Easily accessible tools that reliably stratify Mycobacterium tuberculosis (MTB) infection are needed to facilitate the improvement of clinical management. The current study attempts to reveal lymphocyte-related immune characteristics of active tuberculosis (ATB) patients and establish immunodiagnostic model for discriminating ATB from latent tuberculosis infection (LTBI) and healthy controls (HC).A total of 171 subjects consisted of 54 ATB, 57 LTBI, and 60 HC were consecutively recruited at Tongji hospital from January 2019 to January 2021. All participants were tested for lymphocyte subsets, phenotype, and function. Other examination including T-SPOT and microbiological detection for MTB were performed simultaneously.Compared with LTBI and HC, ATB patients exhibited significantly lower number and function of lymphocytes including CD4+ T cells, CD8+ T cells and NK cells, and significantly higher T cell activation represented by HLA-DR and proportion of immunosuppressive cells represented by Treg. An immunodiagnostic model based on the combination of NK cell number, HLA-DR+CD3+ T cells, Treg, CD4+ T cell function, and NK cell function was built using logistic regression. Based on receiver operating characteristic curve analysis, the area under the curve (AUC) of the diagnostic model was 0.920 (95% CI, 0.867-0.973) in distinguishing ATB from LTBI, while the cut-off value of 0.676 produced a sensitivity of 81.48% (95% CI, 69.16%-89.62%) and specificity of 91.23% (95% CI, 81.06%-96.20%). Meanwhile, AUC analysis between ATB and HC according to the diagnostic model was 0.911 (95% CI, 0.855-0.967), with a sensitivity of 81.48% (95% CI, 69.16%-89.62%) and a specificity of 90.00% (95% CI, 79.85%-95.34%).Our study demonstrated that the immunodiagnostic model established by the combination of lymphocyte-related indicators could facilitate the status differentiation of MTB infection.Copyright © 2021 Luo, Xue, Tang, Cai, Yuan, Lin, Song, Liu, Mao, Zhou, Chen, Zhu, Liu, Wu, Wang and Sun.