{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:18:58Z","timestamp":1791220738776,"version":"4.1.0"},"reference-count":38,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5392","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[1998,11,13]]},"abstract":"<jats:p>Self tolerance is acquired by the developing immune system. As reported here, particular properties of the neonatal tissue contribute to this process. Neonatal skin, but not adult skin, was accessible for na\u0131\u0308ve CD8 T cells. In mouse bone marrow chimeras generated at different ages, recent thymic emigrants were tolerized to a skin-expressed major histocompatibility complex class I antigen only during a neonatal period but not during adulthood. Blockade of T cell migration neonatally prevented tolerance induction. Thus, T cell trafficking through nonlymphoid tissues in the neonate is crucial for the establishment of self tolerance to sessile, skin-expressed antigens.<\/jats:p>","DOI":"10.1126\/science.282.5392.1338","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T05:44:47Z","timestamp":1027748687000},"page":"1338-1341","source":"Crossref","is-referenced-by-count":104,"title":["Control of Neonatal Tolerance to Tissue Antigens by Peripheral T Cell Trafficking"],"prefix":"10.1126","volume":"282","author":[{"given":"Judith","family":"Alferink","sequence":"first","affiliation":[{"name":"J. Alferink, A. Tafuri, G. J. Ha\u0308mmerling, B. Arnold, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany. D. Vestweber, Institute of Cell Biology, University of Mu\u0308nster, 48149 Mu\u0308nster, Germany. R. Hallmann, Institute for Experimental Medicine, University of Erlangen-Nu\u0308rnberg, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Tafuri","sequence":"additional","affiliation":[{"name":"J. Alferink, A. Tafuri, G. J. Ha\u0308mmerling, B. Arnold, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany. D. Vestweber, Institute of Cell Biology, University of Mu\u0308nster, 48149 Mu\u0308nster, Germany. R. Hallmann, Institute for Experimental Medicine, University of Erlangen-Nu\u0308rnberg, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietmar","family":"Vestweber","sequence":"additional","affiliation":[{"name":"J. Alferink, A. Tafuri, G. J. Ha\u0308mmerling, B. Arnold, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany. D. Vestweber, Institute of Cell Biology, University of Mu\u0308nster, 48149 Mu\u0308nster, Germany. R. Hallmann, Institute for Experimental Medicine, University of Erlangen-Nu\u0308rnberg, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupert","family":"Hallmann","sequence":"additional","affiliation":[{"name":"J. Alferink, A. Tafuri, G. J. Ha\u0308mmerling, B. Arnold, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany. D. Vestweber, Institute of Cell Biology, University of Mu\u0308nster, 48149 Mu\u0308nster, Germany. R. Hallmann, Institute for Experimental Medicine, University of Erlangen-Nu\u0308rnberg, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gu\u0308nter J.","family":"Ha\u0308mmerling","sequence":"additional","affiliation":[{"name":"J. Alferink, A. Tafuri, G. J. Ha\u0308mmerling, B. Arnold, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany. D. Vestweber, Institute of Cell Biology, University of Mu\u0308nster, 48149 Mu\u0308nster, Germany. R. Hallmann, Institute for Experimental Medicine, University of Erlangen-Nu\u0308rnberg, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Arnold","sequence":"additional","affiliation":[{"name":"J. Alferink, A. Tafuri, G. J. Ha\u0308mmerling, B. Arnold, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany. D. Vestweber, Institute of Cell Biology, University of Mu\u0308nster, 48149 Mu\u0308nster, Germany. R. Hallmann, Institute for Experimental Medicine, University of Erlangen-Nu\u0308rnberg, 91054 Erlangen, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/172603a0"},{"key":"e_1_3_2_3_2","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1002\/eji.1830200805","volume":"20","author":"Abramowicz D.","year":"1990","unstructured":"Abramowicz D., et al., Eur. J. Immunol. 20, 1647 (1990);","journal-title":"Eur. J. Immunol."},{"key":"e_1_3_2_3_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/00007890-199107000-00001","volume":"52","author":"Streilein J. W.","year":"1991","unstructured":"Streilein J. W., Transplantation 52, 1 (1991);","journal-title":"Transplantation"},{"key":"e_1_3_2_3_4","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1084\/jem.154.3.581","volume":"154","author":"Piguet P.-F.","year":"1981","unstructured":"Piguet P.-F., Irle C., Kollatte E., Vassalli P., J. Exp. Med. 154, 581 (1981);","journal-title":"J. Exp. Med."},{"key":"e_1_3_2_3_5","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1093\/intimm\/6.6.795","volume":"6","author":"Martin C.","year":"1994","unstructured":"Martin C., Belo M., Le Douarin N. M., Corbel C., Int. Immunol. 6, 795 (1994);","journal-title":"Int. Immunol."},{"key":"e_1_3_2_3_6","doi-asserted-by":"crossref","first-page":"3661","DOI":"10.4049\/jimmunol.138.11.3661","volume":"138","author":"Wood P. J.","year":"1987","unstructured":"Wood P. J., Strome P. G., Streilein J. W., J. Immunol. 138, 3661 (1987);","journal-title":"J. Immunol."},{"key":"e_1_3_2_3_7","doi-asserted-by":"publisher","DOI":"10.1126\/science.271.5256.1728"},{"key":"e_1_3_2_3_8","unstructured":"; J. P. Ridge E. J. Fuchs P. Matzinger ibid. p. 1723; M. Sarzotti D. S. Robbins P. M. Hoffman ibid. p. 1726."},{"key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1093\/intimm\/7.10.1567","volume":"7","author":"Kimpton W. G.","year":"1995","unstructured":"Kimpton W. G., Washington E. A., Cahill R. N. P., Int. Immunol. 7, 1567 (1995);","journal-title":"Int. Immunol."},{"key":"e_1_3_2_4_3","doi-asserted-by":"publisher","DOI":"10.1084\/jem.171.3.801"},{"key":"e_1_3_2_4_4","doi-asserted-by":"crossref","first-page":"3062","DOI":"10.4049\/jimmunol.154.7.3062","volume":"154","author":"Brezinschek R. J.","year":"1995","unstructured":"Brezinschek R. J., Lipsky P. E., Galea P., Vita R., Oppenheimer-Marks N., J. Immunol. 154, 3062 (1995).","journal-title":"J. Immunol."},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1093\/intimm\/7.2.331","volume":"7","author":"Alferink J.","year":"1995","unstructured":"Alferink J., Schittek B., Sch\u00f6nrich G., H\u00e4mmerling G. J., Arnold B., Int. Immunol. 7, 331 (1995);","journal-title":"Int. Immunol."},{"key":"e_1_3_2_5_3","first-page":"581","volume":"4","author":"Sch\u00f6nrich G.","year":"1992","unstructured":"Sch\u00f6nrich G., et al., ibid. 4, 581 (1992).","journal-title":"ibid."},{"key":"e_1_3_2_6_2","unstructured":"Chimeras were generated by intravenous inoculation of T cell\u2013depleted BM cells from Des-TCR mice into nonirradiated 2.4KerIV-K b .Rag-2 \u2013\/\u2013 mice at different ages. For neonatal mice 2 \u00d7 10 5 cells were injected into the anterior facial vein; 15-day-old and adult recipients were injected with 10 6 cells and 2 \u00d7 10 6 cells respectively in the tail vein. Phenotypic analysis of spleen and lymph node cells was performed with mAbs specific for the clonotypic Des-TCR (D\u00e9sir\u00e9-1) (6) and for mouse CD8 (53-6.7 Pharmingen)."},{"key":"e_1_3_2_7_2","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.4049\/jimmunol.136.6.1937","volume":"136","author":"Hua C.","year":"1986","unstructured":"Hua C., Boyer C., Buferne M., Schmitt-Verhulst A.-M., J. Immunol. 136, 1937 (1986).","journal-title":"J. Immunol."},{"key":"e_1_3_2_8_2","unstructured":"Des-TCRx2.4KerIV-K b and Des-TCR mice have been described (4). All mice were kept under specific pathogen\u2013free conditions at the central animal facility of the German Cancer Research Center. Tumor growth was evaluated as described (4)."},{"key":"e_1_3_2_9_2","unstructured":"Des-TCR \u2192 2.4KerIV-K b .Rag-2 \u2013\/\u2013 chimeras were grafted under anesthesia on their lateral thoracic walls with skin autografts from their tails. Chronic rejection accompanied by hair loss of the skin autografts and contracted scar formation started after 14 days. After 4 weeks a second skin transplant was rejected by the majority of chimeras (median survival time 15 days). No autoimmune response against the endogenous K b transgene\u2013expressing keratinocytes could be seen by immunofluorescence histology as judged by the absence of infiltrating Des-TCR T cells in the thoracic wall skin from the grafted and contralateral side."},{"key":"e_1_3_2_10_2","unstructured":"Neonatal Des-TCRx2.4KerIV-K b mice were injected every third day with 50 \u03bcg of D\u00e9sir\u00e9-1 mAb during the first 15 days after birth which reduced the Des-TCR T cells to less than 1%. Injection of P815.K b was performed at the age of 6 weeks."},{"key":"e_1_3_2_11_2","unstructured":"J. Alferink A. Tafuri D. Vestweber R. Hallmann G. J. H\u00e4mmerling B. Arnold data not shown."},{"key":"e_1_3_2_12_2","unstructured":"Sixteen Des-TCR mice grafted on their lateral thoracic walls with skin grafts from either neonatal or 5-week-old 2.4KerIV-K b .Rag-2 \u2013\/\u2013 mice (eight mice per group) rejected the transplanted skin (median survival time 24 days)."},{"key":"e_1_3_2_13_2","unstructured":"B cell\u2013depleted spleen and lymph node cells from Des-TCR mice were 51 Cr-labeled and injected intravenously into groups of at least six neonatal (2 \u00d7 10 5 cells) and adult 2.4KerIV-K b (2 \u00d7 10 6 cells) recipients. After whole-body perfusion the distribution of radioactivity in various organs was determined in a \u03b3-counter. Radiolabeled cells accumulated in neonatal versus adult skin in ratios of 8.41:1 6.22:1 and 10:1 in three independent experiments."},{"key":"e_1_3_2_14_2","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1097\/00007890-197209000-00009","volume":"14","author":"Halstead T. E.","year":"1972","unstructured":"Halstead T. E., Hall J. G., Transplantation 14, 339 (1972).","journal-title":"Transplantation"},{"key":"e_1_3_2_15_2","unstructured":"B cell\u2013depleted spleen and lymph node cells (10 6 ) from Des-TCR mice were labeled with 5 6-carboxy-succinimidyl fluorescein-ester (CFSE 0.5 \u03bcm\/ml; Molecular Probes) at 37\u00b0C for 15 min and injected into adult or neonatal 2.4KerIV-K b mice. After 4 hours whole-body perfusion was performed and the number of CFSE-labeled cells was determined by immunohistological analysis of the skin. CFSE-positive cells were enriched in neonatal skin and were only rarely visible in adult skin."},{"key":"e_1_3_2_16_2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/385081a0","volume":"385","author":"Austrup F.","year":"1997","unstructured":"Austrup F., et al., Nature 385, 81 (1997);","journal-title":"Nature"},{"key":"e_1_3_2_16_3","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/(SICI)1096-9896(199611)180:3<317::AID-PATH670>3.0.CO;2-O","volume":"180","author":"Henseleit U.","year":"1996","unstructured":"Henseleit U., et al., J. Pathol. 180, 317 (1996).","journal-title":"J. Pathol."},{"key":"e_1_3_2_17_2","unstructured":"Neonatal Des-TCRx2.4KerIV-K b mice were injected intraperitoneally every second day with 20 \u03bcg of mouse E-selectin mAb UZ4 [rat immunoglobulin M (IgM)] and mouse P-selectin mAb RB40.34 (rat IgG1) from day 0 until day 7 and with 40 \u03bcg of antibody mixture from day 8 until day 15 ["},{"key":"e_1_3_2_17_3","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3109\/03009749509100909","volume":"101","author":"Hallmann R.","year":"1995","unstructured":"Hallmann R., Zimmermann U., Sorokin L. M., Needham L., Von der Mark K., Scand. J. Rheumatol. Suppl. 101, 107 (1995);","journal-title":"Scand. J. Rheumatol. Suppl."},{"key":"e_1_3_2_17_4","doi-asserted-by":"crossref","first-page":"3019","DOI":"10.1002\/eji.1830241215","volume":"24","author":"Bosse R.","year":"1994","unstructured":"Bosse R., Vestweber D., Eur. J. Immunol. 24, 3019 (1994);","journal-title":"Eur. J. Immunol."},{"key":"e_1_3_2_17_5","unstructured":"]. Control groups were either noninjected or received an equivalent amount of purified irrelevant rat serum Ig containing IgM and IgG1. Four weeks after the treatment with mAbs recipient mice were challenged with 10 5 P815.K b tumor cells. The observed inhibition does not exclude the possibility that migration of na\u0131\u0308ve T cells into the neonatal skin is controlled by the expression of additional developmentally regulated adhesion molecules."},{"key":"e_1_3_2_18_2","unstructured":"E- and P-selectin are up-regulated on vascular endothelium during inflammation. The presence of P-selectin in noninflamed tissue appears to be low and seems to require highly sensitive techniques for detection (18). In agreement with this finding we observed low expression of P-selectin immunohistochemically in the skin of 5 of 10 newborn mice."},{"key":"e_1_3_2_19_2","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1161\/01.RES.79.3.560","volume":"79","author":"Eppihimer M. J.","year":"1996","unstructured":"Eppihimer M. J., Wolitzky B., Anderson D. C., Labow M. A., Granger D. N., Circ. Res. 79, 560 (1996).","journal-title":"Circ. Res."},{"key":"e_1_3_2_20_2","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1084\/jem.172.6.1701","volume":"172","author":"Powrie F.","year":"1990","unstructured":"Powrie F., Mason D., J. Exp. Med. 172, 1701 (1990);","journal-title":"J. Exp. Med."},{"key":"e_1_3_2_20_3","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1073\/pnas.89.1.421","volume":"89","author":"Miller A.","year":"1992","unstructured":"Miller A., Lider O., Roberts A. B., Sporn M. B., Weiner H. L., Proc. Natl. Acad. Sci. U.S.A. 89, 421 (1992);","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_2_20_4","doi-asserted-by":"publisher","DOI":"10.1126\/science.8094901"},{"key":"e_1_3_2_20_5","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/j.1600-065X.1996.tb00903.x","volume":"149","author":"Modigliani Y.","year":"1996","unstructured":"Modigliani Y., Bandeira A., Coutinho A., Immunol. Rev. 149, 155 (1996).","journal-title":"Immunol. Rev."},{"key":"e_1_3_2_21_2","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1084\/jem.187.10.1549","volume":"187","author":"Heath W. R.","year":"1998","unstructured":"Heath W. R., Kurts C., Miller J. F. A. P., Carbone F. R., J. Exp. Med. 187, 1549 (1998);","journal-title":"J. Exp. Med."},{"key":"e_1_3_2_21_3","first-page":"923","volume":"184","author":"Kurts C.","year":"1996","unstructured":"Kurts C., et al., ibid. 184, 923 (1996).","journal-title":"ibid."},{"key":"e_1_3_2_22_2","unstructured":"We thank F. W. Alt for Rag-2 \u2013\/\u2013 mice; J. Sch\u00f6ffel A. Klevenz S. Schmitt and G. K\u00fcblbeck for excellent technical assistance; E. Armandola T. Sacher and A. Forde for critical reading of the manuscript; A. Frenznick C. Ley and S. Hartmann for animal husbandry; S. Copson for help with the manuscript; and G. Moldenhauer for providing control antibody. Supported by grants from Deutsche Forschungsgemeinschaft (SFB 405) the European Union (BIO4-CT-960077 and BIO4-97-2151) and VW-Stiftung (I\/72422)."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.282.5392.1338","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T00:33:21Z","timestamp":1705106001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.282.5392.1338"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,11,13]]},"references-count":38,"journal-issue":{"issue":"5392","published-print":{"date-parts":[[1998,11,13]]}},"alternative-id":["10.1126\/science.282.5392.1338"],"URL":"https:\/\/doi.org\/10.1126\/science.282.5392.1338","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.3921956.3670054","asserted-by":"object"}]},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,11,13]]}}}