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* Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115;
Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029; and
School of Biosciences, University of Birmingham, Birmingham, United Kingdom
NKT cells play a protective role in immune responses against infectious pathogens. However, when the NKT cell response to infection is initiated and terminated is unknown. In this study, we demonstrate that NKT cells become activated, proliferate, and exert their effector function before MHC-restricted T cells during infection with Mycobacterium bovis bacillus Calmette-Guérin in mice. After a cell expansion phase, NKT cells underwent cell death, which contracts their numbers back to baseline. Surprisingly, despite ongoing infection, the remaining NKT cells were profoundly unresponsive to TCR stimulation, while MHC-restricted T cells were vigorously proliferating and producing IFN-
. Similarly, we show that NKT cells became unresponsive in uninfected mice after receiving a single exposure to a TLR agonist LPS, suggesting that NKT cell unresponsiveness may be a major mechanism of terminating their response in many infectious conditions. This characterization of the NKT cell response in antimicrobial immunity indicates that rapid NKT cell activation contributes to the innate phase of the response to the infectious pathogen, but then, the NKT cell response is shut down by two mechanisms; apoptotic contraction and marked unresponsiveness to TCR stimulation, as a synchronized hand off to MHC-restricted T cells occurs.
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 the Arthritis foundation (to A.C.) and the National Institutes of Health (R01AI063428 to M.B.B.). G.S.B. acknowledges support in the form of a Personal Research Chair from James Bardrick, Royal Society Wolfson Research Merit Award, as a former Lister Institute-Jenner Research Fellow, the Medical Research Council, and the Wellcome Trust (081569/Z/06/Z).
2 Address correspondence and reprint requests to Dr. Michael B Brenner, Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital and Harvard Medical School, One Jimmy Fund Way, Smith Building, Room 552, Boston, MA 02115. E-mail address: mbrenner{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: 
GalCer, -galactosylceramide; DC, dendritic cell; BCG, bacillus Calmette-Guérin; BM-DC, bone marrow-derived DC; MFI, mean fluorescence intensity; LCMV, lymphocytic choriomeningitis virus.
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