Maintenance of graft tissue–resident Foxp3+ cells is necessary for lung transplant tolerance in mice
Mechanisms that mediate allograft tolerance differ between organs. We have previously shown that Foxp3+ T cell-enriched bronchus-associated lymphoid tissue (BALT) is induced in tolerant murine lung allografts and that these Foxp3+ cells suppress alloimmune responses locally and systemically. Here, we demonstrated that Foxp3+ cells that reside in tolerant lung allografts differed phenotypically and transcriptionally from those in the periphery and were clonally expanded. Using a mouse lung retransplant model, we showed that recipient Foxp3+ cells were continuously recruited to the BALT within tolerant allografts. We identified distinguishing features of graft-resident and newly recruited Foxp3+ cells and showed that graft-infiltrating Foxp3+ cells acquired transcriptional profiles resembling those of graft-resident Foxp3+ cells over time. Allografts underwent combined antibody-mediated rejection and acute cellular rejection when recruitment of recipient Foxp3+ cells was prevented. Finally, we showed that local administration of IL-33 could expand and activate allograft-resident Foxp3+ cells, providing a platform for the design of tolerogenic therapies for lung transplant recipients. Our findings establish graft-resident Foxp3+ cells as critical orchestrators of lung transplant tolerance and highlight the need to develop lung-specific immunosuppression.
Authors
- Jon H. Ritter (ORCID: https://orcid.org/0009-0003-4514-6935)
- Junedh Amrute (ORCID: https://orcid.org/0000-0002-6851-0168)
- Kory J. Lavine (ORCID: https://orcid.org/0000-0003-1948-9945)
- Hailey M. Shepherd (ORCID: https://orcid.org/0000-0001-6798-6415)
- Peter T. Sage (ORCID: https://orcid.org/0000-0002-7287-0326)
- Jason M. Gauthier (ORCID: https://orcid.org/0000-0003-3326-8727)
- Ruben G. Nava (ORCID: https://orcid.org/0000-0001-5685-9445)
- Ankit Bharat (ORCID: https://orcid.org/0000-0002-1248-0457)
- Daniel Kreisel (ORCID: https://orcid.org/0000-0002-7711-8651)
- Yuriko Terada (ORCID: https://orcid.org/0000-0003-1598-9360)
- Amit Bery (ORCID: https://orcid.org/0000-0002-1020-8839)
- М. В. Терехова
- Alexander S. Krupnick (ORCID: https://orcid.org/0000-0002-1790-6197)
- Ramsey R. Hachem (ORCID: https://orcid.org/0000-0002-0708-1937)
- Maxim N. Artyomov (ORCID: https://orcid.org/0000-0002-1133-4212)
- Andrew E. Gelman (ORCID: https://orcid.org/0000-0002-0711-6343)
- Hēth Turnquist (ORCID: https://orcid.org/0000-0002-4173-4014)
- Varun Puri (ORCID: https://orcid.org/0000-0001-7761-8421)
- Wenjun Li (ORCID: https://orcid.org/0000-0001-5335-7386)
- Yun Zhu Bai (ORCID: https://orcid.org/0000-0002-7290-6739)
- Yuhei Yokoyama (ORCID: https://orcid.org/0009-0004-4577-2554)
- Alessandro Alessandrini (ORCID: https://orcid.org/0000-0003-0347-1927)
- Zhiyi Liu
Institutions
- Boston University (US)
- Northwestern University (US)
- University of Maryland, Baltimore (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Pittsburgh (US)
- Washington University in St. Louis (US)
- Massachusetts General Hospital (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-03-18
- DOI
- https://doi.org/10.1172/jci178975
- Citations
- 3
- Primary Topic
- Transplantation: Methods and Outcomes
- Type
- article
- Field-Weighted Citation Impact
- 6.02
Funders
- National Institutes of Health