title: Phenolic-glycolipid-1 and lipoarabinomannan preferentially modulate TCR- and CD28-triggered proximal biochemical events, leading to T-cell unresponsiveness in mycobacterial diseases.
abstract: BACKGROUND
  Advanced stages of leprosy show T cell unresponsiveness and lipids of mycobacterial origin are speculated to modulate immune responses in these patients. Present study elucidates the role of phenolicglycolipid (PGL-1) and Mannose-capped lipoarabinomannan (Man-LAM) on TCR- and TCR/CD28- mediated signalling.
  
  
  RESULTS
  We observed that lipid antigens significantly inhibit proximal early signalling events like Zap-70 phosphorylation and calcium mobilization. Interestingly, these antigens preferentially curtailed TCR-triggered early downstream signalling events like p38 phosphorylation whereas potentiated that of Erk1/2. Further, at later stages inhibition of NFAT binding, IL-2 message, CD25 expression and T-cell blastogenesis by PGL-1 and Man-LAM was noted.
  
  
  CONCLUSIONS
  Altogether, we report that Man-LAM and PGL-1 preferentially interfere with TCR/CD28-triggered upstream cell signalling events, leading to reduced IL-2 secretion and T-cell blastogenesis which potentially could lead to immunosupression and thus, disease exacerbation, as noted in disease spectrum.
authors.affiliation: Immunology Laboratory, National JALMA Institute for Leprosy and Other Mycobacterial Diseases-ICMR, Dr. M. Miyazaki Marg, Tajganj, Agra 282001, India.
authors.forename: Pradeep Kumar
authors.initials: PK
authors.lastname: Dagur
authors.forename: Bhawna
authors.initials: B
authors.lastname: Sharma
authors.forename: Rajni
authors.initials: R
authors.lastname: Upadhyay
authors.forename: Bhavyata
authors.initials: B
authors.lastname: Dua
authors.forename: Arshad
authors.initials: A
authors.lastname: Rizvi
authors.forename: Naim Akhtar
authors.initials: NA
authors.lastname: Khan
authors.forename: Vishwa Mohan
authors.initials: VM
authors.lastname: Katoch
authors.forename: Utpal
authors.initials: U
authors.lastname: Sengupta
authors.forename: Beenu
authors.initials: B
authors.lastname: Joshi
mesh_terms: D000942:Antigens, Bacterial / Q000276:immunology / Q000494:pharmacology*; D018106:CD28 Antigens / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D006017:Glycolipids / Q000276:immunology / Q000494:pharmacology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007111:Immunity, Cellular; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D007918:Leprosy / Q000276:immunology / Q000382:microbiology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D009166:Mycobacterium leprae / Q000276:immunology; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D018106:CD28 Antigens; D006017:Glycolipids; C508594:IL2 protein, human; C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D008070:Lipopolysaccharides; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; C050016:lipoarabinomannan; C045169:phenolic glycolipid I, Mycobacterium leprae; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases