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

Area of Science:

• Immunology
• Transplantation Biology
• Pulmonary Medicine

Background:

• Chronic lung allograft dysfunction (CLAD) significantly impacts long-term survival after lung transplantation.
• Identifying therapeutic targets is crucial for preventing CLAD and improving patient outcomes.

Purpose of the Study:

• To investigate the role of T cells in CLAD pathogenesis.
• To identify potential therapeutic targets for CLAD prevention.

Main Methods:

• Single-cell RNA sequencing and TCR sequencing were performed on T cells from explanted CLAD lungs and controls.
• A murine model of orthotopic lung transplantation was used to validate findings.
• NKG2D blockade was tested in vivo.

Main Results:

• A clonally expanded population of cytotoxic CD8+ tissue-resident memory T cells (TRMs) expressing NKG2D was identified in CLAD lungs.
• These CD8+ TRMs showed increased accumulation around airways and greater overlap with lymph nodes in CLAD.
• In a mouse model, NKG2D blockade reduced airway remodeling and CD8+ T cell accumulation.

Conclusions:

• Cytotoxic CD8+ TRMs play a key role in CLAD development.
• NKG2D is implicated in the accumulation of these T cells and airway remodeling.
• NKG2D represents a potential therapeutic target for preventing and treating CLAD.