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J Clin Invest. 2019 Feb 1;129(2):556-568. doi: 10.1172/JCI122083. Epub 2018 Dec 18.

Bronchus-associated lymphoid tissue-resident Foxp3+ T lymphocytes prevent antibody-mediated lung rejection.

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Department of Surgery.
Department of Pathology & Immunology, and.
Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
Department of Surgery, Northwestern University, Chicago, Illinois, USA.
Department of Surgery, The University of Virginia, Charlottesville, Virginia, USA.
Department of Immunology, Cleveland Clinic, Lerner Research Institute, Cleveland, Ohio, USA.
Department of Medicine, Duke University, Durham, North Carolina, USA.


Antibody-mediated rejection (AMR) is a principal cause of acute and chronic failure of lung allografts. However, mechanisms mediating this oftentimes fatal complication are poorly understood. Here, we show that Foxp3+ T cells formed aggregates in rejection-free human lung grafts and accumulated within induced bronchus-associated lymphoid tissue (BALT) of tolerant mouse lungs. Using a retransplantation model, we show that selective depletion of graft-resident Foxp3+ T lymphocytes resulted in the generation of donor-specific antibodies (DSA) and AMR, which was associated with complement deposition and destruction of airway epithelium. AMR was dependent on graft infiltration by B and T cells. Depletion of graft-resident Foxp3+ T lymphocytes resulted in prolonged interactions between B and CD4+ T cells within transplanted lungs, which was dependent on CXCR5-CXCL13. Blockade of CXCL13 as well as inhibition of the CD40 ligand and the ICOS ligand suppressed DSA production and prevented AMR. Thus, we have shown that regulatory Foxp3+ T cells residing within BALT of tolerant pulmonary allografts function to suppress B cell activation, a finding that challenges the prevailing view that regulation of humoral responses occurs peripherally. As pulmonary AMR is largely refractory to current immunosuppression, our findings provide a platform for developing therapies that target local immune responses.


Immunology; Organ transplantation; T cells; Tolerance; Transplantation

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