title: Isolation of a distinct Mycobacterium tuberculosis mannose-capped lipoarabinomannan isoform responsible for recognition by CD1b-restricted T cells.
abstract: Mannose-capped lipoarabinomannan (ManLAM) is a complex lipoglycan abundantly present in the Mycobacterium tuberculosis cell envelope. Many biological properties have been ascribed to ManLAM, from directly interacting with the host and participating in the intracellular survival of M. tuberculosis, to triggering innate and adaptive immune responses, including the activation of CD1b-restricted T cells. Due to its structural complexity, ManLAM is considered a heterogeneous population of molecules which may explain its different biological properties. The presence of various modifications such as fatty acids, succinates, lactates, phosphoinositides and methylthioxylose in ManLAM have proven to correlate directly with its biological activity and may potentially be involved in the interactions between CD1b and the T cell population. To further delineate the specific ManLAM epitopes involved in CD1b-restricted T cell recognition, and their potential roles in mediating immune responses in M. tuberculosis infection, we established a method to resolve ManLAM into eight different isoforms based on their different isoelectric values. Our results show that a ManLAM isoform with an isoelectric value of 5.8 was the most potent in stimulating the production of interferon-γ in different CD1b-restricted T-cell lines. Compositional analyses of these isoforms of ManLAM revealed a direct relationship between the overall charge of the ManLAM molecule and its capacity to be presented to T cells via the CD1 compartment.
authors.affiliation: Mycobacterial Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA. jordi.torrelles@osumc.edu
authors.forename: Jordi B
authors.initials: JB
authors.lastname: Torrelles
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sieling
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhang
authors.forename: Mark A
authors.initials: MA
authors.lastname: Keen
authors.forename: Michael R
authors.initials: MR
authors.lastname: McNeil
authors.forename: John T
authors.initials: JT
authors.lastname: Belisle
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Brennan
authors.forename: Delphi
authors.initials: D
authors.lastname: Chatterjee
mesh_terms: D018949:Antigens, CD1 / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007526:Isoelectric Point; D007918:Leprosy / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism*; D008358:Mannose / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism; D020033:Protein Isoforms; D013386:Succinates / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014376:Tuberculosis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology
chemical_list: D018949:Antigens, CD1; C419394:CD1b antigen; D008070:Lipopolysaccharides; D010710:Phosphates; D020033:Protein Isoforms; D013386:Succinates; C050016:lipoarabinomannan; D007371:Interferon-gamma; D008358:Mannose