PMID- 26552486 OWN - NLM STAT- MEDLINE DCOM- 20160630 LR - 20181113 IS - 1471-2172 (Electronic) IS - 1471-2172 (Linking) VI - 16 DP - 2015 Nov 9 TI - Mycobacterium tuberculosis secretory proteins downregulate T cell activation by interfering with proximal and downstream T cell signalling events. PG - 67 LID - 10.1186/s12865-015-0128-6 [doi] LID - 67 AB - BACKGROUND: Mycobacterium 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. METHODS: Here, 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 NFkappaB by Electrophorectic mobility shift assay (EMSA). RESULTS: We 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 NFkappaB 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. CONCLUSION: To 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. FAU - Sharma, Bhawna AU - Sharma B AD - Department of Immunology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases (ICMR), Dr.M.Miyazaki Marg, Tajganj, Agra, 282001, India. bhavnamicrobio@gmail.com. FAU - Upadhyay, Rajni AU - Upadhyay R AD - Department of Immunology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases (ICMR), Dr.M.Miyazaki Marg, Tajganj, Agra, 282001, India. rajniupadhyay@gmail.com. FAU - Dua, Bhavyata AU - Dua B AD - Department of Immunology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases (ICMR), Dr.M.Miyazaki Marg, Tajganj, Agra, 282001, India. bhavidua08@gmail.com. FAU - Khan, Naim Akhtar AU - Khan NA AD - UPRES EA 4183 Lipides & Signalisation Cellulaire, Faculte des Sciences de la vie, Universite de Bourgogne, 6, Boulevard Gabriel, Dijon, 21000, France. Naim.Khan@u-bourgogne.fr. FAU - Katoch, Vishwa Mohan AU - Katoch VM AD - Formerly in Department of Health Research and ICMR, Ansari Nagar, New Delhi-29, India. vishwamohan_katoch@yahoo.co.in. FAU - Bajaj, Bharat AU - Bajaj B AD - State TB Training & Demonstration Centre, S.N. Medical College Campus, Agra, 282 002, India. bharatbajaj10062@gmail.com. FAU - Joshi, Beenu AU - Joshi B AD - Department of Immunology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases (ICMR), Dr.M.Miyazaki Marg, Tajganj, Agra, 282001, India. beenuj2002@yahoo.co.in. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151109 PL - England TA - BMC Immunol JT - BMC immunology JID - 100966980 RN - 0 (Antigens, Bacterial) RN - 0 (Bacterial Proteins) RN - 0 (CD28 Antigens) RN - 0 (ESAT-6 protein, Mycobacterium tuberculosis) RN - 0 (NF-kappa B) RN - 0 (NFATC Transcription Factors) RN - 0 (Receptors, Antigen, T-Cell) RN - 144058-44-6 (Mycobacterium tuberculosis antigens) RN - EC 2.3.- (Acyltransferases) RN - EC 2.3.1.- (antigen 85A, Mycobacterium tuberculosis) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - SY7Q814VUP (Calcium) SB - IM MH - Acyltransferases/immunology/metabolism MH - Antigens, Bacterial/immunology/metabolism MH - Bacterial Proteins/*immunology/*metabolism MH - CD28 Antigens/metabolism MH - Calcium/metabolism MH - Humans MH - Intracellular Space/metabolism MH - Leukocytes, Mononuclear/immunology/metabolism MH - Lymphocyte Activation/*immunology MH - Mitogen-Activated Protein Kinases/metabolism MH - Mycobacterium tuberculosis/*immunology/*metabolism MH - NF-kappa B/metabolism MH - NFATC Transcription Factors/metabolism MH - Receptors, Antigen, T-Cell/metabolism MH - *Signal Transduction MH - T-Lymphocytes/*immunology/*metabolism PMC - PMC4640201 EDAT- 2015/11/11 06:00 MHDA- 2016/07/01 06:00 PMCR- 2015/11/09 CRDT- 2015/11/11 06:00 PHST- 2015/05/19 00:00 [received] PHST- 2015/10/20 00:00 [accepted] PHST- 2015/11/11 06:00 [entrez] PHST- 2015/11/11 06:00 [pubmed] PHST- 2016/07/01 06:00 [medline] PHST- 2015/11/09 00:00 [pmc-release] AID - 10.1186/s12865-015-0128-6 [pii] AID - 128 [pii] AID - 10.1186/s12865-015-0128-6 [doi] PST - epublish SO - BMC Immunol. 2015 Nov 9;16:67. doi: 10.1186/s12865-015-0128-6.