title: Mycobacterium tuberculosis PstS1 amplifies IFN-γ and induces IL-17/IL-22 responses by unrelated memory CD4+ T cells via dendritic cell activation.
abstract: The immunological mechanisms that modulate protection during Mycobacterium tuberculosis (Mtb) infection or vaccination are not fully understood. Secretion of IFN-γ and, to a lesser extent, of IL-17 by CD4(+) T cells plays a major role both in protection and immunopathology. Few Mtb Ags interacting with DCs affect priming, activation, and regulation of Ag-unrelated CD4(+) T-cell responses. Here we demonstrate that PstS1, a 38 kDa-lipoprotein of Mtb, promotes Ag-independent activation of memory T lymphocytes specific for Ag85B or Ag85A, two immunodominant protective Ags of Mtb. PstS1 expands CD4(+) and CD8(+) memory T cells, amplifies secretion of IFN-γ and IL-22 and induces IL-17 production by effector memory cells in an Ag-unrelated manner in vitro and in vivo. These effects were mediated through the stimulation of DCs, particularly of the CD8α(-) subtype, which respond to PstS1 by undergoing phenotypic maturation and by secreting IL-6, IL-1β and, to a lower extent, IL-23. IL-6 secretion by PstS1-stimulated DCs was required for IFN-γ, and to a lesser extent for IL-22 responses by Ag85B-specific memory T cells. These results may open new perspectives for immunotherapeutic strategies to control Th1/Th17 immune responses in Mtb infections and in vaccinations against tuberculosis.
authors.affiliation: Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Palma
authors.forename: Giovanna
authors.initials: G
authors.lastname: Schiavoni
authors.forename: Laura
authors.initials: L
authors.lastname: Abalsamo
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Mattei
authors.forename: Giovanni
authors.initials: G
authors.lastname: Piccaro
authors.forename: Massimo
authors.initials: M
authors.lastname: Sanchez
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernandez
authors.forename: Mahavir
authors.initials: M
authors.lastname: Singh
authors.forename: Lucia
authors.initials: L
authors.lastname: Gabriele
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000217:Acyltransferases / Q000276:immunology; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics; D014376:Tuberculosis / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D018528:ATP-Binding Cassette Transporters; D000217:Acyltransferases; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016827:CD8 Antigens; D007371:Interferon-gamma; D020381:Interleukin-17; D053583:Interleukin-1beta; D053759:Interleukin-23; D015850:Interleukin-6; D007378:Interleukins; D051195:Toll-Like Receptor 2; D000097043:Interleukin-22; C581205:PstS-1 protein, Mycobacterium tuberculosis; C493486:Tlr2 protein, mouse; C112580:antigen 85A, Mycobacterium tuberculosis; C121433:antigen 85B, Mycobacterium tuberculosis
keywords: DC; Memory T cells; Mycobacterium tuberculosis Ags; Th1 response; Th17 response