CD1d-restricted T cells regulate dendritic cell function and antitumor immunity in a granulocyte–macrophage colony-stimulating factor-dependent fashion

doi:10.1073/pnas.1033098100

CD1d-restricted T cells regulate dendritic cell function and antitumor immunity in a granulocyte–macrophage colony-stimulating factor-dependent fashion

^*Department of Medical Oncology, Dana–Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115; ^†Cancer Immunology and AIDS, Dana–Farber Cancer Institute, 44 Binney Street, Boston, MA 02115; ^‡Gastrointestinal Division, Brigham and Women's Hospital, Boston, MA 02115; ^§Cancer Biology Program, Hematology/Oncology Division, Beth Israel Deaconess Medical Center, Boston, MA 02115; ^¶Department of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital East, 149 13th Street, Room 8304, Charlestown, MA 02129; ^∥Core Research for Evolutional Science and Technology Project and Department of Molecular Immunology, Chiba University, Chiba 260-8670, Japan; ^**Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138; and ^‡‡Diabetes Research Laboratories, Massachusetts General Hospital, Cambridge, MA 02138

Contributed by Jack L. Strominger, May 21, 2003

Abstract

CD1d-restricted T cells contribute to tumor protection, but their precise roles remain unclear. Here we show that tumor cells engineered to secrete granulocyte–macrophage colony-stimulating factor induce the expansion of CD1d-restricted T cells through a mechanism that involves CD1d and macrophage inflammatory protein 2 expression by CD8α^–, CD11c⁺ dendritic cells (DCs). The antitumor immunity stimulated by vaccination with irradiated, granulocyte-macrophage colony-stimulating factor-secreting tumor cells was abrogated in CD1d- and Jα281-deficient mice, revealing a critical role for CD1d-restricted T cells in this response. The loss of antitumor immunity was associated with impaired tumorinduced T helper 2 cytokine production, although IFN-γ secretion and cytotoxicity were preserved. DCs from immunized CD1d-deficient mice showed compromised maturation and function. Together, these results delineate a role for CD1d-restricted T cell–DC cross talk in the shaping of antitumor immunity.

Footnotes

↵ †† To whom correspondence should be addressed. E-mail: brian_wilson{at}dfci.harvard.edu or glenn_dranoff{at}dfci.harvard.edu.
Abbreviations: DC, dendritic cell; GM-CSF, granulocyte–macrophage colony-stimulating factor; FL, Flt3 ligand; FACS, fluorescence-activated cell sorting; TCR, T cell receptor; MIP-2, macrophage inflammatory protein 2; MLR, mixed leukocyte reaction; Th, T helper.