title: Mycobacterium tuberculosis lipoproteins directly regulate human memory CD4(+) T cell activation via Toll-like receptors 1 and 2.
abstract: The success of Mycobacterium tuberculosis as a pathogen relies on its ability to regulate the host immune response. M. tuberculosis can manipulate adaptive T cell responses indirectly by modulating antigen-presenting cell (APC) function or by directly interacting with T cells. Little is known about the role of M. tuberculosis molecules in direct regulation of T cell function. Using a biochemical approach, we identified lipoproteins LprG and LpqH as major molecules in M. tuberculosis lysate responsible for costimulation of primary human CD4(+) T cells. In the absence of APCs, activation of memory CD4(+) T cells with LprG or LpqH in combination with anti-CD3 antibody induces Th1 cytokine secretion and cellular proliferation. Lipoprotein-induced T cell costimulation was inhibited by blocking antibodies to Toll-like receptor 2 (TLR2) and TLR1, indicating that human CD4(+) T cells can use TLR2/TLR1 heterodimers to directly respond to M. tuberculosis products. M. tuberculosis lipoproteins induced NF-κB activation in CD4(+) T cells in the absence of TCR co-engagement. Thus, TLR2/TLR1 engagement alone by M. tuberculosis lipoprotein triggered intracellular signaling, but upregulation of cytokine production and proliferation required co-engagement of the TCR. In conclusion, our results demonstrate that M. tuberculosis lipoproteins LprG and LpqH participate in the regulation of adaptive immunity not only by inducing cytokine secretion and costimulatory molecules in innate immune cells but also through directly regulating the activation of memory T lymphocytes.
authors.affiliation: Department of Pediatrics, Case Western Reserve School of Medicine, Cleveland, Ohio 44106, USA. clancioni1@aol.com
authors.forename: Christina L
authors.initials: CL
authors.lastname: Lancioni
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Thomas
authors.forename: XueDong
authors.initials: X
authors.lastname: Ding
authors.forename: Bonnie
authors.initials: B
authors.lastname: Thiel
authors.forename: Michael G
authors.initials: MG
authors.lastname: Drage
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Pecora
authors.forename: Assem G
authors.initials: AG
authors.lastname: Ziady
authors.forename: Samuel
authors.initials: S
authors.lastname: Shank
authors.forename: Clifford V
authors.initials: CV
authors.lastname: Harding
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.forename: Roxana E
authors.initials: RE
authors.lastname: Rojas
mesh_terms: D000215:Acylation; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D007156:Immunologic Memory / Q000502:physiology; D008074:Lipoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000502:physiology*; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000378:metabolism*; D051194:Toll-Like Receptor 1 / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D008074:Lipoproteins; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2