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Human IgE exhibits only one isotype and lacks polymorphisms; IgE is pivotal in mediating diverse, allergen\u2010specific allergies. Therefore, by disrupting self\u2010IgE tolerance via costimulation, the CTLs induced by nECPs can serve as universal allergy vaccines (UAVs) in humans to dampen IgE production mediated by diverse allergen\u2010specific IgE\u2010secreting B cells and plasma cells expressing surface nECP\u2010MHCIa as targets. The study herein has enabled the identification of nECPs, A32 and SP\u20101\/SP\u20102 nonameric natural peptides\u00a0produced through the correspondence principle. Vaccination using nECP induced nECP\u2010specific CTL that profoundly suppressed human IgE production in vitro as well as chimeric human IgE production in human IgE\/HLA\u2010A2.01\/HLA\u2010B7.02 triple transgenic rodents. Furthermore, nECP\u2010tetramer\u2010specific CTLs were found to be converted into CD4 Tregs that restored IgE competence via the homeostatic principle, mediatepred by SREBP\u20101c suppressed DCs. Thus, nECPs showed causal efficacy and safety as UAVs for treating categorically type I hypersensitivity IgE\u2010mediated allergies. The applied vaccination concept presented provides the foundation to unify, integrate through a singular class of tetramer\u2010specific TCR clonotypes for regulaing human IgE production. The three signal theory pertains to mechanisms of three cells underlying central tolerance (S), breaking self tolerance (NS) and regaining peripheral tolerance (S) via homeostasis\u00a0concerning nECP as an efficacious and safe UAV to treat type I IgE\u2010mediated hypersensitivity. The three signal theory impirically extended, may be heuritic for immuno\u2010regulation of adaptive immune repertoire in general.<\/jats:p>","DOI":"10.1111\/imm.13753","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T23:34:15Z","timestamp":1706830455000},"page":"91-108","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Abrogation and homeostatic restoration of\n                    <scp>IgE<\/scp>\n                    responses by a universal\n                    <scp>IgE<\/scp>\n                    allergy\n                    <scp>CTL<\/scp>\n                    vaccine\u2014The three signal self\/\n                    <scp>non\u2010self<\/scp>\n                    \/self (S\/\n                    <scp>NS<\/scp>\n                    \/S) theory"],"prefix":"10.1111","volume":"172","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2508-7707","authenticated-orcid":false,"given":"Swey\u2010Shen","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Immunology and Inflammation AAIIT LLC  San Diego California USA"},{"name":"Division of Vaccinology and Immunotherapy IGE Therapeutics and Pharmaceuticals, Inc  San Diego California USA"},{"name":"Department of Protein Display and Molecular Evolution The Institute of Genetics at San Diego  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hailan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology and Inflammation AAIIT LLC  San Diego California USA"},{"name":"Division of Vaccinology and Immunotherapy IGE Therapeutics and Pharmaceuticals, Inc  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,2]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.1991.tb01575.x"},{"key":"e_1_2_9_3_1","unstructured":"ChenS\u2010S.Immunoglobulin E vaccines and methods of use thereof USPTO 2009; US Patent 7 604 955."},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.157.2.772"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.160.4.953"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830211024"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830220209"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830260513"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abm0594"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep11581"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2005.02.005"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2008.06.008"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s002510050594"},{"key":"e_1_2_9_14_1","unstructured":"ChenS\u2010S.Universal non\u2010classical MHC I vaccines: HLA\u2010E\u2010restricted antigenic peptides as universal vaccines to treat allergy inflammation autoimmune and infectious diseases and cancers. 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