NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway.
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.
Terabe
M
M
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Matsui
S
S
Noben-Trauth
N
N
Chen
H
H
Watson
C
C
Donaldson
D D
DD
Carbone
D P
DP
Paul
W E
WE
Berzofsky
J A
JA
D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007167:Immunotherapy; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009365:Neoplasm Regression, Spontaneous / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D050800:STAT6 Transcription Factor; D013601:T-Lymphocytes / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D018949:Antigens, CD1; D015704:CD4 Antigens; D016207:Cytokines; D018793:Interleukin-13; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators