The Journal of Experimental Medicine
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Published 5 December 2005. doi:10.1084/jem.20050956
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 11, 1507-1516
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ARTICLE

 Innate NKT lymphocytes confer superior adaptive immunity via tumor-capturing dendritic cells

Kang Liu1, Juliana Idoyaga2, Anna Charalambous1, Shin-ichiro Fujii1, Anthony Bonito1, Jose Mordoh2, Rosa Wainstok2,3, Xue-Feng Bai4, Yang Liu4, and Ralph M. Steinman1

1 Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021
2 Instituto Leloir, Instituto de Investigaciones Bioquimicas
3 Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1650 Buenos Aires, Argentina
4 Division of Cancer Immunology, Department of Pathology, Ohio State University Medical Center, Columbus, OH 43210

CORRESPONDENCE Ralph M. Steinman: steinma{at}mail.rockefeller.edu

If irradiated tumor cells could be rendered immunogenic, they would provide a safe, broad, and patient-specific array of antigens for immunotherapies. Prior approaches have emphasized genetic transduction of live tumor cells to express cytokines, costimulators, and surrogate foreign antigens. We asked if immunity could be achieved by delivering irradiated, major histocompatibility complex–negative plasmacytoma cells to maturing mouse dendritic cells (DCs) within lymphoid organs. Tumor cells injected intravenously (i.v.) were captured by splenic DCs, whereas subcutaneous (s.c.) injection led only to weak uptake in lymph node or spleen. The natural killer T (NKT) cells mobilizing glycolipid {alpha}-galactosyl ceramide, used to mature splenic DCs, served as an effective adjuvant to induce protective immunity. This adjuvant function was mimicked by a combination of poly IC and agonistic {alpha}CD40 antibody. The adjuvant glycolipid had to be coadministered with tumor cells i.v. rather than s.c. Specific resistance was generated both to a plasmacytoma and lymphoma. The resistance afforded by a single vaccination lasted >2 mo and required both CD4+ and CD8+ T cells. Mature tumor capturing DCs stimulated the differentiation of P1A tumor antigen-specific, CD8+ T cells and uniquely transferred tumor resistance to naive mice. Therefore, the access of dying tumor cells to DCs that are maturing to activated NKT cells efficiently induces long-lived adaptive resistance.

Abbreviations used: {alpha}-Gal Cer, {alpha}-galactosyl ceramide; CFSE, carboxyfluorescein diacetate succinimidyl ester; NKT, natural killer T.


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