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

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.