title: TLR4 and NKT cell synergy in immunotherapy against visceral leishmaniasis.
abstract: NKT cells play an important role in autoimmune diseases, tumor surveillance, and infectious diseases, providing in most cases protection against infection. NKT cells are reactive to CD1d presented glycolipid antigens. They can modulate immune responses by promoting the secretion of type 1, type 2, or immune regulatory cytokines. Pathogen-derived signals to dendritic cells mediated via Toll like Receptors (TLR) can be modulated by activated invariant Natural Killer T (iNKT) cells. The terminal β-(1-4)-galactose residues of glycans can modulate host responsiveness in a T helper type-1 direction via IFN-γ and TLRs. We have attempted to develop a defined immunotherapeutic, based on the cooperative action of a TLR ligand and iNKT cell using a mouse model of visceral leishmaniasis. We evaluated the anti-Leishmania immune responses and the protective efficacy of the β-(1-4)-galactose terminal NKT cell ligand glycosphingophospholipid (GSPL) antigen of L. donovani parasites. Our results suggest that TLR4 can function as an upstream sensor for GSPL and provoke intracellular inflammatory signaling necessary for parasite killing. Treatment with GSPL was able to induce a strong effective T cell response that contributed to effective control of acute parasite burden and led to undetectable parasite persistence in the infected animals. These studies for the first time demonstrate the interactions between a TLR ligand and iNKT cell activation in visceral leishmaniasis immunotherapeutic.
authors.affiliation: Division of Infectious Disease and Immunology, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, India.
authors.forename: Subir
authors.initials: S
authors.lastname: Karmakar
authors.forename: Siddhartha Kumar
authors.initials: SK
authors.lastname: Bhaumik
authors.forename: Joydeep
authors.initials: J
authors.lastname: Paul
authors.forename: Tripti
authors.initials: T
authors.lastname: De
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects* / Q000235:genetics; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D006224:Cricetinae; D006028:Glycosphingolipids / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods*; D007893:Leishmania donovani / Q000276:immunology* / Q000378:metabolism; D007898:Leishmaniasis, Visceral / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D011134:Polysaccharides / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; D000953:Antigens, Protozoan; C526879:Cd1d1 protein, mouse; D006028:Glycosphingolipids; D011134:Polysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4