"2023072507111247000_B3","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1146\/annurev.iy.10.040192.002125","article-title":"Regulation of immunity to parasites by T cells and T cell\u2013derived cytokines","volume":"10","author":"Sher","year":"1992","journal-title":"Annu Rev Immunol"},{"key":"2023072507111247000_B4","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/0167-5699(95)80068-9","article-title":"Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases","volume":"16","author":"Liblau","year":"1995","journal-title":"Immunol Today"},{"key":"2023072507111247000_B5","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1146\/annurev.iy.08.040190.003051","article-title":"The T lymphocyte in experimental allergic encephalomyelitis","volume":"8","author":"Zamvil","year":"1990","journal-title":"Annu Rev Immunol"},{"key":"2023072507111247000_B6","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.4049\/jimmunol.155.5.2737","article-title":"Reversal of acute experimental autoimmune encephalomyelitis and prevention of relapses by treatment with a myelin basic protein peptide analogue modified to form long-lived peptide-MHC complexes","volume":"155","author":"Samson","year":"1995","journal-title":"J Immunol"},{"key":"2023072507111247000_B7","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1093\/intimm\/5.9.1159","article-title":"Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity","volume":"5","author":"Metzler","year":"1993","journal-title":"Int Immunol"},{"key":"2023072507111247000_B8","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1126\/science.1279812","article-title":"Amelioration of autoimmune encephalomyelitis by myelin basic protein synthetic peptide-induced anergy","volume":"258","author":"Gaur","year":"1992","journal-title":"Science (Wash DC)"},{"key":"2023072507111247000_B9","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1126\/science.7509084","article-title":"T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis","volume":"263","author":"Critchfield","year":"1994","journal-title":"Science (Wash DC)"},{"key":"2023072507111247000_B10","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/0092-8674(89)90287-0","article-title":"Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy","volume":"59","author":"Wraith","year":"1989","journal-title":"Cell"},{"key":"2023072507111247000_B11","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/BF03401615","article-title":"Quantitative analysis of peptides from myelin basic protein binding to the MHC class II protein, I-Au, which confers susceptibility to experimental allergic encephalomyelitis","volume":"2","author":"Fugger","year":"1996","journal-title":"Mol Med"},{"key":"2023072507111247000_B12","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1093\/intimm\/5.9.1151","article-title":"An autoantigenic T cell epitope forms unstable complexes with class II MHC: a novel route for escape from tolerance induction","volume":"5","author":"Fairchild","year":"1993","journal-title":"Int Immunol"},{"key":"2023072507111247000_B13","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1084\/jem.180.6.2227","article-title":"Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon \u03b3 and tumor necrosis factor \u03b1 production","volume":"180","author":"Karin","year":"1994","journal-title":"J Exp Med"},{"key":"2023072507111247000_B14","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/379343a0","article-title":"Treatment of experimental encephalomyelitis with a peptide analogue of myelin basic protein","volume":"379","author":"Brocke","year":"1996","journal-title":"Nature (Lond)"},{"key":"2023072507111247000_B15","doi-asserted-by":"crossref","first-page":"3031","DOI":"10.1073\/pnas.93.7.3031","article-title":"Intravenous injection of soluble antigen induces thymic and peripheral T-cell apoptosis","volume":"93","author":"Liblau","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072507111247000_B16","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/1074-7613(94)90084-1","article-title":"Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo","volume":"1","author":"Kearney","year":"1994","journal-title":"Immunity"},{"key":"2023072507111247000_B17","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1016\/0092-8674(90)90420-J","article-title":"Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity","volume":"63","author":"Webb","year":"1990","journal-title":"Cell"},{"key":"2023072507111247000_B18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1084\/jem.175.1.9","article-title":"The injection of deaggregated gamma globulins in adult mice induces antigen-specific unresponsiveness of T helper type 1 but not type 2 lymphocytes","volume":"175","author":"De Wit","year":"1992","journal-title":"J Exp Med"},{"key":"2023072507111247000_B19","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1093\/intimm\/7.2.199","article-title":"Induction of Th2 responses to soluble proteins is independent of B cell tolerance status","volume":"7","author":"Van Mechelen","year":"1995","journal-title":"Int Immunol"},{"key":"2023072507111247000_B20","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1084\/jem.177.2.457","article-title":"In vivo role of interleukin 4 in T cell tolerance induced by aqueous protein antigen","volume":"177","author":"Burstein","year":"1993","journal-title":"J Exp Med"},{"key":"2023072507111247000_B21"},{"key":"2023072507111247000_B22","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/j.1600-065X.1994.tb00890.x","article-title":"High-dose soluble antigen: peripheral T-cell proliferation or apoptosis","volume":"142","author":"Liblau","year":"1994","journal-title":"Immunol Rev"},{"key":"2023072507111247000_B23","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.4049\/jimmunol.150.6.2281","article-title":"Transfer of putative complementarity-determining region loops of T cell receptor V domains confers toxin reactivity but not peptide\/MHC specificity","volume":"150","author":"Patten","year":"1993","journal-title":"J Immunol"},{"key":"2023072507111247000_B24"},{"key":"2023072507111247000_B25","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/362245a0","article-title":"Disruption of the murine IL-4 gene blocks Th2 cytokine responses","volume":"362","author":"Kopf","year":"1993","journal-title":"Nature (Lond)"},{"key":"2023072507111247000_B26","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/332035a0","article-title":"Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex","volume":"332","author":"Kappler","year":"1989","journal-title":"Nature (Lond)"},{"key":"2023072507111247000_B27","doi-asserted-by":"crossref","first-page":"751","DOI":"10.4049\/jimmunol.128.2.751","article-title":"Clonal analysis of B and T cell responses to Ia antigens. III. Characterization of 12 xenogeneic anti-idiotypic antisera to A.TH-derived anti\u2013I-Ak and anti\u2013I-Ekmonoclonal antibodies","volume":"128","author":"Devaux","year":"1982","journal-title":"J Immunol"},{"key":"2023072507111247000_B28","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1084\/jem.157.1.202","article-title":"The \u201cLy-1 B\u201d cell subpopulation in normal, immunodefective, and autoimmune mice","volume":"157","author":"Hayakawa","year":"1983","journal-title":"J Exp Med"},{"key":"2023072507111247000_B29","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0022-1759(93)90361-A","article-title":"Similar frequencies and kinetics of cytokine producing cells in murine peripheral blood and sera","volume":"166","author":"Sander","year":"1993","journal-title":"J Immunol Methods"},{"key":"2023072507111247000_B30","doi-asserted-by":"crossref","first-page":"5208","DOI":"10.4049\/jimmunol.152.11.5208","article-title":"Regulation of immunostimulatory function and costimulatory molecule (B7-1 and B7-2) expression on murine dendritic cells","volume":"152","author":"Larsen","year":"1994","journal-title":"J Immunol"},{"key":"2023072507111247000_B31","first-page":"115","article-title":"Properties of monoclonal antibodies to mouse Ig allotypes, H-2 and Ia antigens","volume":"81","author":"Oi","year":"1978","journal-title":"Curr Top Microbiol Immunol"},{"key":"2023072507111247000_B32","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1083\/jcb.119.3.493","article-title":"Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation","volume":"119","author":"Gavrieli","year":"1992","journal-title":"J Cell Biol"},{"key":"2023072507111247000_B33","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/eji.1830200119","article-title":"Immunohistology of T cell differentiation in the thymus of H-Y\u2013specific T cell receptor \u03b1\/\u03b2 transgenic mice","volume":"20","author":"Van Ewijk","year":"1990","journal-title":"Eur J Immunol"},{"key":"2023072507111247000_B33a"},{"key":"2023072507111247000_B34","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/340559a0","article-title":"Phenotypic differences between \u03b1\u03b2 versus \u03b2 T-cell receptor transgenic mice undergoing negative selection","volume":"340","author":"Berg","year":"1989","journal-title":"Nature (Lond)"},{"key":"2023072507111247000_B35"},{"key":"2023072507111247000_B36","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1126\/science.2125367","article-title":"Induction by antigen of intrathymic apoptosis of CD4+CD8+ TCRlothymocytes in vivo","volume":"250","author":"Murphy","year":"1990","journal-title":"Science (Wash DC)"},{"key":"2023072507111247000_B37","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/1074-7613(94)90067-1","article-title":"The Fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice","volume":"1","author":"Singer","year":"1994","journal-title":"Immunity"},{"key":"2023072507111247000_B38","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S1074-7613(00)80306-4","article-title":"Effect of the lpr\/lpr mutant Fas gene and tumor necrosis factor (TNF) on antigen induced programmed cell death in HNTTCR transgenic mice","volume":"5","author":"Sytwu","year":"1996","journal-title":"Immunity"},{"key":"2023072507111247000_B39","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/377348a0","article-title":"Induction of apoptosis in mature T cells by tumour necrosis factor","volume":"377","author":"Zheng","year":"1995","journal-title":"Nature (Lond)"},{"key":"2023072507111247000_B40","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/1074-7613(95)90169-8","article-title":"An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis","volume":"3","author":"Nicholson","year":"1995","journal-title":"Immunity"},{"key":"2023072507111247000_B41","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/1074-7613(95)90170-1","article-title":"Low avidity recognition of self-antigen by T cells permits escape from central tolerance","volume":"3","author":"Liu","year":"1995","journal-title":"Immunity"},{"key":"2023072507111247000_B42","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1084\/jem.182.5.1579","article-title":"The effect of antigen dose on CD4+T helper cell phenotype development in a T cell receptor\u2013\u03b1\u03b2\u2013transgenic model","volume":"182","author":"Hosken","year":"1995","journal-title":"J Exp Med"},{"key":"2023072507111247000_B43","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1126\/science.1636090","article-title":"Establishment of stable, cell-mediated immunity that makes \u201csusceptible\u201d mice resistant to Leishmania major.","volume":"257","author":"Bretscher","year":"1992","journal-title":"Science (Wash DC)"},{"key":"2023072507111247000_B44","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/eji.1830220239","article-title":"Major histocompatibility complex (MHC) control of CD4 T cell subset activation. II. A single peptide induces either humoral or cell-mediated responses in mice of distinct MHC genotype","volume":"22","author":"Murray","year":"1992","journal-title":"Eur J Immunol"},{"key":"2023072507111247000_B45","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1084\/jem.182.5.1591","article-title":"Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+T cells","volume":"182","author":"Constant","year":"1995","journal-title":"J Exp Med"},{"key":"2023072507111247000_B46","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/0092-8674(95)90349-6","article-title":"B7-1 and B7-2 costimulatory molecules activate differentially the Th1\/Th2 developmental pathways: application to autoimmune disease therapy","volume":"80","author":"Kuchroo","year":"1995","journal-title":"Cell"},{"key":"2023072507111247000_B47","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/1074-7613(95)90032-2","article-title":"B7-1 and B7-2 do not deliver identical costimulatory signals, since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4","volume":"2","author":"Freeman","year":"1995","journal-title":"Immunity"},{"key":"2023072507111247000_B48","doi-asserted-by":"crossref","first-page":"9510","DOI":"10.1073\/pnas.92.21.9510","article-title":"Major histocompatibility complex binding affinity of an antigenic determinant is crucial for the differential secretion of interleukin 4\/5 or interferon \u03b3 by T cells","volume":"92","author":"Kumar","year":"1995","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072507111247000_B49","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/0952-7915(95)80035-2","article-title":"Significance of T-cell stimulation by altered peptide ligands in T cell biology","volume":"7","author":"Sloan-Lancaster","year":"1995","journal-title":"Curr Opin Immunol"},{"key":"2023072507111247000_B50","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/360266a0","article-title":"Signalling through the MHC class II cytoplasmic domain is required for antigen presentation and induces B7 expression","volume":"360","author":"Nabavi","year":"1992","journal-title":"Nature (Lond)"},{"key":"2023072507111247000_B51","doi-asserted-by":"crossref","first-page":"11054","DOI":"10.1073\/pnas.90.23.11054","article-title":"Expression and functional significance of an additional ligand for CTLA-4","volume":"90","author":"Lenschow","year":"1993","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072507111247000_B52","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1084\/jem.175.3.655","article-title":"Targeting autoantigen to B cells prevents the induction of a cell-mediated autoimmune disease in rats","volume":"175","author":"Day","year":"1992","journal-title":"J Exp Med"},{"key":"2023072507111247000_B53","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1084\/jem.181.2.713","article-title":"T cell genetic background determines default T helper phenotype development in vitro","volume":"181","author":"Hsieh","year":"1995","journal-title":"J Exp Med"},{"key":"2023072507111247000_B54","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1126\/science.271.5251.984","article-title":"Genetic susceptibility to Leishmania: IL-12 responsiveness in Th1 cell development","volume":"271","author":"Guler","year":"1996","journal-title":"Science (Wash DC)"},{"key":"2023072507111247000_B55","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/1074-7613(94)90011-6","article-title":"A role for non-MHC genetic polymorphism in susceptibility to spontaneous autoimmunity","volume":"1","author":"Scott","year":"1994","journal-title":"Immunity"},{"key":"2023072507111247000_B56","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/jcb.240530409","article-title":"Cytokines in the differentiation of Th1\/Th2 CD4+subsets in leishmaniasis","volume":"53","author":"Reiner","year":"1993","journal-title":"J Cell Biochem"},{"key":"2023072507111247000_B57","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/1074-7613(95)90011-X","article-title":"Developmental commitment to the Th2 lineage by extinction of IL-12 signaling","volume":"2","author":"Szabo","year":"1995","journal-title":"Immunity"},{"key":"2023072507111247000_B58","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/0092-8674(94)90332-8","article-title":"Lymphocyte responses and cytokines","volume":"76","author":"Paul","year":"1994","journal-title":"Cell"},{"key":"2023072507111247000_B59","first-page":"1","article-title":"Role of cytokines in development of Th1 and Th2 cells","volume":"63","author":"O'Garra","year":"1996","journal-title":"Chem Immunol"},{"key":"2023072507111247000_B60","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1093\/intimm\/6.10.1545","article-title":"Differential ability of Th1 and Th2 T cells to express Fas ligand and to undergo activation-induced cell death","volume":"6","author":"Ramsdell","year":"1994","journal-title":"Int Immunol"}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/185\/4\/583\/1681758\/5406.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/185\/4\/583\/1681758\/5406.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T07:45:57Z","timestamp":1690271157000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/185\/4\/583\/7115\/Induction-of-Apoptosis-and-T-Helper-2-Th2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,2,17]]},"references-count":61,"journal-issue":{"issue":"4","published-print":{"date-parts":[[1997,2,17]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.185.4.583","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,2,17]]}}}