A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression.
Regulatory T cells (T(reg) cells) suppress autoreactive immune responses and limit the efficacy of tumor vaccines; however, it remains a challenge to selectively eliminate or inhibit T(reg) cells. In this study, the zinc-finger A20, a negative regulator of the Toll-like receptor and tumor necrosis factor receptor signaling pathways, was found to play a crucial part in controlling the maturation, cytokine production and immunostimulatory potency of dendritic cells (DCs). A20-silenced DCs showed spontaneous and enhanced expression of costimulatory molecules and proinflammatory cytokines and had different effects on T cell subsets: they inhibited T(reg) cells and hyperactivated tumor-infiltrating cytotoxic T lymphocytes and T helper cells that produced interleukin-6 and tumor necrosis factor-alpha and were refractory to T(reg) cell-mediated suppression. Hence, this study identifies A20 as an antigen presentation attenuator in control of antitumor immune responses during both the priming and the effector phases and provides a strategy to overcome T(reg) cell-mediated suppression in an antigen-specific manner, reducing the need to directly target T(reg) cells.
Song
Xiao-Tong
XT
Center for Cell and Gene Therapy, Baylor College of Medicine (BCM), One Baylor Plaza, Houston, Texas 77030, USA.
Evel-Kabler
Kevin
K
Shen
Lei
L
Rollins
Lisa
L
Huang
Xue F
XF
Chen
Si-Yi
SY
D000818:Animals; D017951:Antigen Presentation; D002454:Cell Differentiation; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020868:Gene Silencing; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology; D034741:RNA, Small Interfering; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse