Chemokine “beacons” to recruit CCR8+ decidual-like Tregs for graft-local tolerance

Recent single-cell work uncovered a highly active CCR8+ Treg subset that is essential for maternal-fetal tolerance, with CCL1 supplied by decidual NK cells (Li et al., 2025, Science Immunology). In transplantation, antigen-specific Treg therapy shows promise but often needs help to accumulate and persist at the graft (Seltrecht et al., 2024). Marrying these insights, this proposal engineers “chemokine beacons”—biomaterial coatings or gene therapy cassettes on the graft’s vasculature that secrete CCL1 in response to local inflammation. We would test whether this recruits CCR8+ Tregs (endogenous and/or adoptively transferred) into grafts, stabilizes their suppressive phenotype, and reduces the need for systemic immunosuppression. Compared to generic Treg expansion (Sakaguchi, 2004; 2008) or broader chemokine approaches, this leverages a pregnancy-evolved, highly localized axis with proven necessity for tolerance, aiming to deliver the kind of durable, local Treg enrichment that Seltrecht et al. (2024) found to be critical for operational tolerance.

References:

1. Regulatory T Cells and Immune Tolerance. S. Sakaguchi, Tomoyuki Yamaguchi, T. Nomura, M. Ono (2008). Cell.
2. Graft-Specific Regulatory T Cells for Long-Lasting, Local Tolerance Induction. N. Seltrecht, M. Hardtke‐Wolenski, Konstantinos Iordanidis, D. Jonigk, Melanie Galla, Axel Schambach, L. E. Buitrago‐Molina, Heiner Wedemeyer, F. Noyan, E. Jaeckel (2024). Cells.
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4. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses.. S. Sakaguchi (2004). Annual Review of Immunology.
5. CCR8+ decidual regulatory T cells maintain maternal-fetal immune tolerance during early pregnancy.. Zhuqing Li, Pinxin Si, Tingting Meng, Xiaoran Zhao, Chendi Zhu, Dunfang Zhang, Shutong Meng, Nianyu Li, Ran Liu, T. Ni, Junhao Yan, Hongchang Li, Ning Zhao, Chao Zhong, Yingying Qin, WanJun Chen, Zi-jiang Chen, Xue Jiao (2025). Science immunology.