NKG2D blockade impairs cytotoxic CD8+ tissue resident memory T cell accumulation and attenuates severity of chronic lung allograft dysfunction after transplantation

Chronic lung allograft dysfunction (CLAD) significantly limits long-term survival following lung transplantation. To identify potential targets for CLAD prevention, T cells from explanted CLAD lungs and lung-draining lymph nodes, as well as diseased and non-diseased controls were isolated and single-cell RNA sequencing and TCR sequencing were performed. TCR sequencing revealed a clonally expanded population of tissue resident memory (TRM) CD8+ T cells with high cytotoxic potential including upregulation KLRK1, encoding the co-receptor NKG2D. These cytotoxic CD8+ TRM accumulated around the CLAD airways and had 100-fold increase in clonal overlap with lung draining lymph nodes when compared to non-CLAD lungs. Using a murine model of orthotopic lung transplant, we confirmed that cytotoxic CD8+ TRM accumulation was due to chronic rejection and not transplant alone. Furthermore, blocking NKG2D in-vivo attenuated the airway remodeling following transplantation and diminished airway accumulation of CD8+ T cells. Our findings support NKG2D as a potential therapeutic target for CLAD, affecting cytotoxic CD8+ TRM accumulation.