{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T07:31:59Z","timestamp":1792654319769,"version":"4.5.0"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2014,2,2]],"date-time":"2014-02-02T00:00:00Z","timestamp":1391299200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nat Immunol"],"published-print":{"date-parts":[[2014,3]]},"DOI":"10.1038\/ni.2822","type":"journal-article","created":{"date-parts":[[2014,2,2]],"date-time":"2014-02-02T14:35:19Z","timestamp":1391351719000},"page":"266-274","source":"Crossref","is-referenced-by-count":171,"title":["Intrinsic CD4+ T cell sensitivity and response to a pathogen are set and sustained by avidity for thymic and peripheral complexes of self peptide and MHC"],"prefix":"10.1038","volume":"15","author":[{"given":"Stephen P","family":"Persaud","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsea R","family":"Parker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Lin","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K Scott","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,2,2]]},"reference":[{"key":"BFni2822_CR1","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1146\/annurev.immunol.21.120601.141036","volume":"21","author":"PA van der Merwe","year":"2003","unstructured":"van der Merwe, P.A. & Davis, S.J. Molecular interactions mediating T cell antigen recognition. Annu. Rev. Immunol. 21, 659\u2013684 (2003).","journal-title":"Annu. Rev. Immunol."},{"key":"BFni2822_CR2","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1146\/annurev.immunol.16.1.523","volume":"16","author":"MM Davis","year":"1998","unstructured":"Davis, M.M. et al. Ligand recognition by \u03b1\u03b2 T cell receptors. Annu. Rev. Immunol. 16, 523\u2013544 (1998).","journal-title":"Annu. Rev. Immunol."},{"key":"BFni2822_CR3","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/ni.2190","volume":"13","author":"GP Morris","year":"2012","unstructured":"Morris, G.P. & Allen, P.M. How the TCR balances sensitivity and specificity for the recognition of self and pathogens. Nat. Immunol. 13, 121\u2013128 (2012).","journal-title":"Nat. Immunol."},{"key":"BFni2822_CR4","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S1074-7613(00)80092-8","volume":"11","author":"B Ernst","year":"1999","unstructured":"Ernst, B., Lee, D.S., Chang, J.M., Sprent, J. & Surh, C.D. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11, 173\u2013181 (1999).","journal-title":"Immunity"},{"key":"BFni2822_CR5","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature03391","volume":"434","author":"M Krogsgaard","year":"2005","unstructured":"Krogsgaard, M. et al. Agonist\/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity. Nature 434, 238\u2013243 (2005).","journal-title":"Nature"},{"key":"BFni2822_CR6","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1038\/ni.1796","volume":"10","author":"WL Lo","year":"2009","unstructured":"Lo, W.L. et al. An endogenous peptide positively selects and augments the activation and survival of peripheral CD4+ T cells. Nat. Immunol. 10, 1155\u20131161 (2009).","journal-title":"Nat. Immunol."},{"key":"BFni2822_CR7","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1084\/jem.186.8.1269","volume":"186","author":"J Kirberg","year":"1997","unstructured":"Kirberg, J., Berns, A. & von Boehmer, H. Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex-encoded molecules. J. Exp. Med. 186, 1269\u20131275 (1997).","journal-title":"J. Exp. Med."},{"key":"BFni2822_CR8","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.immuni.2009.11.014","volume":"32","author":"JH Cho","year":"2010","unstructured":"Cho, J.H., Kim, H.O., Surh, C.D. & Sprent, J. T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis. Immunity 32, 214\u2013226 (2010).","journal-title":"Immunity"},{"key":"BFni2822_CR9","doi-asserted-by":"crossref","first-page":"3345","DOI":"10.4049\/jimmunol.166.5.3345","volume":"166","author":"GJ Kersh","year":"2001","unstructured":"Kersh, G.J. et al. Structural and functional consequences of altering a peptide MHC anchor residue. J. Immunol. 166, 3345\u20133354 (2001).","journal-title":"J. Immunol."},{"key":"BFni2822_CR10","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1126\/science.1124228","volume":"312","author":"J Hataye","year":"2006","unstructured":"Hataye, J., Moon, J.J., Khoruts, A., Reilly, C. & Jenkins, M.K. Naive and memory CD4+ T cell survival controlled by clonal abundance. Science 312, 114\u2013116 (2006).","journal-title":"Science"},{"key":"BFni2822_CR11","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.immuni.2008.04.010","volume":"28","author":"JJ Obar","year":"2008","unstructured":"Obar, J.J., Khanna, K.M. & Lefrancois, L. Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28, 859\u2013869 (2008).","journal-title":"Immunity"},{"key":"BFni2822_CR12","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.immuni.2004.09.008","volume":"21","author":"L Malherbe","year":"2004","unstructured":"Malherbe, L., Hausl, C., Teyton, L. & McHeyzer-Williams, M.G. Clonal selection of helper T cells is determined by an affinity threshold with no further skewing of TCR binding properties. Immunity 21, 669\u2013679 (2004).","journal-title":"Immunity"},{"key":"BFni2822_CR13","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1084\/jem.189.4.701","volume":"189","author":"DH Busch","year":"1999","unstructured":"Busch, D.H. & Pamer, E.G. T cell affinity maturation by selective expansion during infection. J. Exp. Med. 189, 701\u2013710 (1999).","journal-title":"J. Exp. Med."},{"key":"BFni2822_CR14","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.immuni.2007.07.007","volume":"27","author":"JJ Moon","year":"2007","unstructured":"Moon, J.J. et al. Naive CD4+ T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27, 203\u2013213 (2007).","journal-title":"Immunity"},{"key":"BFni2822_CR15","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/nature07657","volume":"458","author":"D Zehn","year":"2009","unstructured":"Zehn, D., Lee, S.Y. & Bevan, M.J. Complete but curtailed T-cell response to very low-affinity antigen. Nature 458, 211\u2013214 (2009).","journal-title":"Nature"},{"key":"BFni2822_CR16","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1084\/jem.188.12.2301","volume":"188","author":"HS Azzam","year":"1998","unstructured":"Azzam, H.S. et al. CD5 expression is developmentally regulated by T cell receptor (TCR) signals and TCR avidity. J. Exp. Med. 188, 2301\u20132311 (1998).","journal-title":"J. Exp. Med."},{"key":"BFni2822_CR17","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.immuni.2012.09.011","volume":"38","author":"JN Mandl","year":"2013","unstructured":"Mandl, J.N., Monteiro, J.P., Vrisekoop, N. & Germain, R.N. T cell-positive selection uses self-ligand binding strength to optimize repertoire recognition of foreign antigens. Immunity 38, 263\u2013274 (2013).","journal-title":"Immunity"},{"key":"BFni2822_CR18","doi-asserted-by":"crossref","first-page":"9511","DOI":"10.1073\/pnas.1202408109","volume":"109","author":"KS Weber","year":"2012","unstructured":"Weber, K.S. et al. Distinct CD4+ helper T cells involved in primary and secondary responses to infection. Proc. Natl. Acad. Sci. USA 109, 9511\u20139516 (2012).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFni2822_CR19","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1146\/annurev.immunol.17.1.221","volume":"17","author":"M Lenardo","year":"1999","unstructured":"Lenardo, M. et al. Mature T lymphocyte apoptosis\u2013immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17, 221\u2013253 (1999).","journal-title":"Annu. Rev. Immunol."},{"key":"BFni2822_CR20","doi-asserted-by":"crossref","first-page":"5931","DOI":"10.1073\/pnas.0911877107","volume":"107","author":"K Hochweller","year":"2010","unstructured":"Hochweller, K. et al. Dendritic cells control T cell tonic signaling required for responsiveness to foreign antigen. Proc. Natl. Acad. Sci. USA 107, 5931\u20135936 (2010).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFni2822_CR21","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nature01146","volume":"420","author":"I Stefanov\u00e1","year":"2002","unstructured":"Stefanov\u00e1, I., Dorfman, J.R. & Germain, R.N. Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420, 429\u2013434 (2002).","journal-title":"Nature"},{"key":"BFni2822_CR22","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/ni.2379","volume":"13","author":"WL Lo","year":"2012","unstructured":"Lo, W.L., Donermeyer, D.L. & Allen, P.M. A voltage-gated sodium channel is essential for the positive selection of CD4+ T cells. Nat. Immunol. 13, 880\u2013887 (2012).","journal-title":"Nat. Immunol."},{"key":"BFni2822_CR23","first-page":"269","volume":"3","author":"J Kaye","year":"1991","unstructured":"Kaye, J., Kersh, G., Engel, I. & Hedrick, S.M. Structure and specificity of the T cell antigen receptor. Semin. Immunol. 3, 269\u2013281 (1991).","journal-title":"Semin. Immunol."},{"key":"BFni2822_CR24","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1084\/jem.20110308","volume":"208","author":"AE Moran","year":"2011","unstructured":"Moran, A.E. et al. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279\u20131289 (2011).","journal-title":"J. Exp. Med."},{"key":"BFni2822_CR25","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1084\/jem.194.9.1253","volume":"194","author":"K Smith","year":"2001","unstructured":"Smith, K. et al. Sensory adaptation in naive peripheral CD4 T cells. J. Exp. Med. 194, 1253\u20131261 (2001).","journal-title":"J. Exp. Med."},{"key":"BFni2822_CR26","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.4049\/jimmunol.167.4.2209","volume":"167","author":"M Skoberne","year":"2001","unstructured":"Skoberne, M., Holtappels, R., Hof, H. & Geginat, G. Dynamic antigen presentation patterns of Listeria monocytogenes-derived CD8 T cell epitopes in vivo. J. Immunol. 167, 2209\u20132218 (2001).","journal-title":"J. Immunol."},{"key":"BFni2822_CR27","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1126\/science.7542801","volume":"269","author":"A Tarakhovsky","year":"1995","unstructured":"Tarakhovsky, A. et al. A role for CD5 in TCR-mediated signal transduction and thymocyte selection. Science 269, 535\u2013537 (1995).","journal-title":"Science"},{"key":"BFni2822_CR28","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.4049\/jimmunol.164.3.1260","volume":"164","author":"XY Zhou","year":"2000","unstructured":"Zhou, X.Y. et al. CD5 costimulation up-regulates the signaling to extracellular signal-regulated kinase activation in CD4+CD8+ thymocytes and supports their differentiation to the CD4 lineage. J. Immunol. 164, 1260\u20131268 (2000).","journal-title":"J. Immunol."},{"key":"BFni2822_CR29","doi-asserted-by":"crossref","first-page":"6494","DOI":"10.4049\/jimmunol.163.12.6494","volume":"163","author":"C Pe\u00f1a-Rossi","year":"1999","unstructured":"Pe\u00f1a-Rossi, C. et al. Negative regulation of CD4 lineage development and responses by CD5. J. Immunol. 163, 6494\u20136501 (1999).","journal-title":"J. Immunol."},{"key":"BFni2822_CR30","doi-asserted-by":"crossref","first-page":"5464","DOI":"10.4049\/jimmunol.166.9.5464","volume":"166","author":"HS Azzam","year":"2001","unstructured":"Azzam, H.S. et al. Fine tuning of TCR signaling by CD5. J. Immunol. 166, 5464\u20135472 (2001).","journal-title":"J. Immunol."},{"key":"BFni2822_CR31","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1038\/ni710","volume":"2","author":"L Gapin","year":"2001","unstructured":"Gapin, L., Matsuda, J.L., Surh, C.D. & Kronenberg, M. NKT cells derive from double-positive thymocytes that are positively selected by CD1d. Nat. Immunol. 2, 971\u2013978 (2001).","journal-title":"Nat. Immunol."},{"key":"BFni2822_CR32","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.immuni.2007.11.021","volume":"28","author":"CW Lio","year":"2008","unstructured":"Lio, C.W. & Hsieh, C.S. A two-step process for thymic regulatory T cell development. Immunity 28, 100\u2013111 (2008).","journal-title":"Immunity"},{"key":"BFni2822_CR33","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1146\/annurev-immunol-020711-075035","volume":"30","author":"GL Stritesky","year":"2012","unstructured":"Stritesky, G.L., Jameson, S.C. & Hogquist, K.A. Selection of self-reactive T cells in the thymus. Annu. Rev. Immunol. 30, 95\u2013114 (2012).","journal-title":"Annu. Rev. Immunol."},{"key":"BFni2822_CR34","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/nature11311","volume":"489","author":"J Zikherman","year":"2012","unstructured":"Zikherman, J., Parameswaran, R. & Weiss, A. Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature 489, 160\u2013164 (2012).","journal-title":"Nature"},{"key":"BFni2822_CR35","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/nature05269","volume":"444","author":"MA Daniels","year":"2006","unstructured":"Daniels, M.A. et al. Thymic selection threshold defined by compartmentalization of Ras\/MAPK signalling. Nature 444, 724\u2013729 (2006).","journal-title":"Nature"},{"key":"BFni2822_CR36","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1038\/nature08944","volume":"464","author":"J Huang","year":"2010","unstructured":"Huang, J. et al. The kinetics of two-dimensional TCR and pMHC interactions determine T-cell responsiveness. Nature 464, 932\u2013936 (2010).","journal-title":"Nature"},{"key":"BFni2822_CR37","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1084\/jem.20101574","volume":"208","author":"JJ Sabatino Jr.","year":"2011","unstructured":"Sabatino, J.J. Jr., Huang, J., Zhu, C. & Evavold, B.D. High prevalence of low affinity peptide-MHC II tetramer-negative effectors during polyclonal CD4+ T cell responses. J. Exp. Med. 208, 81\u201390 (2011).","journal-title":"J. Exp. Med."},{"key":"BFni2822_CR38","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.cell.2013.04.007","volume":"153","author":"NJ Tubo","year":"2013","unstructured":"Tubo, N.J. et al. Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell 153, 785\u2013796 (2013).","journal-title":"Cell"},{"key":"BFni2822_CR39","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.immuni.2013.08.033","volume":"39","author":"C Kim","year":"2013","unstructured":"Kim, C., Wilson, T., Fischer, K.F. & Williams, M.A. Sustained interactions between T cell receptors and antigens promote the differentiation of CD4+ memory T cells. Immunity 39, 508\u2013520 (2013).","journal-title":"Immunity"},{"key":"BFni2822_CR40","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1038\/ncomms3209","volume":"4","author":"B Martin","year":"2013","unstructured":"Martin, B. et al. Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells. Nat. Commun. 4, 2209 (2013).","journal-title":"Nat. Commun."},{"key":"BFni2822_CR41","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1126\/science.281.5376.572","volume":"281","author":"EN Kersh","year":"1998","unstructured":"Kersh, E.N., Shaw, A.S. & Allen, P.M. Fidelity of T cell activation through multistep T cell receptor zeta phosphorylation. Science 281, 572\u2013575 (1998).","journal-title":"Science"},{"key":"BFni2822_CR42","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1016\/j.molimm.2010.02.013","volume":"47","author":"SP Persaud","year":"2010","unstructured":"Persaud, S.P., Donermeyer, D.L., Weber, K.S., Kranz, D.M. & Allen, P.M. High-affinity T cell receptor differentiates cognate peptide-MHC and altered peptide ligands with distinct kinetics and thermodynamics. Mol. Immunol. 47, 1793\u20131801 (2010).","journal-title":"Mol. Immunol."},{"key":"BFni2822_CR43","doi-asserted-by":"crossref","first-page":"19033","DOI":"10.1073\/pnas.0507554102","volume":"102","author":"KS Weber","year":"2005","unstructured":"Weber, K.S., Donermeyer, D.L., Allen, P.M. & Kranz, D.M. Class II-restricted T cell receptor engineered in vitro for higher affinity retains peptide specificity and function. Proc. Natl. Acad. Sci. USA 102, 19033\u201319038 (2005).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFni2822_CR44","doi-asserted-by":"crossref","first-page":"6818","DOI":"10.1073\/pnas.111161198","volume":"98","author":"KC Garcia","year":"2001","unstructured":"Garcia, K.C., Radu, C.G., Ho, J., Ober, R.J. & Ward, E.S. Kinetics and thermodynamics of T cell receptor- autoantigen interactions in murine experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 98, 6818\u20136823 (2001).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFni2822_CR45","doi-asserted-by":"crossref","first-page":"H782","DOI":"10.1152\/ajpheart.00817.2010","volume":"302","author":"H Hallaq","year":"2012","unstructured":"Hallaq, H. et al. Activation of protein kinase C alters the intracellular distribution and mobility of cardiac Na+ channels. Am. J. Physiol. Heart Circ. Physiol. 302, H782\u2013H789 (2012).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"BFni2822_CR46","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nprot.2009.9","volume":"4","author":"JJ Moon","year":"2009","unstructured":"Moon, J.J. et al. Tracking epitope-specific T cells. Nat. Protoc. 4, 565\u2013581 (2009).","journal-title":"Nat. Protoc."}],"container-title":["Nature Immunology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/ni.2822.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/ni.2822","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/ni.2822.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T02:08:32Z","timestamp":1688954912000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ni.2822"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,2,2]]},"references-count":46,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2014,3]]}},"alternative-id":["BFni2822"],"URL":"https:\/\/doi.org\/10.1038\/ni.2822","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.718262119.793494402","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.718262119.793506544","asserted-by":"object"}]},"ISSN":["1529-2908","1529-2916"],"issn-type":[{"value":"1529-2908","type":"print"},{"value":"1529-2916","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,2,2]]}}}