Frequency of Mycobacterium tuberculosis-specific CD8+ T-cells in the course of anti-tuberculosis treatment

Abstract

Anti-tuberculosis drug treatment is known to affect the number, phenotype, and effector functionality of antigen-specific T-cells. In order to objectively gauge Mycobacterium tuberculosis (MTB)-specific CD8+ T-cells at the single-cell level, we developed soluble major histocompatibility complex (MHC) class I multimers/peptide multimers, which allow analysis of antigen-specific T-cells without ex vivo manipulation or functional tests. We constructed 38 MHC class I multimers covering some of the most frequent MHC class I alleles (HLA-A*02:01, A*24:02, A*30:01, A*30:02, A*68:01, B*58:01, and C*07:01) pertinent to a South African or Zambian population, and presenting the following MTB-derived peptides: the early expressed secreted antigens TB10.4 (Rv0288), Ag85B (Rv1886c), and ESAT-6 (Rv3875), as well as intracellular enzymes, i.e., glycosyltransferase 1 (Rv2957), glycosyltransferase 2 (Rv2958c), and cyclopropane fatty acid synthase (Rv0447c). Anti-TB treatment appeared to impact on the frequency of multimer-positive CD8+ T-cells, with a general decrease after 6 months of therapy. Also, a reduction in the total central memory CD8+ T-cell frequencies, as well as the antigen-specific compartment in CD45RA-CCR7+ T-cells was observed. We discuss our findings on the basis of differential dynamics of MTB-specific T-cell frequencies, impact of MTB antigen load on T-cell phenotype, and antigen-specific T-cell responses in tuberculosis.

Mycobacterium tuberculosis proteins involved in cell wall lipid biosynthesis improve BCG vaccine efficacy in a murine TB model

“…The presence of circulating antigen-specific IgG indicates that Rv2958c, Rv2957 and Rv0447c can on their own (without adjuvant) induce measurable humoral immune responses À which is a key desirable feature of novel TB vaccines. 38 The results presented here further strengthen and are in line with our previous reports describing the immunogenic potential of Rv2958c, Rv2957 and Rv0447c based on human T-cell assays, 26,39,40 in terms of cellular immune activation.…”

New Verapamil Analogs Inhibit Intracellular Mycobacteria without Affecting the Functions of Mycobacterium-Specific T Cells

“…Our results showed that macrophage activation and autophagy are unlikely to be the major mechanisms of the anti-TB activity of verapamil. M. tuberculosis-specific immunity is essential to limit the progression of TB, and it enhances anti-TB treatment and cure (27)(28)(29)(30)(31). Available evidence indicates that verapamil inhibits the proliferation of T and B cells, leading some to consider this drug to be an immunosuppressive agent (38)(39)(40).…”

“…Verapamil and norverapamil inhibit expansion of M. tuberculosis-specific T cells. M. tuberculosis-specific immunity is important to limit the progression of TB and improve the cure rate of anti-TB treatment (27)(28)(29)(30)(31). Because previous reports have shown that verapamil inhibits tumor-specific T cells (32), we next studied the effects of verapamil and norverapamil on M. tuberculosis-specific T cells.…”

Coxiella burnetii epitope-specific T-cell responses in chronic Q fever patients

“…Moreover, a previous study showed that duration of antibiotic treatment following diagnosis of chronic Q fever, and whether subjects received treatment or not, did not influence IFNγ secretion, at least not in a whole blood stimulation assay using whole-cell C. burnetii (14). Of note, CD8 responses have been shown to decline rapidly following Mycobacterium tuberculosis treatment (10, 11) and we cannot exclude that this might have also impacted class I responses in the present cohort. The question whether and which class I epitopes should be included in a T-cell targeted Q fever vaccine for humans therefore requires further investigation during a new outbreak or a vaccination campaign.…”

“…In these naturally exposed subjects, we demonstrated long-lived immunoreactivity to promiscuous CD4 T-cell epitopes, while HLA class I epitope responses were sparse in this cohort (7). One possible explanation for the latter was that class I responses might have contracted faster than class II responses, as previously observed following smallpox infection or vaccination and tuberculosis treatment (8–11). In this initial study, there were no striking differences between past asymptomatic or symptomatic infected individuals, all of whom successfully cleared acute C. burnetii infection.…”