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The Acquired Immune Response to the Mucosal Adjuvant LTK63 Imprints the Mouse Lung with a Protective Signature

Elaine Tritto^*, Alessandro Muzzi^*, Isabella Pesce^*, Elisabetta Monaci^*, Sandra Nuti^*, Grazia Galli^*, Andreas Wack^*, Rino Rappuoli^*, Tracy Hussell and Ennio De Gregorio^1,*

^* Novartis Vaccines and Diagnostics, Siena, Italy; and Kennedy Institute, Imperial College of Science, Technology and Medicine, London, United Kingdom

LTK63, a nontoxic mutant of Escherichia coli heat labile enterotoxin (LT), is a potent and safe mucosal adjuvant that has also been shown to confer generic protection to several respiratory pathogens. To understand the mechanisms of action underlying the LTK63 protective effect, we analyzed the molecular and cellular events triggered by its administration in vivo. We show here that LTK63 intrapulmonary administration induced in the mouse lung a specific gene expression signature characterized by the up-regulation of cell cycle genes, several host defense genes, chemokines, chemokine receptors, and immune cell-associated genes. Such a transcriptional profile reflected the activation of alveolar macrophages and the recruitment to the lung of T and B cells and innate immune cells such as granulocytes, NK, and dendritic cells. All of these events were T cell dependent and specific for LTK63 because they were absent in SCID and nude mice. Additionally, we showed that LTK63 induces a potent adaptive immune response against itself directed to the lung. We propose that acquired response to LTK63 is the driving force for the local recruitment of both adaptive and innate immune cells. Our data suggest that LTK63 acts as an airway infection mimic that establishes a generic protective environment limiting respiratory infection by innate immune mechanisms and by improving adaptive responses to invading pathogens.

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 Address correspondence and reprint requests to Dr. Ennio De Gregorio, Novartis Vaccines, Via Fiorentina, Siena, Italy. E-mail address: ennio.de_gregorio{at}novartis.com

² Abbreviations used in this paper: LT, Escherichia coli heat-labile enterotoxin; BAL, bronchoalveolar lavage; DC, dendritic cell; FSC, forward scatter; PMN, polymorphonuclear cell; SSC, side scatter.

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