TY - JOUR KW - Antigens, Bacterial KW - Antigens, CD KW - Antigens, Differentiation, T-Lymphocyte KW - Calcium KW - CD28 Antigens KW - Cell Proliferation KW - Clonal Anergy KW - Enzyme Inhibitors KW - Gene Expression Regulation KW - Humans KW - Interleukin-2 KW - Interleukin-2 Receptor alpha Subunit KW - Ionomycin KW - Ionophores KW - Jurkat Cells KW - Lectins, C-Type KW - leprosy KW - Lymphocyte Activation KW - MAP Kinase Signaling System KW - Mitogen-Activated Protein Kinase 3 KW - Mycobacterium leprae KW - NFATC Transcription Factors KW - P38 Mitogen-Activated Protein Kinases KW - Promoter Regions, Genetic KW - Protein Kinase C KW - Receptors, Antigen, T-Cell KW - T-Lymphocytes KW - Thapsigargin KW - ZAP-70 Protein-Tyrosine Kinase AU - Dagur P AU - Sharma B AU - Kumar G AU - Khan NA AU - Katoch VM AU - Sengupta U AU - Joshi B AB -

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.

BT - Molecular immunology C1 - http://www.ncbi.nlm.nih.gov/pubmed/20018378?dopt=Abstract DA - 2010 Feb DO - 10.1016/j.molimm.2009.11.009 IS - 5 J2 - Mol. Immunol. LA - eng N2 -

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.

PY - 2010 SP - 943 EP - 52 T2 - Molecular immunology TI - Mycobacterial antigen(s) induce anergy by altering TCR- and TCR/CD28-induced signalling events: insights into T-cell unresponsiveness in leprosy. VL - 47 SN - 1872-9142 ER -