Abstract
BackgroundMycobacterium tuberculosis (M. tuberculosis) modulates host immune response, mainly T cell responses for its own survival leading to disease or latent infection. The molecules and mechanisms utilized to accomplish immune subversion by M. tuberculosis are not fully understood. Understanding the molecular mechanism of T cell response to M. tuberculosis is important for development of efficacious vaccine against TB.MethodsHere, we investigated effect of M. tuberculosis antigens Ag85A and ESAT-6 on T cell signalling events in CD3/CD28 induced Peripheral blood mononuclear cells (PBMCs) of PPD+ve healthy individuals and pulmonary TB patients. We studied CD3 induced intracellular calcium mobilization in PBMCs of healthy individuals and TB patients by spectrofluorimetry, CD3 and CD28 induced activation of mitogen activated protein kinases (MAPKs) in PBMCs of healthy individuals and TB patients by western blotting and binding of transcription factors NFAT and NFκB by Electrophorectic mobility shift assay (EMSA).ResultsWe observed CD3 triggered modulations in free intracellular calcium concentrations in PPD+ve healthy individuals and pulmonary TB patients after the treatment of M. tuberculosis antigens. As regards the downstream signalling events, phosphorylation of MAPKs, Extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 was curtailed by M. tuberculosis antigens in TB patients whereas, in PPD+ve healthy individuals only ERK1/2 phosphorylation was inhibited. Besides, the terminal signalling events like binding of transcription factors NFAT and NFκB was also altered by M. tuberculosis antigens. Altogether, our results suggest that M. tuberculosis antigens, specifically ESAT-6, interfere with TCR/CD28-induced upstream as well as downstream signalling events which might be responsible for defective IL-2 production which further contributed in T-cell unresponsiveness, implicated in the progression of disease.ConclusionTo the best of our knowledge, this is the first study to investigate effect of Ag85A and ESAT-6 on TCR- and TCR/CD28- induced upstream and downstream signalling events of T-cell activation in TB patients. This study showed the effect of secretory antigens of M. tuberculosis in the modulation of T cell signalling pathways. This inflection is accomplished by altering the proximal and distal events of signalling cascade which could be involved in T-cell dysfunctioning during the progression of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-015-0128-6) contains supplementary material, which is available to authorized users.
Highlights
Mycobacterium tuberculosis (M. tuberculosis) modulates host immune response, mainly T cell responses for its own survival leading to disease or latent infection
M. tuberculosis antigens differentially curtail T cell receptor (TCR) triggered intracellular calcium mobilization To find out the effect of M. tuberculosis antigens on intracellular calcium mobilization, we measured intracellular calcium concentration by spectrofluorometer
We assessed TCR-triggered calcium mobilization by adding anti-CD3 antibody on cells pretreated with optimum doses of M. tuberculosis antigens (Ag85A, Early secretory antigenic target −6 (ESAT-6), Purified protein derivative (PPD) and H37Rv)
Summary
Mycobacterium tuberculosis (M. tuberculosis) modulates host immune response, mainly T cell responses for its own survival leading to disease or latent infection. The resurgence of TB worldwide has intensified research efforts directed on examining the host defence and pathogenic mechanisms operative in Mycobacterium tuberculosis (M. tuberculosis) infection. This is primarily because the organism lives inside the cells and T cells, rather than antibodies are required to eliminate bacteria [2, 3]. Inhibition of polyclonal murine CD4+ T cell activation by M. tuberculosis cell wall glycolipids by blocking ZAP-70 phosphorylation has been shown by Mahon et al [8] and later they extended their study by reporting ManLAM induced inhibition of TCR signalling by interference with ZAP-70, Lck and LAT phosphorylation in antigen-specific murine CD4+ T cells and primary human T cells [9]. Regulation of IFN-γ production by ERK and p38 MAPK signalling pathway and through SLAM costimulation has been suggested in TB [10]
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