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 2

Depletion of graft-resident Foxp3+ T cells triggers AMR.

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Depletion of graft-resident Foxp3+ T cells triggers AMR. (A) Schematic d...
(A) Schematic depicting experimental model. CSB, costimulation blockade. Plots and quantification of CD4+Foxp3+ cells from (B) primary (CD45.2) or (C) secondary recipient (CD45.1) in BALB/c lungs, transplanted into immunosuppressed WT B6 (CD45.2) (circles) or Foxp3-DTR B6 (CD45.2) (inverted triangles) mice and retransplanted into DT-treated B6 (CD45.1) hosts at least 30 days later. Plots are gated on live CD45.2+CD45.1–CD90.2+ and live CD45.2–CD45.1+CD90.2+ cells. (D) Plots and quantification of distribution of CD45.1 vs. CD45.2 on live CD90.2+CD4+CD8–Foxp3+ cells without and with depletion of graft-resident (CD45.2) Foxp3+ cells. Gross and histological appearance (H&E) of BALB/c lungs, transplanted into immunosuppressed WT (E and G) or Foxp3-DTR (F and H) B6 CD45.2+ mice and, at least 30 days later, retransplanted into DT-treated B6 CD45.1+ hosts (n = 4 mice per group). (I) Airway epithelium (arrow) in human lung diagnosed with AMR (H&E) (n = 11). Staining of (J and K) MT (blue), (L and M) CCSP (red), AcT (green), and (N and O) C4d (brown) in BALB/c lungs, transplanted into immunosuppressed (J, L, and N) WT or (K, M, and O) Foxp3-DTR B6 CD45.2+ mice and, at least 30 days later, retransplanted into DT-treated B6 CD45.1+ hosts. Scale bars: 100 μm. Arrows in G, J, and L point to BALT. (P) Donor-specific IgM antibody titers 7 days after retransplantation of BALB/c lungs into DT-treated B6 CD45.1+ hosts at least 30 days after initial engraftment into immunosuppressed B6 WT (red) or B6 Foxp3-DTR (blue) mice. (Q) Reactivity of serum IgM antibodies, following depletion of graft-resident Foxp3 cells, against donor (BALB/c), recipient (B6), and third-party (CBA) antigen (n = 4 mice per group). Data are expressed as mean ± SEM. Mann-Whitney U test was used to compare the means.