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

Abstract

Purpose Human tuberculosis is characterized by immunopathology that affects T-cell phenotype and functions. Previous studies found impaired T-cell response to phytohemagglutinin (PHA) in patients with acute tuberculosis. However, the influence of disease severity, affected T-cell subsets, and underlying mechanisms remain elusive. Methods Here we investigated PHA-induced and antigen-specific T-cell effector cytokines in tuberculosis patients (n = 55) as well as in healthy asymptomatic contacts (n = 32) from Ghana. Effects of Mycobacterium (M.) tuberculosis sputum burden and treatment response were analyzed and compared during follow-up. Finally, cytokine characteristics of the aberrant plasma milieu in tuberculosis were analyzed as a potential cause for impaired PHA response. Results PHA-induced IFN-γ expression was significantly lower in sputum-positive tuberculosis patients as compared to both, contacts and paucibacillary cases, and efficiently discriminated the study groups. T-cell responses to PHA increased significantly early during treatment and this was more pronounced in tuberculosis patients with rapid treatment response. Analysis of alternative cytokines revealed distinct patterns and IL-22, as well as IL-10, showed comparable expression to IFN-γ in response to PHA. Finally, we found that high IL-6 plasma levels were strongly associated with impaired IFN-γ and IL-22 response to PHA. Conclusion We conclude that impaired T-cell response to PHA stimulation in acute tuberculosis patients (i) was potentially caused by the aberrant plasma milieu, (ii) affected differentially polarized T-cell subsets, (iii) normalized early during treatment. This study shed light on the mechanisms of impaired T-cell functions in tuberculosis and yielded promising biomarker candidates for diagnosis and monitoring of treatment response.

Immunopathology in human pulmonary tuberculosis: Inflammatory changes in the plasma milieu and impaired host immune cell functions

“…High IL‐6 plasma levels decrease rapidly under treatment [20, 59], and normalisation was also seen for PHA‐induced response [92, 127]. In accordance, a recent study by Vivekanandan et al found that impaired PHA response in tuberculosis patients before treatment was associated with high IL‐6 plasma levels [92].…”

“…This rendered a causative relationship between aberrant high IL‐6 plasma levels with impaired T‐cell functions in patients with tuberculosis likely. There is initial evidence that not all T‐cells are affected to the same extent by impaired PHA response and a negative correlation with plasma IL‐6 levels was solely seen for IFN‐γ, IL‐22 and IL‐10 [92]. As expected, these three cytokines showed increasing response to PHA during treatment, whereas other cytokines, including IL‐6 and IP‐10, did not change during treatment [92].…”

“…High IL‐6 plasma levels decrease rapidly under treatment [20, 59], and normalisation was also seen for PHA‐induced response [92, 127]. In accordance, a recent study by Vivekanandan et al found that impaired PHA response in tuberculosis patients before treatment was associated with high IL‐6 plasma levels [92]. This rendered a causative relationship between aberrant high IL‐6 plasma levels with impaired T‐cell functions in patients with tuberculosis likely.…”

“…The impaired immune response to PHA in a subgroup of tuberculosis patients is well described and has already been identified in the last century [87]. PHA hypo‐responsiveness is consistently seen in several studies from different regions and qualifies as a common feature of immunopathology in a subgroup of tuberculosis patients [88–93]. Importantly, pioneering research from the group of J.J. Ellner demonstrated that plasma samples from pulmonary tuberculosis patients were sufficient to transfer hypo‐responsiveness to immune cells from healthy individuals [94].…”

Monocyte pathology in human tuberculosis is due to plasma milieu changes and aberrant STAT signalling

“…High constitutive STAT3 phosphorylation as well as high Suppressor of Cytokine Signalling (SOCS)3 levels were found in acute tuberculosis patients and aberrant pSTAT3 levels were associated with high IL‐6/IL‐10 plasma concentrations [17]. In addition, we could show recently that aberrant high IL‐6 plasma levels were associated with impaired mitogen‐induced IFN‐γ expression by T cells in patients with tuberculosis [18]. Changes in the plasma milieu and aberrant cytokine concentrations in tuberculosis patients have been described [19–21].…”