Blood Immunopathology of Tuberculosis Patients Disrupts Monocyte‐Dependent T‐Cell Activation and Cytokine Expression

Abstract

ABSTRACT Pulmonary tuberculosis in humans is characterised by features of immunopathology, which influence both antimycobacterial therapy and the long‐term prognosis. In the blood of tuberculosis patients, immunopathology manifests itself in reduced immune responses to mitogenic substances. Previous studies have demonstrated the influence of tuberculosis serum on T‐cell and monocyte function, but the exact mechanisms remain unclear. Here, we performed a case/control study to analyse the influence of tuberculosis serum milieu changes on (i) T‐cell stimulation (using Staphylococcal Enterotoxin B), (ii) monocyte stimulation (using the Toll‐like receptor agonist Pam3CSK4), (iii) T‐cell/monocyte interaction characterised by the response against the lectin phytohemagglutinin, by using a novel peripheral blood mononuclear cell in vitro assay. Cell‐specific activation marker and cytokine expression were determined by multicolor flow cytometry. Staphylococcal Enterotoxin B mainly induced cytokine expression by T cells, while Pam3CSK4 stimulated monocytes to secrete distinct cytokine signatures. Phytohemagglutinin induced activation and cytokine expression in both T cells and monocytes. Notably, tuberculosis patient serum samples affected exclusively phytohemagglutinin stimulated T‐cell responses and particularly activation marker as well as CD40L/IL‐2 positive CD4 + T‐cell subsets were decreased as compared to serum from healthy contacts. Neither Staphylococcal Enterotoxin B‐mediated T‐cell stimulation nor phytohemagglutinin or Pam3CSK4 induced monocyte cytokines (i.e., Interleukin‐6, Interleukin‐8, Tumour Necrosis Factor‐α) were affected by the tuberculosis patients' serum samples. These results highlight the immunosuppressive influence of the tuberculosis serum milieu, which specifically reduced T‐cell responses to phytohemagglutinin, probably through impaired function of the accessory monocytes required for stimulation.