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NKT Cells Are Critical to Initiate an Inflammatory Response after Pseudomonas aeruginosa Ocular Infection in Susceptible Mice¹

Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, Detroit, MI 48201

CD4⁺ T cells produce IFN- contributing to corneal perforation in C57BL/6 (B6) mice after Pseudomonas aeruginosa infection. To determine the role of NK and NKT cells, infected corneas of B6 mice were dual immunolabeled. Initially, more NKT than NK cells were detected, but as disease progressed, NK cells increased, while NKT cells decreased. Therefore, B6 mice were depleted of NK/NKT cells with anti-asialo GM1 or anti-NK1.1 Ab. Either treatment accelerated time to perforation, increased bacterial load and polymorphonuclear neutrophils, but decreased IFN- and IL-12p40 mRNA expression vs controls. Next, RAG-1 knockout (–/–; no T/NKT cells), B6.TCR J281^–/– (NKT cell deficient), -galactosylceramide (GalCer) (anergized NKT cells) injected and IL-12p40^–/– vs B6 controls were tested. IFN- mRNA was undetectable in RAG-1^–/–- and GalCer-treated mice at 5 h and was significantly reduced vs controls at 1 day postinfection. It also was reduced significantly in B6.TCR J281^–/–, GalCer-treated, and IL-12p40^–/– (activated CD4⁺ T cells also reduced) vs control mice at 5 days postinfection. In vitro studies tested whether endotoxin (LPS) stimulated Langerhans cells and macrophages (M; from B6 mice) provided signals to activate NKT cells. LPS up-regulated mRNA expression for IL-12p40, costimulatory molecules CD80 and CD86, NF-B, and CD1d, and addition of rIFN- potentiated M CD1d levels. Together, these data suggest that Langerhans cell/M recognition of microbial LPS regulates IL-12p40 (and CD1d) driven IFN- production by NKT cells, that IFN- is required to optimally activate NK cells to produce IFN-, and that depletion of both NKT/NK cells results in earlier corneal perforation.

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 work was supported by National Institutes of Health R01EY02986 and P30EY04068.

² Address correspondence and reprint requests to Dr. Linda D. Hazlett, Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, 540 East Canfield, Detroit, MI 48201. E-mail address: lhazlett{at}med.wayne.edu

³ Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; M, macrophage; SP, substance P; DC, dendritic cell; pAb, polyclonal Ab; p.i., postinfection; MPO, myeloperoxidase; LC, Langerhans cell; MMLV, Moloney murine leukemia virus; RT, reverse transcriptase; GalCer, -galactosylceramide.

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