Naturally activated V gamma 4 gamma delta T cells play a protective role in tumor immunity through expression of eomesodermin.
We previously demonstrated that gammadelta T cells played an important role in tumor immune surveillance by providing an early source of IFN-gamma. The precise role of different subsets of gammadelta T cells in the antitumor immune response, however, is unknown. Vgamma1 and Vgamma4 gammadelta T cells are the principal subsets of peripheral lymphoid gammadelta T cells and they might play distinct roles in tumor immunity. In support of this, we observed that reconstitution of TCRdelta(-/-) mice with Vgamma4, but not Vgamma1, gammadelta T cells restored the antitumor response. We also found that these effects were exerted by the activated (CD44(high)) portion of Vgamma4 gammadelta T cells. We further determined that IFN-gamma and perforin are critical elements in the Vgamma4-mediated antitumor immune response. Indeed, CD44(high) Vgamma4 gammadelta T cells produced significantly more IFN-gamma and perforin on activation, and showed greater cytolytic activity than did CD44(high) Vgamma1 gammadelta T cells, apparently due to the high level of eomesodermin (Eomes) in these activated Vgamma4 gammadelta T cells. Consistently, transfection of dominant-negative Eomes in Vgamma4 gammadelta T cells diminished the level of IFN-gamma secretion, indicating a critical role of Eomes in the effector function of these gammadelta T cells. Our results thus reveal distinct functions of Vgamma4 and Vgamma1 gammadelta T cells in antitumor immune response, and identify a protective role of activated Vgamma4 gammadelta T cells, with possible implications for tumor immune therapy.
He
Weifeng
W
Chongqing Key Laboratory for Diseases Proteomics, Southwest Hospital, Third Military Medical University, Chongqing, China.
Hao
Jianlei
J
Dong
Siyuan
S
Gao
Yunfei
Y
Tao
Jian
J
Chi
Hongbo
H
Flavell
Richard
R
O'Brien
Rebecca L
RL
Born
Willi K
WK
Craft
Joseph
J
Han
Jihong
J
Wang
Puyue
P
Zhao
Liqing
L
Wu
Jun
J
Yin
Zhinan
Z
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054353:Perforin / Q000096:biosynthesis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000096:biosynthesis* / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology*
C476399:Cd44 protein, mouse; C491198:Eomes protein, mouse; D018960:Hyaluronan Receptors; D016692:Receptors, Antigen, T-Cell, gamma-delta; D020825:T-Box Domain Proteins; D054353:Perforin; D007371:Interferon-gamma