CD161 expression in tuberculosis and functional effects of CD161–LLT1 blockade

Introduction CD161 (KLRB1) is a C-type lectin-like immune receptor expressed on multiple immune-cell subsets and has context-dependent immunoregulatory functions. Methods We generated human anti-CD161 monoclonal antibodies, established a customized in-house sandwich ELISA for soluble CD161 (sCD161), and identified antibodies that block the CD161–LLT1 interaction. In a single-center cross-sectional cohort, we evaluated 63 untreated patients with active pulmonary tuberculosis (TB), together with 52 healthy controls (HCs), 6 patients with community-acquired pneumonia (CAP), and 5 individuals with latent TB infection (LTBI) for plasma sCD161. Membrane CD161-positive cell frequencies were assessed in 57 TB patients and 27 HCs. CD161 distribution in lung and lymph-node tissues and the effects of CD161–LLT1 blockade on cytokine responses in an ESAT6-CFP10 antigen-stimulated PBMC system were also examined. Results Plasma sCD161 levels were higher in TB patients, particularly those classified as severe by radiographic criteria, and showed weak inverse associations with selected membrane CD161-positive T-cell frequencies. CD161 staining was increased in perigranulomatous regions and decreased in necrotic regions. Blocking CD161–LLT1 altered cytokine secretion, with reduced IFN-γ, IL-6, and TNF and increased IL-17A in selected antibody conditions. Discussion These findings indicate that circulating sCD161 is associated with TB and radiographic disease severity in this cohort, while CD161–LLT1 blockade modulates cytokine responses in an antigen-stimulated PBMC system. Larger, independently validated and longitudinal studies are required to determine the diagnostic and treatment-monitoring utility of sCD161 and to define the cellular mechanisms underlying CD161–LLT1 signaling in TB.