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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Li, W; Gauthier, JM; Higashikubo, R; Hsiao, H-M; Tanaka, S; Vuong, L; Ritter, JH; Tong, AY; Wong, BW; Hachem, RR; Puri, V; Bharat, A; Krupnick, AS; Hsieh, CS; Baldwin, WM; Kelly, FL; Palmer, SM; Gelman, AE; Kreisel, D

Published Date

  • February 1, 2019

Published In

Volume / Issue

  • 129 / 2

Start / End Page

  • 556 - 568

PubMed ID

  • 30561386

Pubmed Central ID

  • 30561386

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI122083


  • eng

Conference Location

  • United States