PSEUDOMONAS aeruginosa infection increases the risk of antibody-mediated rejection (AMR) in lung transplant recipients by inducing apoptosis of regulatory T cells and promoting B cell responses that drive rejection, a new study found.
Lung transplant recipients are particularly vulnerable to bacterial pneumonia, with P. aeruginosa being a leading cause. While bacterial infections are known to complicate post-transplant outcomes, their direct role in triggering AMR has been unclear. A study investigated the mechanisms by which P. aeruginosa contributes to lung allograft rejection, focusing on immune responses within the graft following infection.
Using a mouse model of lung transplantation, researchers infected transplant recipients with P. aeruginosa and monitored the development of AMR. Intravital two-photon microscopy revealed that P. aeruginosa rapidly infiltrated bronchial-associated lymphoid tissues, triggering acute lymphocytotoxicity, including the death of Foxp3+CD4+ regulatory T cells essential for suppressing AMR. The bacteria’s Type III secretion system (T3SS) was necessary for this effect, with its exotoxin T inducing apoptosis in graft-resident regulatory T cells. The resulting immune imbalance led to a Myd88-dependent expansion of T-bet+ and CXCR3+ germinal center and memory B cells with high donor antigen avidity, driving AMR. Analysis of human lung transplant biopsy samples confirmed elevated levels of these B cells in patients diagnosed with AMR. Furthermore, in mice, genetic deletion of CXCR3 in B cells or pharmacological CXCR3 blockade prevented AMR despite P. aeruginosa infection, demonstrating a key role for CXCR3+ B cells in mediating rejection.
These findings highlight a previously unrecognised link between bacterial virulence and lung allograft rejection. Clinically, this suggests that lung transplant recipients with P. aeruginosa infections are at increased risk of AMR, particularly those with conditions such as cystic fibrosis. The identification of CXCR3+ B cells as key mediators of rejection provides a potential therapeutic target, with CXCR3 blockade emerging as a promising strategy to mitigate AMR risk following bacterial infection.
Jenna Lorge, EMJ
Reference
Fuyi Liao et al. Pseudomonas aeruginosa infection induces intragraft lymphocytotoxicity that triggers lung transplant antibody-mediated rejection. Sci Transl Med. 2025;DOI:10.1126/scitranslmed.adp1349.
