Up-regulation of GITRL on dendritic cells by WGP improves anti-tumor immunity in murine Lewis lung carcinoma.
BACKGROUND
β-Glucans have been shown to function as a potent immunomodulator to stimulate innate and adaptive immune responses, which contributes to their anti-tumor property. However, their mechanisms of action are still elusive. Glucocorticoid-induced TNF receptor ligand (GITRL), a member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells, generates a positive co-stimulatory signal implicated in a wide range of T cell functions, which is important for the development of immune responses.


RESULTS
In this study, we found that whole β-glucan particles (WGPs) could activate dendritic cells (DCs) via dectin-1 receptor, and increase the expression of GITRL on DCs in vitro and in vivo. Furthermore, we demonstrated that the increased GITRL on DCs could impair the regulartory T cell (Treg)-mediated suppression and enhance effector T cell proliferation in a GITR/GITRL dependent way. In tumor models, DCs with high levels of GITRL were of great potential to prime cytotoxic T lymphocyte (CTL) responses and down-regulate the suppressive activity of Treg cells, thereby leading to the delayed tumor progression.


CONCLUSIONS
These findings suggest that particulate β-glucans can be used as an immunomodulator to stimulate potent T cell-mediated adaptive immunity while down-regulate suppressive immune activity via GITR/GITRL interaction, leading to a more efficient defense mechanism against tumor development.
Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University School of Medical Science and Laboratory Medicine, Zhenjiang, China.
Jie
J
Tian
Jie
J
Ma
Ke
K
Ma
Bin
B
Ma
Xinyi
X
Tang
Samuel Essien
SE
Baidoo
Jia
J
Tong
Jun
J
Yan
Liwei
L
Lu
Huaxi
H
Xu
Shengjun
S
Wang
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007111:Immunity, Cellular / Q000187:drug effects; D007155:Immunologic Factors / Q000276:immunology / Q000302:isolation & purification / Q000627:therapeutic use*; D037181:Lectins, C-Type / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D048069:Tumor Necrosis Factors / Q000235:genetics* / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects; D047071:beta-Glucans / Q000276:immunology / Q000302:isolation & purification / Q000627:therapeutic use*; D000099181:Dectin-1
D007155:Immunologic Factors; D037181:Lectins, C-Type; D048069:Tumor Necrosis Factors; D047071:beta-Glucans; D000099181:Dectin-1; C478966:Tnfsf18 protein, mouse