Induction of protective immunity against Mycobacterium tuberculosis by delivery of ESX antigens into airway dendritic cells

Mucosal Immunol. 2013 May;6(3):522-34. doi: 10.1038/mi.2012.92. Epub 2012 Oct 3.

Abstract

As the Bacillus Calmette-Guérin (BCG) vaccine does not confer long-lasting protection against lung Mycobacterium tuberculosis infection, the development of more efficient vaccines is greatly needed. Here, we used mycobacterial low-molecular weight proteins of the 6-kDa Early Secreted Antigenic Target (ESAT-6) protein family (ESX) antigens for the evaluation of a novel vaccine delivery strategy that enables versatile in vivo targeting of antigens into specialized dendritic cell (DC) subsets. ESX antigens were genetically fused to the tetramerizing core of streptavidin (SA) to form high-affinity complexes with biotin (biot)-conjugated antibodies recognizing DC surface receptors. When directed through the CD11b or CD11c β2-integrins or diverse C-type lectins, the ESX-SA:biot-antibody complexes were efficiently captured and presented on major histocompatibility complex molecules of DCs to specific T-cell receptors. Robust ESX-specific T-cell responses were induced by immunization with as little as several picomoles of ESX-SA targeted to DC subsets. Moreover, directing of TB10.4-SA to airway CD205(+) cells enabled the induction of mucosal T-cell responses and provided significant protection against virulent M. tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / genetics
  • Antibodies, Monoclonal / immunology
  • Antigen Presentation
  • Antigens, Bacterial / immunology*
  • Antigens, CD / metabolism
  • Bacterial Proteins / immunology*
  • CD11b Antigen / immunology
  • CD11c Antigen / immunology
  • CD18 Antigens / immunology
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Female
  • Humans
  • Immunity, Active
  • Lectins, C-Type / metabolism
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Minor Histocompatibility Antigens
  • Mycobacterium tuberculosis / immunology*
  • Receptors, Cell Surface / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Respiratory System / pathology
  • T-Lymphocytes / immunology
  • Tuberculosis Vaccines / immunology*
  • Tuberculosis, Pulmonary / prevention & control*

Substances

  • Antibodies, Monoclonal
  • Antigens, Bacterial
  • Antigens, CD
  • Bacterial Proteins
  • CD11b Antigen
  • CD11c Antigen
  • CD18 Antigens
  • DEC-205 receptor
  • ESAT-6 protein, Mycobacterium tuberculosis
  • Lectins, C-Type
  • Minor Histocompatibility Antigens
  • Receptors, Cell Surface
  • Recombinant Fusion Proteins
  • Tuberculosis Vaccines