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, Francine L. Kelly, Scott M. Palmer, Andrew E. Gelman, Daniel Kreisel*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)556-568
Number of pages13
JournalJournal of Clinical Investigation
Volume129
Issue number2
DOIs
StatePublished - Feb 1 2019

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Bronchi
T-Lymphocytes
Lung
Antibodies
Transplants
Lymphoid Tissue
Allografts
B-Lymphocytes
CD40 Ligand
Regulatory T-Lymphocytes
Immunosuppression
Antibody Formation
Epithelium
Ligands

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Li, W., Gauthier, J. M., Higashikubo, R., Hsiao, H. M., Tanaka, S., Vuong, L., ... Kreisel, D. (2019). Bronchus-associated lymphoid tissue–resident Foxp3 + T lymphocytes prevent antibody-mediated lung rejection Journal of Clinical Investigation, 129(2), 556-568. https://doi.org/10.1172/JCI122083
Li, Wenjun ; Gauthier, Jason M. ; Higashikubo, Ryuji ; Hsiao, Hsi Min ; Tanaka, Satona ; Vuong, Linh ; Ritter, Jon H. ; Tong, Alice Y. ; Wong, Brian W. ; Hachem, Ramsey R. ; Puri, Varun ; Bharat, Ankit ; Krupnick, Alexander S. ; Hsieh, Chyi S. ; Baldwin, William M. ; Kelly, Francine L. ; Palmer, Scott M. ; Gelman, Andrew E. ; Kreisel, Daniel. / Bronchus-associated lymphoid tissue–resident Foxp3 + T lymphocytes prevent antibody-mediated lung rejection In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 2. pp. 556-568.
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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.",
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Li, W, Gauthier, JM, Higashikubo, R, Hsiao, HM, 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 2019, ' Bronchus-associated lymphoid tissue–resident Foxp3 + T lymphocytes prevent antibody-mediated lung rejection ', Journal of Clinical Investigation, vol. 129, no. 2, pp. 556-568. https://doi.org/10.1172/JCI122083

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

In: Journal of Clinical Investigation, Vol. 129, No. 2, 01.02.2019, p. 556-568.

Research output: Contribution to journalArticle

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T1 - Bronchus-associated lymphoid tissue–resident Foxp3 + T lymphocytes prevent antibody-mediated lung rejection

AU - Li, Wenjun

AU - Gauthier, Jason M.

AU - Higashikubo, Ryuji

AU - Hsiao, Hsi Min

AU - Tanaka, Satona

AU - Vuong, Linh

AU - Ritter, Jon H.

AU - Tong, Alice Y.

AU - Wong, Brian W.

AU - Hachem, Ramsey R.

AU - Puri, Varun

AU - Bharat, Ankit

AU - Krupnick, Alexander S.

AU - Hsieh, Chyi S.

AU - Baldwin, William M.

AU - Kelly, Francine L.

AU - Palmer, Scott M.

AU - Gelman, Andrew E.

AU - Kreisel, Daniel

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

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