Critical Dynamics of Peripheral Immune Tolerance: A Treg-Tpex Antagonism Framework for Phase Transition and Immune State Stratification

Critical Dynamics of Peripheral Immune Tolerance: A Treg-Tpex Antagonism Framework for Phase Transition and Immune State Stratification | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Critical Dynamics of Peripheral Immune Tolerance: A Treg-Tpex Antagonism Framework for Phase Transition and Immune State Stratification Yuanshan Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9648114/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Paradigm shift: Peripheral immune tolerance is proposed here not as a static steady state but as a critical dynamical system, driven by the continuous accumulation of progenitor-exhausted T cells (Tpex). Under specific conditions, minor perturbations may trigger a nonlinear phase transition toward effector immunity. Core concept: This paper introduces a conceptual Tolerance Stability Index, S = F_Treg / N_Tpex, where F_Treg is a composite Treg suppressive function score (integrating CTLA-4 expression, IL-10 secretion, and in vitro suppression IC50), and N_Tpex is the antigen-specific Tpex load (cells per immune niche, focusing on CD4 + Tpex with phenotype CD4 + CD45RO + PD-1 + TCF-1+). As a dimensionless theoretical order parameter, S is proposed to characterize the system's response tendency to chronic antigens with established tolerance. When S approaches a critical threshold S*, the system enters a highly sensitive state. The following regimes are hypothesized: S > > S* (e.g., before 4–6 years of age) → strong tolerance S slightly above S* (e.g., young adulthood) → requires sufficient danger signals to trigger a response S = < S* (e.g., self-antigens in the elderly) → minor perturbations may shift the system to an effector state A simplified research estimator S_clin ≈ Treg% / Tpex% is provided strictly for trend monitoring under standardized protocols and is strictly prohibited for clinical decision-making. This framework applies to chronic antigens exposed from infancy with established long-term tolerance (self-antigens, chronic HBV, latent viruses). Responses to novel adult-onset antigens further depend on the naive T-cell repertoire. Detailed formulas and protocols are in the Supplementary Materials. Mechanistic insight: Specific immune responses are initiated by a hierarchical four-gate model (APC activation, repertoire, suppression, and effector amplification). This framework focuses on Treg-Tpex antagonism within the suppression gate. Persistent chronic antigen stimulation drives T cells to differentiate into Tpex, whose accumulation increases the denominator of S, occupies immune niche space, and consumes homeostatic cytokines (IL-7/IL-15). The elderly may exhibit a "dual-track" pattern: a reduced naive T-cell repertoire limits responses to new antigens, while preserved Tpex reserves support rhythmic fluctuations to chronic/self-antigens (theoretical speculation requiring experimental testing). Clinical unification: The framework conceptually unifies the age-dependent chronicity of HBV, relapse-remission in autoimmune diseases, and tumor immune escape, thereby offering a theoretical basis for immune interventions in chronic antigen-related diseases. Conclusion: Tolerance can be viewed as a controllable critical system. S provides a quantitative bridge for immune status monitoring, but clinical translation requires multi-center calibration and prospective validation. Peripheral immune tolerance Treg-Tpex antagonism Tolerance Stability Index S phase transition dynamics four-gate model immune niche Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9648114","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":636541636,"identity":"ecb5439d-1775-48a6-bc5e-a05fa8c7b88d","order_by":0,"name":"Yuanshan Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYFACHghlAMTMIAY/M/PhB6RpkWxnSzMgTYvBeR4FCXwaDI6fPSbNU3PH3pz97OHPBTV37DYf5gHqr7GJxqVFsicvTZrn2LPEnT15CcYzjj1L3naY98ADhmNpuQ04tPBL8JhJ87AdTjA4kGOQDGQkmx3mSzBgbDiMUwsbWMu/w/YG598YHAYyko2beQwk8GkB28Lbdphxw40cw2Ygw86AmYAWyZ4cY8u5fYcTN9x4Y8zM23c4QeIwMJAT8PjF4PgZwxtvvoEclmP8mQfI4O8/fPjBhxobnFqAgAUlFhLBKhNwKwcB5g/IPHv8ikfBKBgFo2AkAgAYAll6OMzKuwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0008-6731-8706","institution":"Xuancheng Central Hospital,Xuancheng,China","correspondingAuthor":true,"prefix":"","firstName":"Yuanshan","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2026-05-08 03:09:47","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9648114/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9648114/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109297809,"identity":"4ba54c20-32e2-4fe5-88b9-3d807a8ed42f","added_by":"auto","created_at":"2026-05-15 09:06:10","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":502182,"visible":true,"origin":"","legend":"","description":"","filename":"CriticalDynamicsofPeripheralImmuneTolerance.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9648114/v1_covered_a4bba494-22d2-4d7a-b67b-f072930eb9c5.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eCritical Dynamics of Peripheral Immune Tolerance: A Treg-Tpex Antagonism Framework for Phase Transition and Immune State Stratification\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Xuancheng Central Hospital","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Peripheral immune tolerance, Treg-Tpex antagonism, Tolerance Stability Index S, phase transition dynamics, four-gate model, immune niche","lastPublishedDoi":"10.21203/rs.3.rs-9648114/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9648114/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eParadigm shift: Peripheral immune tolerance is proposed here not as a static steady state but as a critical dynamical system, driven by the continuous accumulation of progenitor-exhausted T cells (Tpex). Under specific conditions, minor perturbations may trigger a nonlinear phase transition toward effector immunity.\u003c/p\u003e \u003cp\u003eCore concept: This paper introduces a conceptual Tolerance Stability Index, S\u0026thinsp;=\u0026thinsp;F_Treg / N_Tpex, where F_Treg is a composite Treg suppressive function score (integrating CTLA-4 expression, IL-10 secretion, and in vitro suppression IC50), and N_Tpex is the antigen-specific Tpex load (cells per immune niche, focusing on CD4\u0026thinsp;+\u0026thinsp;Tpex with phenotype CD4\u0026thinsp;+\u0026thinsp;CD45RO\u0026thinsp;+\u0026thinsp;PD-1\u0026thinsp;+\u0026thinsp;TCF-1+). As a dimensionless theoretical order parameter, S is proposed to characterize the system's response tendency to chronic antigens with established tolerance. When S approaches a critical threshold S*, the system enters a highly sensitive state. The following regimes are hypothesized:\u003c/p\u003e \u003cp\u003eS\u0026thinsp;\u0026gt;\u0026thinsp;\u0026gt;\u0026thinsp;S* (e.g., before 4\u0026ndash;6 years of age) \u0026rarr; strong tolerance\u003c/p\u003e \u003cp\u003eS slightly above S* (e.g., young adulthood) \u0026rarr; requires sufficient danger signals to trigger a response\u003c/p\u003e \u003cp\u003eS\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;S* (e.g., self-antigens in the elderly) \u0026rarr; minor perturbations may shift the system to an effector state\u003c/p\u003e \u003cp\u003eA simplified research estimator S_clin\u0026thinsp;\u0026asymp;\u0026thinsp;Treg% / Tpex% is provided strictly for trend monitoring under standardized protocols and is strictly prohibited for clinical decision-making. This framework applies to chronic antigens exposed from infancy with established long-term tolerance (self-antigens, chronic HBV, latent viruses). Responses to novel adult-onset antigens further depend on the naive T-cell repertoire. Detailed formulas and protocols are in the Supplementary Materials.\u003c/p\u003e \u003cp\u003eMechanistic insight: Specific immune responses are initiated by a hierarchical four-gate model (APC activation, repertoire, suppression, and effector amplification). This framework focuses on Treg-Tpex antagonism within the suppression gate. Persistent chronic antigen stimulation drives T cells to differentiate into Tpex, whose accumulation increases the denominator of S, occupies immune niche space, and consumes homeostatic cytokines (IL-7/IL-15). The elderly may exhibit a \"dual-track\" pattern: a reduced naive T-cell repertoire limits responses to new antigens, while preserved Tpex reserves support rhythmic fluctuations to chronic/self-antigens (theoretical speculation requiring experimental testing).\u003c/p\u003e \u003cp\u003eClinical unification: The framework conceptually unifies the age-dependent chronicity of HBV, relapse-remission in autoimmune diseases, and tumor immune escape, thereby offering a theoretical basis for immune interventions in chronic antigen-related diseases.\u003c/p\u003e \u003cp\u003eConclusion: Tolerance can be viewed as a controllable critical system. S provides a quantitative bridge for immune status monitoring, but clinical translation requires multi-center calibration and prospective validation.\u003c/p\u003e","manuscriptTitle":"Critical Dynamics of Peripheral Immune Tolerance: A Treg-Tpex Antagonism Framework for Phase Transition and Immune State Stratification","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-14 13:19:30","doi":"10.21203/rs.3.rs-9648114/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5d52f666-adf6-438a-ac63-9918b097cee0","owner":[],"postedDate":"May 14th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-14T13:19:30+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-14 13:19:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9648114","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9648114","identity":"rs-9648114","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}