Human lung allografts experience persistent fibrogenic shift following acute cellular rejection

Area of Science:

• Immunology
• Genomics
• Transplantation Biology

Background:

• Acute cellular rejection (ACR) is a primary obstacle in lung transplantation.
• The molecular pathways linking ACR to chronic lung allograft dysfunction (CLAD) are not fully understood.

Purpose of the Study:

• To investigate the cellular and molecular mechanisms of ACR in lung allografts.
• To identify potential therapeutic targets for preventing CLAD.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of lung biopsies from ACR, resolved ACR, and control patients.
• Validation using gene microarray, immunofluorescence, and single-cell ATAC-seq.

Main Results:

• Persistent activation of TGF-β and PI3K/AKT/mTOR signaling pathways observed in both ACR and resolved ACR.
• Fibrogenic cells showed myofibroblast signatures, not epithelial- or endothelial-to-mesenchymal transition.
• Increased Type II Interferon signaling and JAK/STAT pathway activation in endothelial/basal cells; reduced VE-Cadherin.
• Altered immune cell composition with increased cytotoxic T cells, memory T cells, dendritic cells, and reduced natural killer cells.

Conclusions:

• Sustained TGF-β and mTOR pathway activation post-ACR resolution provides insight into the ACR-CLAD link.
• mTOR inhibition and TGF-β blockade are potential therapeutic strategies to prevent CLAD.