NKG2D blockade impairs tissue-resident memory T cell accumulation and reduces chronic lung allograft dysfunction

• DOI: 10.1172/jci.insight.184048
• Publication Date: 2025-02-23T19:00:45Z
• Authors: Kaveh Moghbeli; Madeline A. Lipp; Marta Bueno; Andrew Craig; Michelle Rojas; Minahal Abbas; Zachary I. Lakkis; Byron Chuan; John Sembrat; Kentaro Noda; Daniel J. Kass; Kong Chen; Li Fan; Tim Oury; Zihe Zhou; Xingan Wang; John F. McDyer; Oliver Eickelberg; Mark E. Snyder
• Keywords: NKG2D; Memory T cell

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