Intrinsic Molecular Logic Underpins Adaptive Immune Rhythms: An IL‑2/Treg Axis‑Centered MICU Model

Abstract Adaptive immune responses follow a stereotyped trajectory: initiation, expansion, contraction, and restoration. The intrinsic origin of this periodicity remains elusive. Here we propose that immune rhythms are encoded by the hierarchical affinities of IL‑2 receptor isoforms and by cytokine supply‑demand asymmetry. IL‑2R exists as a high‑affinity trimer (Kd ≈ 10 pM) and an intermediate‑affinity dimer (Kd ≈ 10 nM), a ~1000‑fold difference. Regulatory T cells (Tregs) constitutively express the high‑affinity receptor; effector T cells (Teffs) upregulate CD25 upon activation; memory T cells and progenitor exhausted T cells (Tpex) predominantly use the intermediate‑affinity receptor. Based on these distinctions, we define four thresholds: I (Treg survival, <1 pM), IIa (memory T cell activation, 1‑10 pM), IIb (Tpex→Tex‑int differentiation, 10‑50 pM), III (Teff clonal expansion, 50‑100 pM), and IV (Treg proliferation, 100‑300 pM). This hierarchy enforces an ordered sequence – Treg survival → memory/Tpex activation → effector expansion → negative feedback – generating a self‑organized five‑phase immune cycle. We define the Minimum Immune Control Unit (MICU) as the minimal closed IL‑2‑Teff‑Treg circuit capable of autonomous oscillation via supply‑demand asymmetry and affinity thresholding. Integrating sCD25‑mediated delayed feedback, the model generates three testable predictions: (i) Tex‑int cells accumulate maximally at 10‑50 pM IL‑2; (ii) sCD25 blockade shortens cycle period and increases peak IL‑2; (iii) low‑dose IL‑2 enhances immunity if given during expansion but strengthens suppression if given during contraction. We further emphasize that Treg suppressive efficacy is not constant; it is modulated by chronic Tpex accumulation. Tpex compete for limited immune niche capacity, thereby competitively inhibiting iTreg differentiation and leading to decreased Treg function (see companion paper II). This refinement explains why acute high‑level IL‑2 does not break tolerance, whereas chronic Tpex accumulation, accompanied by declining Treg function, is the key to tolerance breach. Scope: This model describes local MICU fast dynamics driven by a single dominant antigen (cycle length 7‑14 days). Peripheral blood manifestations represent the de‑synchronized integration of numerous MICUs; slow cycles (months to years) are determined by Tpex‑driven decline of Treg function (companion paper II).