Mycobacterium tuberculosis secretory proteins downregulate T cell activation by interfering with proximal and downstream T cell signalling events

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.

The IL-17A rs2275913 single nucleotide polymorphism is associated with protection to tuberculosis but related to higher disease severity in Argentina

“…Accordingly, we observed elevated levels of IL-17A in subjects carrying the AA genotype as compared to individuals that carry the GG genotype, both in plasma and in supernatants of in vitro stimulated PBMC, and independently of the population analyzed. Thus, NFAT might be involved in this differential synthesis of IL-17A, given that this transcription factor promotes the transcription of genes during T lymphocyte activation and was detected in cells stimulated with Mtb antigens304344. However, further studies are required to confirm this hypothesis.…”

ESAT-6 Protein of Mycobacterium tuberculosis Increases Holotransferrin-Mediated Iron Uptake in Macrophages by Downregulating Surface Hemochromatosis Protein HFE

“…ESAT-6/ESAT-6:CFP-10 manipulates many host factors in macrophage and hijacks the host immune system to make a safe niche for the bacilli to survive inside the macrophages. It has been reported earlier that ESAT-6 plays a crucial role in supporting intracellular growth of the bacilli in host (5,7,(39)(40)(41)(42)(43)(44). In the previous study, we have demonstrated that ESAT-6 alone or in complex with CFP-10 (ESAT-6:CFP-10) interacts with b2M, and the C-terminal end of ESAT-6 is crucial for its interaction with b2M as ESAT-6 protein with deletion of 6 aa in the C-terminal end failed to interact with b2M (10).…”

Changes in T-lymphocyte subsets and risk factors in human immunodeficiency virus-negative patients with active tuberculosis

“…Attempts to develop alternative novel methods of adjuvant therapy for TB infections have focused on determining the characteristics of the changes in immune function that occur during TB infection and their risk factors. Consensus has emerged that Mtb downregulates the activation of CD4 T-cells through secreted-protein-mediated interference with T-cell proximal and downstream signals, leading to Th1/Th2 imbalance [ 3 ] and eventually inducing low expression of CD4 [ 4 , 5 ]. However, reports on the changes in CD8 T-cells have been inconsistent.…”