NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway

• Published in: Nature immunology Vol. 1; no. 6; pp. 515 - 520
• Main Authors: Berzofsky, Jay A, Terabe, Masaki, Matsui, So, Noben-Trauth, Nancy, Chen, Hangjiong, Watson, Cynthia, Donaldson, Debra D, Carbone, David P, Paul, William E
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-12-2000
• Subjects: Animals; Antigens, CD1 - genetics; Antigens, CD1 - metabolism; CD4 Antigens - metabolism; Cytokines - biosynthesis; Female; Immunotherapy; interleukin 4 receptors; Interleukin-13 - antagonists & inhibitors; Interleukin-13 - metabolism; Interleukins; Killer Cells, Natural - immunology; Lymphocytes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Regression, Spontaneous - immunology; Neoplasms, Experimental - immunology; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Physiological aspects; Receptors, Interleukin-4 - genetics; Receptors, Interleukin-4 - metabolism; Recurrence; STAT6 Transcription Factor; T cells; T-Lymphocytes - immunology; Trans-Activators - genetics; Trans-Activators - metabolism; Tumor antigens; Tumors; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/82771

Using a mouse model in which tumors show a growth-regression-recurrence pattern, we investigated the mechanisms for down-regulation of cytotoxic T lymphocyte-mediated tumor immunosurveillance. We found that interleukin 4 receptor (IL-4R) knockout and downstream signal transducer and activator of transcription 6 (STAT6) knockout, but not IL-4 knockout, mice resisted tumor recurrence, which implicated IL-13, the only other cytokine that uses the IL-4R-STAT6 pathway. We confirmed this by IL-13 inhibitor (sIL-13R alpha 2-Fc) treatment. Loss of natural killer T cells (NKT cells) in CD1 knockout mice resulted in decreased IL-13 production and resistance to recurrence. Thus, NKT cells and IL-13, possibly produced by NKT cells and signaling through the IL-4R-STAT6 pathway, are necessary for down-regulation of tumor immunosurveillance. IL-13 inhibitors may prove to be a useful tool in cancer immunotherapy.