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 wit 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. (C) 2009 Elsevier Ltd All rights reserved.