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bioRxiv · 10.64898/2026.05.18.725872

Hierarchical Immune Suppressive Functions of Regulatory T Cells Built on Mechanical Force

Liu, X.·Huang, C.·Wang, X.·Kang, J.·Zou, C.·Xu, Y.·Wu, L.·Shi, Y.
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Abstract

Regulatory T (Treg) cells maintain immune tolerance via contact-dependent inhibition and soluble mediators. While canonical suppressive mechanisms are well characterized, their hierarchical spatiotemporal organization remains unclear. We previously showed Foxp3 represses ER Ca2+ channel RyR2, reducing cytoplasmic Ca2+ to inactivate m-Calpain (Calpain-2) and stabilize high-affinity LFA-1-mediated Treg-dendritic cell (DC) adhesion--an early step blocking DC antigen presentation. Using m-Calpain as a molecular switch, we generated mechanically deficient Tregs (TregFD) with constitutively active m-Calpain that abrogated high-force Treg-DC adhesion. TregFD retained a near-wild-type transcriptome (differential expression limited to adhesion pathways), yet failed to suppress autoimmunity or DC-driven T cell proliferation. Stable adhesion was required for localized TGF-{beta}/IL-10 delivery to DCs. Single-cell RNA sequencing of rescued Scurfy mouse lymphoid tissues revealed organ-specific division of labor: non-mechanical modules support homeostasis/tissue repair, while mechanical modules dominate epithelial barrier/antigen presentation suppression. Combined TregFD and RyR2-deficient Tconv transfer restored wild-type Treg activity, demonstrating module synergism. These findings establish a mechanical force-centered, two-tiered hierarchical model of Treg suppression, providing a framework for targeting Treg mechanics in autoimmunity and inflammation.

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Liu, X., Huang, C., Wang, X., Kang, J., Zou, C., Xu, Y., Wu, L., Shi, Y.. 2026-05-21. Hierarchical Immune Suppressive Functions of Regulatory T Cells Built on Mechanical Force. https://doi.org/10.64898/2026.05.18.725872

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