Activation Phenotype of Mycobacterium tuberculosis-Specific CD4+ T Cells Promoting the Discrimination Between Active Tuberculosis and Latent Tuberculosis Infection

Abstract

BackgroundRapid and effective discrimination between active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remains a challenge. There is an urgent need for developing practical and affordable approaches targeting this issue.MethodsParticipants with ATB and LTBI were recruited at Tongji Hospital (Qiaokou cohort) and Sino-French New City Hospital (Caidian cohort) based on positive T-SPOT results from June 2020 to January 2021. The expression of activation markers including HLA-DR, CD38, CD69, and CD25 was examined on Mycobacterium tuberculosis (MTB)-specific CD4+ T cells defined by IFN-γ, TNF-α, and IL-2 expression upon MTB antigen stimulation.ResultsA total of 90 (40 ATB and 50 LTBI) and another 64 (29 ATB and 35 LTBI) subjects were recruited from the Qiaokou cohort and Caidian cohort, respectively. The expression patterns of Th1 cytokines including IFN-γ, TNF-α, and IL-2 upon MTB antigen stimulation could not differentiate ATB patients from LTBI individuals well. However, both HLA-DR and CD38 on MTB-specific cells showed discriminatory value in distinguishing between ATB patients and LTBI individuals. As for developing a single candidate biomarker, HLA-DR had the advantage over CD38. Moreover, HLA-DR on TNF-α+ or IL-2+ cells had superiority over that on IFN-γ+ cells in differentiating ATB patients from LTBI individuals. Besides, HLA-DR on MTB-specific cells defined by multiple cytokine co-expression had a higher ability to discriminate patients with ATB from LTBI individuals than that of MTB-specific cells defined by one kind of cytokine expression. Specially, HLA-DR on TNF-α+IL-2+ cells produced an AUC of 0.901 (95% CI, 0.833–0.969), with a sensitivity of 93.75% (95% CI, 79.85–98.27%) and specificity of 72.97% (95% CI, 57.02–84.60%) as a threshold of 44% was used. Furthermore, the performance of HLA-DR on TNF-α+IL-2+ cells for differential diagnosis was obtained with validation cohort data: 90.91% (95% CI, 72.19–97.47%) sensitivity and 68.97% (95% CI, 50.77–82.73%) specificity.ConclusionsWe demonstrated that HLA-DR on MTB-specific cells was a potentially useful biomarker for accurate discrimination between ATB and LTBI.

Study of CD27, CD38, HLA-DR and Ki-67 immune profiles for the characterization of active tuberculosis, latent infection and end of treatment

“…The rationale behind the discriminative power of the other three markers is simple: they are related to the activation and/or enhancement of immune responses, which commonly follow pathogenic infections. Our data gathered on these also confirms what has been published on the topic: CD38 expression on activated CD4 + T-cells was increased in aTB patients after ESAT-6/ CFP-10 stimulation (Luo et al, 2021), but HLA-DR + and Ki-67 + populations showed the most significant association with active disease in all conditions. These findings are consistent with most of the previous research in the field (Adekambi et al, 2015;Silveira-Mattos et al, 2020).…”

Impaired T-cell response to phytohemagglutinin (PHA) in tuberculosis patients is associated with high IL-6 plasma levels and normalizes early during anti-mycobacterial treatment

“…Besides its effect on IGRA results, low PHA response of tuberculosis patients has been shown to qualify as a biomarker for discrimination between latent M. tuberculosis infection and acute tuberculosis [6,7]. Especially a combination of antigen-specific and PHA-induced IFN-γ expression from IGRAs (i.e., antigen/PHA ratios) gained promising results [6][7][8][9][10]. In addition, a recent study indicated potential capacity of antigen/PHA ratios to monitor efficacy of treatment [11].…”

Transcriptional profiling of human peripheral blood mononuclear cells in household contacts of pulmonary tuberculosis patients provides insights into mechanisms of Mycobacterium tuberculosis control and elimination

“…In recent years, several genome-wide transcriptomic studies have been conducted to identify variations in host gene expression profiles in relation to different states of M. tuberculosis infection [ 10–12 ]. However, while most studies have primarily focused on discerning differences between patients with active TB and individuals with LTBI [ 10 , 13 ], little is known about the diverse host responses among household contacts (HHCs).…”

“…In recent years, several genome-wide transcriptomic studies have been conducted to identify variations in host gene expression profiles in relation to different states of M. tuberculosis infection [ 10–12 ]. However, while most studies have primarily focused on discerning differences between patients with active TB and individuals with LTBI [ 10 , 13 ], little is known about the diverse host responses among household contacts (HHCs). Thus, the objective of this study was to conduct a prospective investigation in mainland China, aiming to evaluate transcriptome signatures in human peripheral blood mononuclear cells (PBMCs) of HHCs with distinct clinical outcomes.…”