Maintenance of graft tissue–resident Foxp3+ cells is necessary for lung transplant tolerance in mice
Wenjun Li, … , Andrew E. Gelman, Daniel Kreisel
Wenjun Li, … , Andrew E. Gelman, Daniel Kreisel
Published March 18, 2025
Citation Information: J Clin Invest. 2025;135(10):e178975. https://doi.org/10.1172/JCI178975.
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Research Article Immunology

Maintenance of graft tissue–resident Foxp3+ cells is necessary for lung transplant tolerance in mice

Abstract

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

Wenjun Li, Yuriko Terada, Yun Zhu Bai, Yuhei Yokoyama, Hailey M. Shepherd, Junedh M. Amrute, Amit I. Bery, Zhiyi Liu, Jason M. Gauthier, Marina Terekhova, Ankit Bharat, Jon H. Ritter, Varun Puri, Ramsey R. Hachem, Hēth R. Turnquist, Peter T. Sage, Alessandro Alessandrini, Maxim N. Artyomov, Kory J. Lavine, Ruben G. Nava, Alexander S. Krupnick, Andrew E. Gelman, Daniel Kreisel

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Figure 7

IL-33 promotes the expansion and activation of lung allograft–resident Foxp3+ cells.

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IL-33 promotes the expansion and activation of lung allograft–resident F...
BALB/c lungs were transplanted into CSB-treated B6 recipients. At least 30 days after transplantation, recipients were treated with intratracheal IL-33 or PBS, and grafts were analyzed 7 days later. (A–E) Representative flow cytometry plots and quantification of abundance of Foxp3-expressing CD45+CD90.2+CD4+CD8– T cells (A), CD25-expressing CD45+CD90.2+CD4+CD8–Foxp3+ T cells (B), effector memory (CD44hiCD62Llo), central memory (CD44hiCD62Lhi), and naive (CD44loCD62Lhi) CD45+CD90.2+CD4+CD8–Foxp3+ T cells (C), CD69-expressing CD45+CD90.2+CD4+CD8–Foxp3+ T cells (D), and (E) PD-1–expressing CD45+CD90.2+CD4+CD8–Foxp3+ T cells in lung allografts after treatment with IL-33 or PBS (n = 4). (F) Gross (top) and histological (H&E; bottom) appearances of left BALB/c lungs that were initially transplanted into CSB-treated B6 recipients and then 30 days later retransplanted into DT-treated B6 Foxp3-DTR secondary recipients that received PBS (left; n = 4) or IL-33 (right; n = 9) intratracheally. Grafts were examined 7 days after retransplantation. Scale bars: 100 μm. (G and H) ISHLT A rejection grades (G) and flow cytometric analysis of serum IgM DSA titers (expressed as mean fluorescence intensity) (H) in recipients depicted in F (PBS, n = 4; IL-33, n = 9). Results expressed as mean ± SEM. *P < 0.05, **P < 0.01. DT, diphtheria toxin; DTR, diphtheria toxin receptor; Tcm, T central memory; Tem, T effector memory; TX, transplanted lung.