Early dynamics of T helper cell cytokines and T regulatory cells in response to treatment of activeMycobacterium tuberculosisinfection

Abstract

Biomarkers that can identify tuberculosis (TB) disease and serve as markers for efficient therapy are requested. We have studied T cell cytokine production [interferon (IFN)-γ, interleukin (IL)-2, tumour necrosis factor (TNF)-α] and degranulation (CD107a) as well as subsets of CD4+ T regulatory cells (Tregs) after in-vitro Mycobacterium tuberculosis (Mtb) antigen stimulation [early secretory antigenic target (ESAT)-6, culture filtrate protein (CFP)-10, antigen 85 (Ag85)] in 32 patients with active tuberculosis (TB) disease throughout 24 weeks of effective TB treatment. A significant decline in the fraction of Mtb-specific total IFN-γ and single IFN-γ-producing T cells was already observed after 2 weeks of treatment, whereas the pool of single IL-2+ cells increased over time for both CD4+ and CD8+ T cells. The Treg subsets CD25highCD127low, CD25highCD147++ and CD25highCD127lowCD161+ expanded significantly after Mtb antigen stimulation in vitro at all time-points, whereas the CD25highCD127lowCD39+ Tregs remained unchanged. The fraction of CD25highCD127low Tregs increased after 8 weeks of treatment. Thus, we revealed an opposing shift of Tregs and intracellular cytokine production during treatment. This may indicate that functional signatures of the CD4+ and CD8+ T cells can serve as immunological correlates of early curative host responses. Whether such signatures can be used as biomarkers in monitoring and follow-up of TB treatment needs to be explored further.

Individualizing management of extensively drug-resistant tuberculosis: diagnostics, treatment, and biomarkers

“…Detailed studies focused on disclosure of patient biomarker with prognostic profiles to demonstrate the disease or treatment success, but remained elusive [76,77]. None the less, the kinetics of nonspecific disease-associated biomarkers are increasingly recognized as having potential for the monitoring of treatment success and could play a role in guiding the therapy of complex (M[X]DR-TB) cases [78,79]. Host-derived markers are universally present in healthy and disease individuals and the levels present in healthy individuals are in almost all cases already established.…”

“…Early evidence suggests that these responses will be informative before culture or microscopic conversion is currently detected [78,79,89,90]. Thus, as measuring the response of host biomarker kinetics has the potential to be both simple and rapid [91], measuring biomarkers deserve attention.…”

“…The kinetics of the most promising biomarkers are now being validated in independent studies and initial data suggest that at least some the associations identified are reproducible [78,79,90,97]. Differences in host marker responses between sensitive and MDR-TB patients have been observed.…”

Adjunct Strategies for Tuberculosis Vaccines: Modulating Key Immune Cell Regulatory Mechanisms to Potentiate Vaccination

“…Multiple studies suggest Tregs delay the arrival of potential effector T cells into the pulmonary lymph nodes during early infection, play a role in reactivation of latent infection, and have a positive correlation with bacterial burden and extent of active disease (80, 81, 87, 88). Contrasting results have been observed in the TB treatment phase, with some studies reporting declining levels of Tregs and others showing a transient increase (86, 89, 90). …”

“…Tregs suppress both T cells and APCs, thus enhancing persistent infection (79, 82–84). Expansion of Tregs in active TB has been observed both at organ-specific sites and in blood (80, 85, 86). Multiple studies suggest Tregs delay the arrival of potential effector T cells into the pulmonary lymph nodes during early infection, play a role in reactivation of latent infection, and have a positive correlation with bacterial burden and extent of active disease (80, 81, 87, 88).…”