Fundamental Characterization of Antibody Fusion-Single-Chain TNF Recombinant Proteins Directed against Costimulatory TNF Receptors Expressed by T-Lymphocytes

Hodaka Nagai, Mitsuki Azuma, Ayaka Sato, Nagito Shibui, Sayaka Ogawara, Yuta Tsutsui, Ayano Suzuki, Tomomi Wakaizumi, Aya Ito, Shimpei Matsuyama, Masashi Morita, Mari Hikosaka Kuniishi, Naoto Ishii, Takanori So*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The costimulatory signal regulated by the members of the tumor necrosis factor receptor (TNFR) superfamily expressed by T cells plays essential roles for T cell responses and has emerged as a promising target for cancer immunotherapy. However, it is unclear how the difference in TNFR costimulation contributes to T cell responses. In this study, to clarify the functional significance of four different TNFRs, OX40, 4-1BB, CD27 and GITR, we prepared corresponding single-chain TNF ligand proteins (scTNFLs) connected to IgG Fc domain with beneficial characteristics, i.e., Fc−scOX40L, Fc−sc4-1BBL, Fc−scCD27L (CD70) and Fc−scGITRL. Without intentional cross-linking, these soluble Fc−scTNFL proteins bound to corresponding TNFRs induced NF-kB signaling and promoted proliferative and cytokine responses in CD4+ and CD8+ T cells with different dose-dependencies in vitro. Mice injected with one of the Fc−scTNFL proteins displayed significantly augmented delayed-type hypersensitivity responses, showing in vivo activity. The results demonstrate that each individual Fc−scTNFL protein provides a critical costimulatory signal and exhibits quantitatively distinct activity toward T cells. Our findings provide important insights into the TNFR costimulation that would be valuable for investigators conducting basic research in cancer immunology and also have implications for T cell-mediated immune regulation by designer TNFL proteins.

Original languageEnglish
Article number1596
JournalCells
Volume12
Issue number12
DOIs
StatePublished - 2023/06

Keywords

  • 4-1BB
  • CD27
  • GITR
  • OX40
  • T cell
  • TNFRSF
  • TNFSF
  • costimulation
  • cytokine
  • cytokine receptor

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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