Soluble CD161 rises with severe tuberculosis and blockade reshapes cytokine responses

Researchers in China have generated human monoclonal antibodies against CD161, an immune receptor with context-dependent regulatory functions, and used them to measure soluble CD161 in the blood of patients with active pulmonary tuberculosis. In a single-center cross-sectional cohort, plasma levels of the soluble form of the receptor were higher in untreated tuberculosis patients than in healthy controls, and were particularly elevated among patients whose disease was classified as severe by radiographic criteria.

The study, published in Frontiers in Cellular and Infection Microbiology, was led by Yuhan Wang and colleagues at the Fifth People’s Hospital of Suzhou, with collaborators from Suzhou Ninth People’s Hospital and the First Affiliated Hospital of Soochow University. CD161, encoded by the KLRB1 gene, is a C-type lectin-like receptor expressed on multiple immune-cell subsets, and its ligand LLT1 has been implicated in immunoregulatory signaling.

To carry out the work, the team generated human anti-CD161 monoclonal antibodies, established a customized in-house sandwich ELISA for soluble CD161, and identified antibodies capable of blocking the interaction between CD161 and LLT1. The ELISA was then applied to plasma samples from 63 untreated patients with active pulmonary tuberculosis, alongside 52 healthy controls, 6 patients with community-acquired pneumonia, and 5 individuals with latent tuberculosis infection.

Membrane CD161-positive cell frequencies were assessed in a smaller subset, comprising 57 tuberculosis patients and 27 healthy controls. The researchers report that plasma soluble CD161 showed weak inverse associations with selected membrane CD161-positive T-cell frequencies, meaning that higher circulating levels of the soluble receptor tended to accompany lower frequencies of certain CD161-expressing T cells, although the authors characterize these associations as weak.

Beyond the blood measurements, the team examined CD161 distribution in lung and lymph-node tissues. Staining revealed that CD161 was increased in perigranulomatous regions of the tissue and decreased in necrotic regions, a pattern that places the receptor’s expression in the immediate vicinity of the granulomatous structures that characterize tuberculosis pathology.

The functional arm of the study tested what happens when the CD161–LLT1 interaction is blocked. In an ESAT6-CFP10 antigen-stimulated peripheral blood mononuclear cell system, the researchers applied their blocking antibodies and measured cytokine secretion. In selected antibody conditions, blockade reduced secretion of IFN-γ, IL-6, and TNF, while increasing IL-17A. The authors note that these effects varied by antibody condition, indicating that the modulation of cytokine responses depended on the specific blocking reagent used.

The findings indicate that circulating soluble CD161 is associated with tuberculosis and with radiographic disease severity in this cohort, while CD161–LLT1 blockade modulates cytokine responses in an antigen-stimulated cell system. The authors are careful to frame these as associations and modulatory effects observed in a single-center cross-sectional design, not as proof of diagnostic or prognostic performance.

Several limitations follow directly from the study design. The cohort was small, particularly the comparison groups of community-acquired pneumonia patients and individuals with latent tuberculosis infection, which numbered six and five respectively. The cross-sectional structure cannot establish whether soluble CD161 changes over the course of disease or treatment, and the cytokine experiments were conducted in an ex vivo antigen-stimulated system rather than in patients.

The authors state that larger, independently validated and longitudinal studies are required to determine the diagnostic and treatment-monitoring utility of soluble CD161 and to define the cellular mechanisms underlying CD161–LLT1 signaling in tuberculosis. Until such studies are completed, the results stand as an early characterization of a soluble immune checkpoint-related molecule in tuberculosis, generated with newly developed antibodies and a purpose-built assay, and as a demonstration that interfering with the CD161–LLT1 axis can shift cytokine output in tuberculosis-relevant cell cultures.

Subject of Research: Soluble CD161 levels and CD161–LLT1 blockade in tuberculosis

Article Title: CD161 expression in tuberculosis and functional effects of CD161–LLT1 blockade

Article References: Wang, Y., Niu, Y., Liu, J., Feng, Y., Sun, Y., Du, M., Gao, S., Zhang, X., Cao, L., & Wu, M. (2026). CD161 expression in tuberculosis and functional effects of CD161–LLT1 blockade. Frontiers in Cellular and Infection Microbiology, 16, Article 1962964. https://doi.org/10.3389/fcimb.2026.1962964

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1962964

Keywords: CD161, KLRB1, LLT1, soluble CD161, tuberculosis, monoclonal antibody, ELISA, cytokines, immune checkpoint, granuloma, IFN-gamma, IL-17A