03010nas a2200553   4500000000100000008004100001260001300042653002400055653001700079653004400096653001200140653001800152653002300170653001800193653002200211653003100233653001100264653001800275653004100293653001400334653001500348653001700363653002000380653001200400653002600412653003200438653003900470653002500509653003200534653004200566653003000608653002100638653003100659653001800690653001700708653003500725100001200760700001300772700001200785700001200797700001400809700001500823700001200838245015000850300001101000490000701011520142401018022001402442       2010                            d  c2010 Feb10aAntigens, Bacterial10aAntigens, CD10aAntigens, Differentiation, T-Lymphocyte10aCalcium10aCD28 Antigens10aCell Proliferation10aClonal Anergy10aEnzyme Inhibitors10aGene Expression Regulation10aHumans10aInterleukin-210aInterleukin-2 Receptor alpha Subunit10aIonomycin10aIonophores10aJurkat Cells10aLectins, C-Type10aleprosy10aLymphocyte Activation10aMAP Kinase Signaling System10aMitogen-Activated Protein Kinase 310aMycobacterium leprae10aNFATC Transcription Factors10aP38 Mitogen-Activated Protein Kinases10aPromoter Regions, Genetic10aProtein Kinase C10aReceptors, Antigen, T-Cell10aT-Lymphocytes10aThapsigargin10aZAP-70 Protein-Tyrosine Kinase1 aDagur P1 aSharma B1 aKumar G1 aKhan NA1 aKatoch VM1 aSengupta U1 aJoshi B00aMycobacterial antigen(s) induce anergy by altering TCR- and TCR/CD28-induced signalling events: insights into T-cell unresponsiveness in leprosy.  a943-520 v473 a<p>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.</p>  a1872-9142