title: Interleukin-17-dependent CXCL13 mediates mucosal vaccine-induced immunity against tuberculosis.
abstract: The variable efficacy of tuberculosis (TB) vaccines and the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) emphasize the urgency for not only generating new and more effective vaccines against TB but also understanding the underlying mechanisms that mediate vaccine-induced protection. We demonstrate that mucosal adjuvants, such as type II heat labile enterotoxin (LT-IIb), delivered through the mucosal route induce pulmonary Mtb-specific T helper type 17 (Th17) responses and provide vaccine-induced protection against Mtb infection. Importantly, protection is interferon-γ (IFNγ)-independent but interleukin-17 (IL-17)-dependent. Our data show that IL-17 mediates C-X-C motif chemokine ligand 13 (CXCL13) induction in the lung for strategic localization of proinflammatory cytokine-producing CXCR5+ (C-X-C motif chemokine receptor 5-positive) T cells within lymphoid structures, thereby promoting early and efficient macrophage activation and the control of Mtb. Our studies highlight the potential value of targeting the IL-17-CXCL13 pathway rather than the IFNγ pathway as a new strategy to improve mucosal vaccines against TB.
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gopal
authors.forename: J
authors.initials: J
authors.lastname: Rangel-Moreno
authors.forename: S
authors.initials: S
authors.lastname: Slight
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.forename: H F
authors.initials: HF
authors.lastname: Nawar
authors.forename: B A
authors.initials: BA
authors.lastname: Fallert Junecko
authors.forename: T A
authors.initials: TA
authors.lastname: Reinhart
authors.forename: J
authors.initials: J
authors.lastname: Kolls
authors.forename: T D
authors.initials: TD
authors.lastname: Randall
authors.forename: T D
authors.initials: TD
authors.lastname: Connell
authors.forename: S A
authors.initials: SA
authors.lastname: Khader
mesh_terms: D000818:Animals; D054382:Chemokine CXCL13 / Q000378:metabolism*; D004768:Enterotoxins / Q000235:genetics; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D008262:Macrophage Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D054380:Receptors, CXCR5 / Q000378:metabolism; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology* / Q000517:prevention & control; D032581:Tuberculosis Vaccines
chemical_list: C095085:CXCR5 protein, human; D054382:Chemokine CXCL13; D004768:Enterotoxins; D020381:Interleukin-17; D054380:Receptors, CXCR5; D032581:Tuberculosis Vaccines