NDLI: Targeting of TLRs inhibits CD4+ regulatory T cell function and activates lymphocytes in human peripheral blood mononuclear cells.

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Targeting of TLRs inhibits CD4+ regulatory T cell function and activates lymphocytes in human peripheral blood mononuclear cells.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Sugimoto, Naoshi Liu, Yong-Jun Weng, Jinsheng Harline, Megan Lundell Bover, Laura Voo, Kui Shin
Description	Author Affiliation: Voo KS ( Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Bover L ( Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Harline ML ( Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Weng J ( Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030); Sugimoto N ( MedImmune, Gaithersburg, MD 20878.); Liu YJ ( MedImmune, Gaithersburg, MD 20878 ksvoo@mdanderson.org liuyo@Medimmune.com.)
Abstract	Accumulating evidence suggests elements within tumors induce exhaustion of effector T cells and infiltration of immunosuppressive regulatory T cells (Tregs), thus preventing the development of durable antitumor immunity. Therefore, the discovery of agents that simultaneously block Treg suppressive function and reinvigorate effector function of lymphocytes is key to the development of effective cancer immunotherapy. Previous studies have shown that TLR ligands (TLRLs) could modulate the function of these T cell targets; however, those studies relied on cell-free or accessory cell-based assay systems that do not accurately reflect in vivo responses. In contrast, we used a human PBMC-based proliferation assay system to simultaneously monitor the effect of TLRLs on T cells (CD4(+), CD8(+), Tregs), B cells, and NK cells, which gave different and even conflicting results. We found that the TLR7/8L:CL097 could simultaneously activate CD8(+) T cells, B cells, and NK cells plus block Treg suppression of T cells and B cells. The TLRLs TLR1/2L:Pam3CSK4, TLR5L:flagellin, TLR4L:LPS, and TLR8/7L:CL075 also blocked Treg suppression of CD4(+) or CD8(+) T cell proliferation, but not B cell proliferation. Besides CL097, TLR2L:PGN, CL075, and TLR9L:CpG-A, CpG-B, and CpG-C) were strong activators of NK cells. Importantly, we found that Pam3CSK4 could: 1) activate CD4(+) T cell proliferation, 2) inhibit the expansion of IL-10(+) naturally occurring FOXP3(+) Tregs and induction of IL-10(+) CD4(+) Tregs (IL-10-producing type 1 Treg), and 3) block naturally occurring FOXP3(+) Tregs suppressive function. Our results suggest these agents could serve as adjuvants to enhance the efficacy of current immunotherapeutic strategies in cancer patients.
ISSN	00221767
e-ISSN	15506606
DOI	10.4049/jimmunol.1203334
Journal	The Journal of Immunology
Issue Number	2
Volume Number	193
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-07-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Leukocytes, Mononuclear Immunology Lymphocyte Activation T-lymphocytes, Regulatory Toll-like Receptors Analysis Of Variance B-lymphocytes Drug Effects Metabolism Cd4-positive T-lymphocytes Cd8-positive T-lymphocytes Cell Proliferation Cells, Cultured Flagellin Pharmacology Forkhead Transcription Factors Imidazoles Interferon-gamma Interleukin-10 Interleukin-6 Killer Cells, Natural Lipopeptides Lipopolysaccharides Quinolines Thiazoles Agonists Tumor Necrosis Factor-alpha Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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Targeting of TLRs inhibits CD4+ regulatory T cell function and activates lymphocytes in human peripheral blood mononuclear cells.

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Targeting of TLRs inhibits CD4+ regulatory T cell function and activates lymphocytes in human peripheral blood mononuclear cells.