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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.

Author information

1
Department of Surgery.
2
Department of Pathology & Immunology, and.
3
Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
4
Department of Surgery, Northwestern University, Chicago, Illinois, USA.
5
Department of Surgery, The University of Virginia, Charlottesville, Virginia, USA.
6
Department of Immunology, Cleveland Clinic, Lerner Research Institute, Cleveland, Ohio, USA.
7
Department of Medicine, Duke University, Durham, North Carolina, USA.

Abstract

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.

KEYWORDS:

Immunology; Organ transplantation; T cells; Tolerance; Transplantation

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