Emergence of a senescent and inflammatory pulmonary CD4+ T cell population prior to lung allograft failure

Abstract

Survival after lung transplantation is limited by chronic lung allograft dysfunction (CLAD), an alloimmune fibrotic process leading to death or retransplantation after a median of 6 years. Immunosuppression fails to prevent CLAD, suggesting the existence of drug-resistant alloimmune pathways. We used time-of-flight mass cytometry to identify cells enriched in the bronchoalveolar lavage of patients with subsequent acute lung allograft dysfunction (ALAD), a risk factor for CLAD. We show that CD4⁺CD57⁺PD1⁺ T cells emerge in stable patients, conferring risks for ALAD, CLAD, and death. These cells are senescent, secrete inflammatory cytokines, and fall into two oligoclonal subsets with putative cytotoxic and follicular helper functions. Last, they are associated with fibrosis in mouse and human lung allografts, where they localize near airway epithelium and B cells. Together, our findings reveal an inflammatory T cell population that predicts future lung allograft dysfunction and may represent a rational therapeutic target.