Toll-Like Receptor 2 Targeted Rectification of Impaired CD8⁺ T Cell Functions in Experimental Leishmania donovani Infection Reinstates Host Protection

• Published in: PloS one 2015-11, Vol.10 (11), p.e0142800
• Main Authors: Bandyopadhyay, Syamdas, Kar Mahapatra, Santanu, Paul Chowdhury, Bidisha, Kumar Jha, Mukesh, Das, Shibali, Halder, Kuntal, Bhattacharyya Majumdar, Suchandra, Saha, Bhaskar, Majumdar, Subrata
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Apoptosis; CD25 antigen; CD28 antigen; CD28 Antigens - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - parasitology; Cell activation; Cell Proliferation; Cell walls; Cytokines; Disease Models, Animal; Effector cells; Granzymes - genetics; Histones - metabolism; Immunoglobulins; Infections; Interferon gamma Receptor; Interferon-gamma - genetics; Interleukin-2 Receptor alpha Subunit - metabolism; Kinases; Leishmania; Leishmania donovani; Leishmaniasis, Visceral - blood; Leishmaniasis, Visceral - immunology; Ligands; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; MAP kinase; Medicine; Mice; Mice, Inbred BALB C; NF-kappa B - metabolism; NF-κB protein; Pathogenesis; Perforin; Pore Forming Cytotoxic Proteins - genetics; Promoter Regions, Genetic; Proteins; Protozoa; Receptors, Interferon - metabolism; Receptors, Interleukin-12 - metabolism; Recovery of function; Signal Transduction; Signaling; T-Box Domain Proteins - metabolism; TLR2 protein; Toll-Like Receptor 2 - metabolism; Toll-like receptors; Transcription; Translocation; Tuberculosis; Up-Regulation; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0142800

Leishmania donovani, a protozoan parasite, causes the disease visceral leishmanisis (VL), characterized by inappropriate CD8+ T-cell activation. Therefore, we examined whether the Toll-like Receptor 2 (TLR2) ligand Ara-LAM, a cell wall glycolipid from non-pathogenic Mycobacterium smegmatis, would restore CD8+ T-cell function during VL. We observed that by efficient upregulation of TLR2 signaling-mediated NF-κB translocation and MAPK signaling in CD8+ T-cells (CD25+CD28+IL-12R+IFN-γR+), Ara-LAM triggered signaling resulted in the activation of T-bet, which in turn, induced transcription favourable histone modification at the IFN-γ, perforin, granzyme-B promoter regions in CD8+ T-cells. Thus, we conclude that Ara-LAM induced efficient activation of effector CD8+ T-cells by upregulating the expression of IFN-γ, perforin and granzyme-B in an NF-κB and MAPK induced T-bet dependent manner in VL.