Interleukin-17-dependent CXCL13 mediates mucosal vaccine-induced immunity against tuberculosis

R. Gopal; J. Rangel-Moreno; S. Slight; Y. Lin; H. F. Nawar; B. A. Fallert Junecko; T. A. Reinhart; J. Kolls; T. D. Randall; T. D. Connell; S. A. Khader

doi:10.1038/mi.2012.135

Interleukin-17-dependent CXCL13 mediates mucosal vaccine-induced immunity against tuberculosis

R. Gopal
, J. Rangel-Moreno
, S. Slight
, Y. Lin
, H. F. Nawar
, B. A. Fallert Junecko
, T. A. Reinhart
, J. Kolls
, T. D. Randall
, T. D. Connell
, S. A. Khader

Research output: Contribution to journal › Article › peer-review

146 Scopus citations

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.

Original language	English
Pages (from-to)	972-984
Number of pages	13
Journal	Mucosal Immunology
Volume	6
Issue number	5
DOIs	https://doi.org/10.1038/mi.2012.135
State	Published - Sep 2013

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@article{3dc1fd077c554f59a683276bf4b9a02e,

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.",

author = "R. Gopal and J. Rangel-Moreno and S. Slight and Y. Lin and Nawar, \{H. F.\} and \{Fallert Junecko\}, \{B. A.\} and Reinhart, \{T. A.\} and J. Kolls and Randall, \{T. D.\} and Connell, \{T. D.\} and Khader, \{S. A.\}",

note = "Funding Information: This work was supported by Children{\textquoteright}s Hospital of Pittsburgh, NIH grants AI083541 and HL105427 to S.A.K., HL69409 to T.D.R., DE13833 to T.D.C., and AI060422 to T.A.R., Department of Medicine, University of Rochester and AI91036 to J.R.-M, a Research Advisory Committee Grants from Children{\textquoteright}s Hospital of Pittsburgh of the UPMC Health System to S.R.S and Y.L. We thank Dr Iwakura, University of Japan, for Il17−/− for breeders and Dr Kaplan, Indiana University School of Medicine for Stat3.Cd4−/− breeders and Hillary Cleveland for mice breeding. We also thank Dr John Alcorn for critical reading of the manuscript.",

year = "2013",

month = sep,

doi = "10.1038/mi.2012.135",

language = "English",

volume = "6",

pages = "972--984",

journal = "Mucosal Immunology",

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T1 - Interleukin-17-dependent CXCL13 mediates mucosal vaccine-induced immunity against tuberculosis

AU - Gopal, R.

AU - Rangel-Moreno, J.

AU - Slight, S.

AU - Lin, Y.

AU - Nawar, H. F.

AU - Fallert Junecko, B. A.

AU - Reinhart, T. A.

AU - Kolls, J.

AU - Randall, T. D.

AU - Connell, T. D.

AU - Khader, S. A.

N1 - Funding Information: This work was supported by Children’s Hospital of Pittsburgh, NIH grants AI083541 and HL105427 to S.A.K., HL69409 to T.D.R., DE13833 to T.D.C., and AI060422 to T.A.R., Department of Medicine, University of Rochester and AI91036 to J.R.-M, a Research Advisory Committee Grants from Children’s Hospital of Pittsburgh of the UPMC Health System to S.R.S and Y.L. We thank Dr Iwakura, University of Japan, for Il17−/− for breeders and Dr Kaplan, Indiana University School of Medicine for Stat3.Cd4−/− breeders and Hillary Cleveland for mice breeding. We also thank Dr John Alcorn for critical reading of the manuscript.

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84879231117

U2 - 10.1038/mi.2012.135

DO - 10.1038/mi.2012.135

M3 - Article

C2 - 23299616

AN - SCOPUS:84879231117

SN - 1933-0219

VL - 6

SP - 972

EP - 984

JO - Mucosal Immunology

JF - Mucosal Immunology

IS - 5

ER -

Interleukin-17-dependent CXCL13 mediates mucosal vaccine-induced immunity against tuberculosis

Abstract

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