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Department of Pathology and Molecular Medicine and Division of Infectious Diseases, Center for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada
Genetic immunization holds great promise for future vaccination against mucosal infectious diseases. However, parenteral genetic immunization is ineffective in control of mucosal intracellular infections, and the underlying mechanisms have remained unclear. By using a model of parenteral i.m. genetic immunization and pulmonary tuberculosis (TB), we have investigated the mechanisms that determine the failure and success of parenteral genetic immunization. We found that lack of protection from pulmonary Mycobacterium tuberculosis (M.tb) challenge by i.m. immunization with a recombinant adenovirus-vectored tuberculosis vaccine was linked to the absence of M.tb Ag-specific T cells within the airway lumen before M.tb challenge despite potent T cell activation in the systemic compartments. Furthermore, pulmonary mycobacterial challenge failed to recruit CD8 T cells into the airway lumen of i.m. immunized mice. Such defect in T cell recruitment, intra-airway CTL, and immune protection was restored by creating acute inflammation in the airway with inflammatory agonists such as virus. However, the Ag-specific T cells recruited as such were not retained in the airway lumen, resulting in a loss of protection. In comparison, airway exposure to low doses of soluble M.tb Ags not only recruited but retained Ag-specific CD8 T cells in the airway lumen over time that provided robust protection against M.tb challenge. Thus, our study reveals that mucosal protection by parenteral immunization is critically determined by T cell geography, i.e., whether Ag-specific T cells are within or outside of the mucosal lumen and presents a feasible solution to empower parenteral immunization strategies against mucosal infectious diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study is supported by funds from the Canadian Institutes of Health Research and the World Health Organization. We also acknowledge the provision of M.tb Ags by Colorado State University through the funds from the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Zhou Xing, Room 4012, Michael DeGroot Center for Learning and Discovery, Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada. E-mail address: xingz{at}mcmaster.ca
3 Abbreviations used in this paper: TB, tuberculosis; Ad, adenovirus; BAL, bronchoalveolar lavage; BCG, bacillus Calmette-Guérin; ICCS, intracellular cytokine staining; i.n., intranasal; M.tb, Mycobacterium tuberculosis; MVA, vaccinia virus Ankara; tPA, tissue plasminogen activator; VSV, vesicular stomatitis virus.
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