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 3

Graft-resident Foxp3+ T cells maintain lung transplant tolerance.

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Graft-resident Foxp3+ T cells maintain lung transplant tolerance. (A and...
(A and E) Gross and (B and F) histological appearance (H&E), (C and G) MT staining (blue), and (D and H) immunofluorescent staining of CCSP (red) and AcT (green) in BALB/c lungs, initially transplanted into immunosuppressed (A–D) B6 (CD45.2+) or (E–H) B6 Foxp3-DTR (CD45.2+) mice and retransplanted into DT-treated secondary B6 (CD45.1+) hosts at least 30 days after primary transplantation. Secondary hosts were examined 30 days after retransplantation. Scale bars: 100 μm. Arrows in B and C point to BALT. Serum titers of donor-specific (I) IgM and (J) IgG antibodies 30 days after retransplantation of BALB/c lungs, initially transplanted into immunosuppressed B6 WT (red) or B6 Foxp3-DTR (blue) mice and, at least 30 days later, retransplanted into B6 45.1+ hosts. (K) Reactivity of serum IgG antibodies, following depletion of graft-resident Foxp3 cells, against donor (BALB/c), recipient (B6), and third-party (CBA) antigen. Data are expressed as mean ± SEM (n = 4 mice per group). Mann-Whitney U test was used to compare the means.