TY - JOUR
T1 - IL-4 together with IL-1β induces antitumor Th9 cell differentiation in the absence of TGF-β signaling
AU - Xue, Gang
AU - Jin, Guangxu
AU - Fang, Jing
AU - Lu, Yong
N1 - Funding Information:
This work was supported by grants from the National Cancer Institute (K99CA190910 and 4R00CA190910-03), the Elsa u. Pardee Foundation Award 2019, and Wake Forest Start-up funds. We also acknowledge the editorial assistance of Karen Klein, MA, in the Wake Forest Clinical and Translational Science Institute (UL1 TR001420; PI: McClain). Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001420 (CTSI Pilot Grant Award 2018, CTSI Pilot Grant Award 2019, and CTSI Ignition Fund Pilot award). This study was also supported by the National Cancer Institute’s Cancer Center Support Grant award number P30CA012197 issued to the Wake Forest Baptist Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - IL-9-producing CD4 + (Th9) cells are a subset of CD4 + T-helper cells that are endowed with powerful antitumor capacity. Both IL-4 and TGF-β have been reported to be indispensable for Th9 cell-priming and differentiation. Here we show, by contrast, that Th9 cell development can occur in the absence of TGF-β signaling. When TGF-β was replaced by IL-1β, the combination of IL-1β and IL-4 efficiently promoted IL-9-producing T cells (Th9 IL-4+IL-1β ). Th9 IL-4+ IL-1β cells are phenotypically distinct T cells compared to classic Th9 cells (Th9 IL-4+TGF-β ) and other Th cells, and are enriched for IL-1 and NF-κB gene signatures. Inhibition of NF-κB but not TGF-β-signaling negates IL-9 production by Th9 IL-4+IL-1β cells. Furthermore, when compared with classic Th9 IL-4+TGF-β cells, Th9 IL-4+IL-1β cells are less exhausted, exhibit cytotoxic T effector gene signature and tumor killing function, and exert a superior antitumor response in a mouse melanoma model. Our study thus describes an alternative pathway for Th9 cell differentiation and provides a potential avenue for antitumor therapies.
AB - IL-9-producing CD4 + (Th9) cells are a subset of CD4 + T-helper cells that are endowed with powerful antitumor capacity. Both IL-4 and TGF-β have been reported to be indispensable for Th9 cell-priming and differentiation. Here we show, by contrast, that Th9 cell development can occur in the absence of TGF-β signaling. When TGF-β was replaced by IL-1β, the combination of IL-1β and IL-4 efficiently promoted IL-9-producing T cells (Th9 IL-4+IL-1β ). Th9 IL-4+ IL-1β cells are phenotypically distinct T cells compared to classic Th9 cells (Th9 IL-4+TGF-β ) and other Th cells, and are enriched for IL-1 and NF-κB gene signatures. Inhibition of NF-κB but not TGF-β-signaling negates IL-9 production by Th9 IL-4+IL-1β cells. Furthermore, when compared with classic Th9 IL-4+TGF-β cells, Th9 IL-4+IL-1β cells are less exhausted, exhibit cytotoxic T effector gene signature and tumor killing function, and exert a superior antitumor response in a mouse melanoma model. Our study thus describes an alternative pathway for Th9 cell differentiation and provides a potential avenue for antitumor therapies.
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U2 - 10.1038/s41467-019-09401-9
DO - 10.1038/s41467-019-09401-9
M3 - Article
C2 - 30914642
AN - SCOPUS:85063542949
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1376
ER -