Generation and characterization of OX40-ligand fusion protein that agonizes OX40 on T-Lymphocytes

Ayaka Sato, Hodaka Nagai, Ayano Suzuki, Aya Ito, Shimpei Matsuyama, Nagito Shibui, Masashi Morita, Mari Hikosaka-Kuniishi, Naoto Ishii, Takanori So*

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

抄録

OX40, a member of the tumor necrosis factor (TNF) receptor superfamily, is expressed on the surface of activated T cells. Upon interaction with its cognate ligand, OX40L, OX40 transmits costimulatory signals to antigen-primed T cells, promoting their activation, differentiation, and survivalprocesses essential for the establishment of adaptive immunity. Although the OX40-OX40L interaction has been extensively studied in the context of disease treatment, developing a substitute for the naturally expressed membrane-bound OX40L, particularly a multimerized OX40L trimers, that effectively regulates OX40-driven T cell responses remains a significant challenge. In this study, we successfully engineered soluble OX40L-fusion proteins capable of robustly activating OX40 on T cells. This was achieved by incorporating functional multimerization domains into the TNF homology domain of OX40L. These OX40L proteins bound to OX40, subsequently activated NF-κB signaling, and induced cytokine production by T cells in vitro. In vivo, mice treated with one of the OX40L-fusion proteinscomprising a single-chain OX40L trimer linked to the C-terminus of the human IgG1 Fc domain, forming a dimer of trimersexhibited significantly enhanced clonal expansion of antigen-specific CD4+ T cells during the primary phase of the immune response. A comparable antibody-fusion single-chain TNF protein incorporating 4-1BBL, CD70 (CD27L), or GITRL in place of OX40L elicited similar in vivo T cell responses. Thus, we propose that optimizing the multimerization of OX40L proteins through innovative design strategies may facilitate the development of more effective agonists for targeted immunotherapies.

本文言語英語
論文番号1473815
ジャーナルFrontiers in Immunology
15
DOI
出版ステータス出版済み - 2024

ASJC Scopus 主題領域

  • 免疫アレルギー学
  • 免疫学

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