The Journal of Experimental Medicine
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Published 1 December 2003. doi:10.1084/jem.20022227
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© Rockefeller University Press, 0022-1007/2003/12/1741 $5.00
The Journal of Experimental Medicine, Volume 198, Number 11, 1741-1752

Transforming Growth Factor-ß Production and Myeloid Cells Are an Effector Mechanism through Which CD1d-restricted T Cells Block Cytotoxic T Lymphocyte–mediated Tumor Immunosurveillance : Abrogation Prevents Tumor Recurrence



Masaki Terabe1, So Matsui1, Jong-Myun Park1, Mizuko Mamura2, Nancy Noben-Trauth5, Debra D. Donaldson6, Wanjun Chen3, Sharon M. Wahl3, Steven Ledbetter7, Bruce Pratt7, John J. Letterio2, William E. Paul4 and Jay A. Berzofsky1

1 Molecular Immunogenetics and Vaccine Research Section, National Cancer Institute
2 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute
3 Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research
4 Laboratory of Immunology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20892
5 Department of Immunology, George Washington University Medical Center, Washington, DC 20037
6 Wyeth Research, Cambridge, MA 02140
7 Genzyme Corporation, Cambridge, MA 01701

Address correspondence to Jay A. Berzofsky, Molecular Immunogenetics and Vaccine Research Section, National Institutes of Health, Building 10, Room 6B-12 (MSC no. 1578), 10 Center Drive, Bethesda, MD 20892. Phone: (301) 496-6874; Fax: (301) 480-0681; email: berzofsk{at}helix.nih.gov

Our previous work demonstrated that cytotoxic T lymphocyte (CTL)-mediated tumor immunosurveillance of the 15-12RM tumor could be suppressed by a CD1d-restricted lymphocyte, most likely a natural killer (NK) T cell, which produces interleukin (IL)-13. Here we present evidence for the effector elements in this suppressive pathway. T cell–reconstituted recombination activating gene (RAG)2 knockout (KO) and RAG2/IL-4 receptor {alpha} double KO mice showed that inhibition of immunosurveillance requires IL-13 responsiveness by a non–T non–B cell. Such nonlymphoid splenocytes from tumor-bearing mice produced more transforming growth factor (TGF)-ß, a potent inhibitor of CTL, ex vivo than such cells from naive mice, and this TGF-ß production was dependent on the presence in vivo of both IL-13 and CD1d-restricted T cells. Ex vivo TGF-ß production was also abrogated by depleting either CD11b+ or Gr-1+ cells from the nonlymphoid cells of tumor-bearing mice. Further, blocking TGF-ß or depleting Gr-1+ cells in vivo prevented the tumor recurrence, implying that TGF-ß made by a CD11b+ Gr-1+ myeloid cell, in an IL-13 and CD1d-restricted T cell–dependent mechanism, is necessary for down-regulation of tumor immunosurveillance. Identification of this stepwise regulation of immunosurveillance, involving CD1-restricted T cells, IL-13, myeloid cells, and TGF-ß, explains previous observations on myeloid suppressor cells or TGF-ß and provides insights for targeted approaches for cancer immunotherapy, including synergistic blockade of TGF-ß and IL-13.

Key Words: TGF-ß • NKT cells • immunologic surveillance • myeloid cells • IL-13

Abbreviations used in this paper: D-NAME, N-nitro-D-arginine-methyl ester; L-NAME, N-nitro-L-arginine-methyl ester; NO, nitric oxide.


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