Mycobacterial antigen(s) induce anergy by altering TCR- and TCR/CD28-induced signalling events: insights into T-cell unresponsiveness in leprosy.
Present study investigates the role of Mycobacterium leprae (M. leprae) antigens on TCR- and TCR/CD28-induced signalling leading to T-cell activation and further correlates these early biochemical events with T-cell anergy, as prevailed in advanced stages of leprosy. We observed that both whole cell lystae (WCL) and soluble fraction of M. leprae sonicate (MLSA) not only inhibited TCR, thapsigargin and ionomycin induced calcium fluxes by diminishing the opening of calcium channels, but also TCR- or TCR/CD28-induced proximal signalling events like phosphorylation of Zap-70 and protein kinase-C (PKC) activity. Study of TCR- and TCR/CD28-induced downstream signals revealed that M. leprae antigens curtail phosphorylation of both Erk1/2 and p38MAPK, consequently altering terminal signalling events like reduced binding of NFAT on IL-2 promoter and transcription of IL-2 gene, diminished expression of activation markers (CD25 and CD69). Furthermore, M. leprae fractions significantly inhibited IL-2 secretion and T-cell blastogenesis in healthy individuals. Altogether, results suggest that M. leprae interferes with TCR/CD28-induced upstream as well as downstream signalling events resulting in reduced IL-2 production and thus inhibition in T-cell proliferation, which might be responsible for T-cell unresponsiveness leading to stage of immunosuppression and consequently, for the progression of disease.
Dagur
Pradeep K
PK
Immunology Division, National JALMA Institute for Leprosy and Other Mycobacterial Diseases (ICMR), Taj Ganj, Agra 282001, U.P., India.
Sharma
Bhawna
B
Kumar
Gavish
G
Khan
Naim A
NA
Katoch
Vishwa M
VM
Sengupta
Utpal
U
Joshi
Beenu
B
D000942:Antigens, Bacterial / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D002118:Calcium / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D019169:Jurkat Cells; D037181:Lectins, C-Type / Q000276:immunology; D007918:Leprosy / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000276:immunology; D009166:Mycobacterium leprae / Q000276:immunology*; D050778:NFATC Transcription Factors / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000276:immunology; D011493:Protein Kinase C / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D019284:Thapsigargin / Q000494:pharmacology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology; D000099192:CD69 Antigens
D000942:Antigens, Bacterial; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D002118:Calcium; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015759:Ionomycin; D007476:Ionophores; D037181:Lectins, C-Type; D048052:Mitogen-Activated Protein Kinase 3; D050778:NFATC Transcription Factors; D011493:Protein Kinase C; D011948:Receptors, Antigen, T-Cell; D019284:Thapsigargin; D051746:ZAP-70 Protein-Tyrosine Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D000099192:CD69 Antigens; C508594:IL2 protein, human; C508017:IL2RA protein, human; C497261:ZAP70 protein, human