Bronchus-associated lymphoid tissue–resident Foxp3+ T lymphocytes prevent antibody-mediated lung rejection
Wenjun Li, Jason M. Gauthier, Ryuji Higashikubo, Hsi-Min Hsiao, Satona Tanaka, Linh Vuong, Jon H. Ritter, Alice Y. Tong, Brian W. Wong, Ramsey R. Hachem, Varun Puri, Ankit Bharat, Alexander S. Krupnick, Chyi S. Hsieh, William M. Baldwin III, Francine L. Kelly, Scott M. Palmer, Andrew E. Gelman, Daniel Kreisel
Wenjun Li, Jason M. Gauthier, Ryuji Higashikubo, Hsi-Min Hsiao, Satona Tanaka, Linh Vuong, Jon H. Ritter, Alice Y. Tong, Brian W. Wong, Ramsey R. Hachem, Varun Puri, Ankit Bharat, Alexander S. Krupnick, Chyi S. Hsieh, William M. Baldwin III, Francine L. Kelly, Scott M. Palmer, Andrew E. Gelman, Daniel Kreisel
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Research Article Immunology

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

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.

Authors

Wenjun Li, Jason M. Gauthier, Ryuji Higashikubo, Hsi-Min Hsiao, Satona Tanaka, Linh Vuong, Jon H. Ritter, Alice Y. Tong, Brian W. Wong, Ramsey R. Hachem, Varun Puri, Ankit Bharat, Alexander S. Krupnick, Chyi S. Hsieh, William M. Baldwin III, Francine L. Kelly, Scott M. Palmer, Andrew E. Gelman, Daniel Kreisel

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Figure 7

AMR of Foxp3+ T cell–depleted lung grafts can be prevented by blocking ICOS/ICOS ligand and CD40/CD40 ligand pathways.

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AMR of Foxp3+ T cell–depleted lung grafts can be prevented by blocking I...
(A) Expression levels of ICOS, ICOS ligand (ICOSL), CD40, CD40 ligand (CD40L), and IL-21 in BALB/c lung grafts, which were initially transplanted into immunosuppressed B6 WT (CD45.2) (circles) or Foxp3-DTR B6 (CD45.2) (inverted triangles) mice and at least 30 days later retransplanted into DT-treated (days 0 and 1) B6 CD45.1 hosts. Grafts were examined 7 days after retransplantation (n = 5 each). **P < 0.01. (B) Gross appearance, (C) histological appearance (H&E), (D) MT (blue) staining, (E) and immunofluorescent staining of CCSP (red) and AcT (green) after depletion of graft-resident Foxp3+ T cells and 7 days after retransplantation into anti-ICOS ligand and anti-CD40 ligand–treated secondary hosts. Scale bars: 100 μm. (F) Serum titers of donor-specific IgM 7 days after retransplantation of BALB/c lungs, initially transplanted into immunosuppressed B6 Foxp3-DTR mice and at least 30 days later retransplanted into DT-treated WT B6 hosts that were treated with anti-ICOS ligand and anti-CD40 ligand (red) or did not receive treatment (blue) (n = 4 mice per group). Data are expressed as mean ± SEM. Mann-Whitney U test was used to compare the means.