Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy

被引:12
作者
Bittner, Sebastian [1 ,2 ]
Ruhland, Brigitte [1 ,2 ]
Hofmann, Veronika [1 ,2 ]
Schmidleithner, Lisa [1 ,2 ]
Schambeck, Kathrin [1 ,2 ]
Pant, Asmita [1 ,2 ]
Stueve, Philipp [1 ,2 ]
Delacher, Michael [3 ]
Echtenacher, Bernd [1 ,2 ]
Edinger, Matthias [1 ,4 ]
Hoffmann, Petra [1 ,4 ]
Rehli, Michael [1 ,4 ]
Gebhard, Claudia [1 ]
Strieder, Nicholas [1 ]
Hehlgans, Thomas [1 ,2 ]
Feuerer, Markus [1 ,2 ]
机构
[1] Leibniz Inst Immunotherapy, D-93053 Regensburg, Germany
[2] Univ Regensburg, Chair Immunol, D-93053 Regensburg, Germany
[3] Univ Med Mainz, Inst Immunol, D-55131 Mainz, Germany
[4] Univ Klinikum Regensburg, Dept Internal Med 3, D-93053 Regensburg, Germany
基金
欧洲研究理事会;
关键词
regulatory T cell; T cell engineering; inflammation; VERSUS-HOST-DISEASE; CHIMERIC ANTIGEN RECEPTOR; EXPRESSION; LIGHT; TUMOR; IDENTIFICATION; COLITIS;
D O I
10.1073/pnas.2208436119
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Engineered regulatory T cell (Treg cell) therapy is a promising strategy to treat patients suffering from inflammatory diseases, autoimmunity, and transplant rejection. However, in many cases, disease-related antigens that can be targeted by Treg cells are not available. In this study, we introduce a class of synthetic biosensors, named artificial immune receptors (AIRs), for murine and human Treg cells. AIRs consist of three domains: (a) extracellular binding domain of a tumor necrosis factor (TNF)-receptor superfamily member, (b) intracellular costimulatory signaling domain of CD28, and (c) T cell receptor signaling domain of CD3-zeta chain. These AIR receptors equip Treg cells with an inflammation-sensing machinery and translate this environmental information into a CD3-zeta chain-dependent TCR-activation program. Different AIRs were generated, recognizing the inflammatory ligands of the TNF-receptor superfamily, including LIGHT, TNF alpha, and TNF-like ligand 1A (TL1A), leading to activation, differentiation, and proliferation of AIR-Treg cells. In a graft-versus-host disease model, Treg cells expressing lymphotoxin beta receptor-AIR, which can be activated by the ligand LIGHT, protect significantly better than control Treg cells. Expression and signaling of the corresponding human AIR in human Treg cells prove that this concept can be translated. Engineering Treg cells that target inflammatory ligands leading to TCR signaling and activation might be used as a Treg cell-based therapy approach for a broad range of inflammation-driven diseases.
引用
收藏
页数:10
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共 52 条
  • [1] snakePipes: facilitating flexible, scalable and integrative epigenomic analysis
    Bhardwaj, Vivek
    Heyne, Steffen
    Sikora, Katarzyna
    Rabbani, Leily
    Rauer, Michael
    Kilpert, Fabian
    Richter, Andreas S.
    Ryan, Devon P.
    Manke, Thomas
    [J]. BIOINFORMATICS, 2019, 35 (22) : 4757 - 4759
  • [2] Bittner S., ARTIFICIAL IMMUNE RE
  • [3] Multifaceted death receptor 3 signaling-promoting survival and triggering death
    Bittner, Sebastian
    Ehrenschwender, Martin
    [J]. FEBS LETTERS, 2017, 591 (17): : 2543 - 2555
  • [4] Suppression of Murine Colitis and its Associated Cancer by Carcinoembryonic Antigen-Specific Regulatory T Cells
    Blat, Dan
    Zigmond, Ehud
    Alteber, Zoya
    Waks, Tova
    Eshhar, Zelig
    [J]. MOLECULAR THERAPY, 2014, 22 (05) : 1018 - 1028
  • [5] Immune regulatory cell infusion for graft-versus-host disease prevention and therapy
    Blazar, Bruce R.
    MacDonald, Kelli P. A.
    Hill, Geoffrey R.
    [J]. BLOOD, 2018, 131 (24) : 2651 - 2660
  • [6] Treg cells-the next frontier of cell therapy Will regulatory T cells be a frontline therapy for autoimmunity and other diseases?
    Bluestone, Jeffrey A.
    Tang, Qizhi
    [J]. SCIENCE, 2018, 362 (6411) : 154 - 155
  • [7] Expression of a Chimeric Antigen Receptor Specific for Donor HLA Class I Enhances the Potency of Human Regulatory T Cells in Preventing Human Skin Transplant Rejection
    Boardman, D. A.
    Philippeos, C.
    Fruhwirth, G. O.
    Ibrahim, M. A. A.
    Hannen, R. F.
    Cooper, D.
    Marelli-Berg, F. M.
    Watt, F. M.
    Lechler, R. I.
    Maher, J.
    Smyth, L. A.
    Lombardi, G.
    [J]. AMERICAN JOURNAL OF TRANSPLANTATION, 2017, 17 (04) : 931 - 943
  • [8] Lymphotoxin: from the physiology to the regeneration of the thymic function
    Borelli, Alexia
    Irla, Magali
    [J]. CELL DEATH AND DIFFERENTIATION, 2021, 28 (08) : 2305 - 2314
  • [9] Branella G. M., 2021, CELLS-BASEL, V11, P1
  • [10] Inhibition of the lymphotoxin pathway as a therapy for autoimmune disease
    Browning, Jeffrey L.
    [J]. IMMUNOLOGICAL REVIEWS, 2008, 223 : 202 - 220