Mycobacterial antigen(s) induce anergy by altering TCR- and TCR/CD28-induced signalling events: insights into T-cell unresponsiveness in leprosy.

6533b82afe1ef96bd128c3aa

RESEARCH PRODUCT

Mycobacterial antigen(s) induce anergy by altering TCR- and TCR/CD28-induced signalling events: insights into T-cell unresponsiveness in leprosy.

Beenu Joshi Naim Akhtar Khan Bhawna Sharma Vishwa Mohan Katoch Gavish Kumar Utpal Sengupta Pradeep K. Dagur

subject

Antigens Differentiation T-Lymphocyte MAP Kinase Signaling System T cell T-Lymphocytes Immunology Receptors Antigen T-Cell chemical and pharmacologic phenomena Biology Lymphocyte Activation Jurkat cells p38 Mitogen-Activated Protein Kinases chemistry.chemical_compound Jurkat Cells CD28 Antigens Antigens CD Leprosy Calcium flux medicine Humans Lectins C-Type Enzyme Inhibitors Promoter Regions Genetic Molecular Biology Mycobacterium leprae Protein Kinase C Cell Proliferation Clonal Anergy Antigens Bacterial Mitogen-Activated Protein Kinase 3 ZAP-70 Protein-Tyrosine Kinase Ionophores NFATC Transcription Factors Ionomycin T-cell receptor Interleukin-2 Receptor alpha Subunit CD28 hemic and immune systems NFAT biology.organism_classification Cell biology Mycobacterium leprae medicine.anatomical_structure chemistry Gene Expression Regulation Ionomycin Immunology Interleukin-2 Thapsigargin Calcium

description

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.

year	journal	country	edition	language
2009-04-29	Molecular immunology

10.1016/j.molimm.2009.11.009 https://pubmed.ncbi.nlm.nih.gov/20018378