Pseudomonas aeruginosa infection induces intragraft lymphocytotoxicity that triggers lung transplant antibody-mediated rejection. Sci Transl Med 2025 Feb 05;17(784):eadp1349
Date
02/05/2025Pubmed ID
39908350Pubmed Central ID
PMC12335241DOI
10.1126/scitranslmed.adp1349Scopus ID
2-s2.0-85218290823 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
How pathogens inhibit transplant tolerance remains unclear. Here, we found that Pseudomonas aeruginosa infection, but not other common bacterial respiratory infections, increases antibody-mediated rejection (AMR) risk in recipients of lung transplants. To explore this relationship, we performed orthotopic lung transplants in mice, infected recipients with P. aeruginosa, and observed for the development of AMR. Intravital two-photon microscopy showed that P. aeruginosa rapidly invaded bronchial-associated lymphoid tissues, which resulted in acute lymphocytotoxicity, including the death of forkhead box P3 (Foxp3)+CD4+ T cells that are required to suppress AMR. P. aeruginosa-mediated AMR required expression of the type III secretion system (T3SS), which injects exotoxins into the cell cytoplasm. Through a combination of mutagenesis and epitope tagging experiments, we revealed that T3SS exotoxin T ADP ribosyl-transferase activity was sufficient for graft-resident Foxp3+CD4+ T cell apoptosis, leading to myeloid differentiation primary response 88 (Myd88)-dependent generation of T-box expressed in T cells (T-bet)- and C-X-C motif chemokine receptor 3 (CXCR3)-positive germinal center and memory B cells with high donor antigen avidity. We also found that T-bet+ and CXCR3+ B cells were elevated in biopsies from recipients of lung transplants who were diagnosed with AMR. In mice, CXCR3 deficiency restricted to B cells or CXCR3 blockade prevented AMR despite P. aeruginosa infection. Our work has identified a previously unrecognized role of bacterial virulence in lung allograft rejection and suggests potential strategies to prevent AMR for those at high risk of P. aeruginosa infection after transplant.
Author List
Liao F, Zhou D, Cano M, Liu Z, Scozzi D, Tague LK, Byers DE, Li W, Sivapackiam J, Sharma V, Krupnick AS, Frank DW, Kreisel D, Kulkarni HS, Hachem RR, Gelman AEAuthor
Dara W. Frank PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies
Apoptosis
CD4-Positive T-Lymphocytes
Graft Rejection
Lung Transplantation
Mice
Mice, Inbred C57BL
Myeloid Differentiation Factor 88
Pseudomonas Infections
Pseudomonas aeruginosa
Type III Secretion Systems
