Cellular and Molecular Immunology | 2021
Aberrant cytokine milieu and signaling affect immune cell phenotypes and functions in tuberculosis pathology: What can we learn from this phenomenon for application to inflammatory syndromes?
Abstract
Our previous study published in Cellular & Molecular Immunology (Harling et al.) described aberrant immunological features in the pathogenesis of tuberculosis. Overall, we provided evidence supporting an impact chain regarding aberrant high interleukin (IL)-6 and IL-10 cytokine expression and respective receptor signaling affecting T-cell functions in acute tuberculosis. Constitutive STAT3 phosphorylation, high expression of its key regulator suppressor of cytokine signaling (SOCS)3 and spontaneous IL-6/IL10 secretion characterized CD4 T cells from tuberculosis patients. As a consequence, effector cytokine expression of Mycobacterium (M.) tuberculosis-specific memory T cells was potentially impaired by SOCS3 blocking IL-2-dependent STAT5 phosphorylation. Notably, based on principal component analysis, IL-6, IL-10, pSTAT3, and SOCS3 were the most influential factors that distinguished tuberculosis patients from healthy controls. The study by Harling et al. and others performed by our group in the same region in Ghana strengthened the assumption about generally impaired immune mechanisms in acute tuberculosis (depicted in Fig. 1). Phenotypic and functional changes in adaptive and innate immune cells provide a complex picture of tuberculosis pathognomonic mechanisms potentially caused by aberrantly high IL-6 and IL-10 levels. Here, we comment on key findings and the potential relevance for inflammatory syndromes in infectious diseases. Tuberculosis is a chronic bacterial disease caused by mycobacteria from the M. tuberculosis complex. Transmitted via aerosol exhaled from patients with active pulmonary tuberculosis, M. tuberculosis infection remains asymptomatic in the vast majority of contacts. Immune surveillance of tuberculous granulomas is central to prevent dissemination and disease progression. Key immune factors (i.e., T cells, IFNγ, and TNFα) contribute to immune protection, and their deficiency or depletion due to interventions frequently leads to M. tuberculosis reactivation. However, there is increasing evidence that the immunopathology of tuberculosis is multifaceted and involves a broad spectrum of immune pathways. Heterogeneity of tuberculosis immunopathology is indicated by cohort differences in previous studies and limited common features identified in meta-analyses. Environmental factors (e.g., coinfections) and immune system genetics likely contribute to these differences. Against this background, we performed several studies, including the highlighted study by Harling et al., in the same region of central Ghana involving comparable cohorts of tuberculosis patients and asymptomatic controls. The study by Harling et al. was based on the hypothesis that pathognomonic features of tuberculosis are detectable in peripheral blood. Evidence supporting this assumption came from immune diagnostic tests (i.e., IFNγ release assays, IGRAs) for the detection of M. tuberculosis infection. IGRAs use short-term in vitro stimulation for the detection of recall T cell responses to M. tuberculosis antigens induced by previous M. tuberculosis infection. In addition to specific antigens (i.e., M. tuberculosis peptides/ proteins), commercially available tests comprise ‘positive controls’ based on mitogen-induced T-cell cytokine production. Mitogeninduced T-cell responses are generally detectable, and the extent should not differ between matched study groups. However, we and others detected lower mitogen-induced IFNγ secretion in tuberculosis patients from Ghana than in healthy controls. Mitogen-induced IFNγ levels were below the detection limit for a subgroup of tuberculosis patients, which led to false-negative or ‘indeterminate’ IGRA results. These results suggested generally impaired T-cell cytokine expression as an immunopathognomonic feature in tuberculosis patients. This assumption was strengthened by T-cell phenotype analyses. T cells from tuberculosis patients showed aberrantly high expression of activation markers (i.e., CD38 and HLA-DR) and reduced levels of the TCR coreceptor CD27. Whereas this effect was initially hypothesized to be solely a feature of M. tuberculosis-specific T cells, we recently showed that the expression of CD27 was generally impaired in tuberculosis patients and that this effect was not restricted to M. tuberculosisspecific T cells. Similarly, we found lower IL-7 receptor (CD127) expression in T cells from tuberculosis patients than in T cells from controls. Aberrant phenotypes in tuberculosis pathology are not restricted to T cells but also affect innate immune cells such as monocytes. Monocyte subsets are characterized by the dominance of a CD14/CD16 phenotype, also termed ‘inflammatory monocytes’. We were able to confirm these findings recently and, moreover, detected reduced CD127 expression in monocytes from