Bronchus-associated lymphoid tissue–resident Foxp3+ T lymphocytes prevent antibody-mediated lung rejection
Wenjun Li, … , Andrew E. Gelman, Daniel Kreisel
Wenjun Li, … , Andrew E. Gelman, Daniel Kreisel
Published December 18, 2018
Citation Information: J Clin Invest. 2019;129(2):556-568. https://doi.org/10.1172/JCI122083.
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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 6

Foxp3+ T lymphocyte depletion–triggered AMR is dependent on CXCL13-mediated chemokinesis.

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Foxp3+ T lymphocyte depletion–triggered AMR is dependent on CXCL13-media...
(A) Foxp3+ (green), B cells (blue), and CD4+ T cells (red) in BALB/c lungs at least 30 days after transplantation into immunosuppressed B6 Foxp3-IRES GFP recipient (n = 3). Scale bar: 10 μm. CXCR5+ B cells from secondary host (recipient) in BALB/c lungs, initially transplanted into immunosuppressed (B) WT or (C) Foxp3-DTR B6 (CD45.2+) recipient and, at least 30 days later, retransplanted into DT-treated B6 CD45.1+ hosts. Plots are gated on live CD45.2–CD45.1+ cells. (D) CD45.1+CXCR5+ B cells in (circles) control and (inverted triangles) Foxp3+ T cell–depleted lungs 7 days after retransplantation (n = 4 each). CXCL13 (brown) in (E) control and (F) Foxp3+ T cell–depleted grafts 7 days after retransplantation. Scale bars: 100 μm. CD4+ T cells (green) and B cells (blue) in BALB/c lungs, initially transplanted into immunosuppressed B6 Foxp3-DTR recipients and, at least 30 days later, retransplanted into B6 hosts, treated with (G) DT/control-Ig (arrows: CD4+ T–B cell interactions) or (H) DT/anti-CXCL13 (n = 2 each) (red, quantum dots). Scale bars: 20 μm. (I) Contact duration between CD4+ T and B cells, (J) CD4+ T, and (K) B cell mean square displacements and (L) CD4+ T and (M) B cell velocities within retransplanted Foxp3+ T cell–depleted BALB/c lungs with and without CXCL13 inhibition. (N) Gross, (O) histological appearance (H&E), staining for (P) MT (blue), (Q) CCSP (red), and AcT (green) in BALB/c lungs, transplanted into immunosuppressed B6 Foxp3-DTR mice and, at least 30 days later, retransplanted into DT- and anti-CXCL13–treated B6 hosts. Scale bars: 100 μm. (R) Donor-specific IgM titers after retransplantation of BALB/c lungs into DT-treated control (blue) or DT/anti-CXCL13 antibody–treated (red) B6 recipients after initial engraftment into immunosuppressed B6 Foxp3-DTR mice (n = 4 mice per group). Data are expressed as mean ± SEM. Mann-Whitney U test was used to compare the means.