KLRG1+CD28⁻CD57+ Ag85A-specific CD8+ T cells mark a severity-associated terminal-differentiation imprint in pulmonary tuberculosis.

Abstract

Background: Pulmonary tuberculosis (PTB) is characterized by prolonged host-pathogen interaction, chronic granulomatous inflammation, and sustained exposure to Mycobacterium tuberculosis (Mtb) antigens. How Mtb antigen-specific CD8⁺ T cell differentiation states relate to clinical disease activity and severity remains incompletely defined. This study investigated the clinical relevance of a terminal differentiation-associated phenotype within Ag85A-specific CD8⁺ T cells across clinically defined states of Mtb infection and disease.

Methods: A total of 124 participants were enrolled, including 55 patients with PTB, 33 individuals with latent tuberculosis infection (LTBI), and 36 healthy controls (HCs). Peripheral blood mononuclear cells were analyzed by flow cytometry to quantify KLRG1⁺CD28^⁻CD57⁺ cells among HLA-A*02:01-restricted Ag85A₄₈-₅₆ tetramer⁺CD8⁺ T cells. Associations with active disease, sputum smear status, clinical severity, selected host-status parameters, and exploratory treatment-related outcomes were assessed.

Results: Patients with PTB showed a significantly higher proportion of KLRG1⁺CD28^⁻CD57⁺ Ag85A-specific CD8⁺ T cells than HCs. This phenotype was enriched in active PTB and was associated with clinically relevant features of disease burden, including sputum smear positivity, higher smear grade, lymphocyte imbalance, and severe pulmonary involvement. Patients with severe PTB had higher proportions of this subset than patients with non-severe PTB. In receiver operating characteristic analysis, this phenotype showed exploratory in-cohort discriminative potential for distinguishing severe from non-severe PTB, with an apparent area under the curve of 0.8333 (95% CI, 0.7268-0.9398; P<0.0001); patient-level bootstrap resampling yielded a bias-corrected AUC of 0.8333.

Conclusions: The accumulation of KLRG1⁺CD28^⁻CD57⁺ Ag85A-specific CD8⁺ T cells is closely associated with active and clinically severe PTB. Rather than establishing a causal mechanism, these findings identify an antigen-specific, terminal differentiation-associated CD8⁺ T-cell phenotype as a potential translational immune correlate of disease severity in human Mtb infection. Its discriminative ability should be regarded as preliminary and requires external validation in larger, prospective, and independently recruited cohorts.