Elucidating the regulatory mechanisms of PD-1 function

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H01029
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Okazaki Taku 東京大学, 定量生命科学研究所, 教授 (00362468)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 免疫補助受容体 / 自己免疫疾患 / シス結合

Outline of Final Research Achievements

We found that CD80 interacts with PD-L1 in cis on antigen presenting cells (APCs), which results in the interference of PD-L1-PD-1 binding. Subsequently, PD-L1 fails to elicit PD-1-mediated inhibition in T cell activation when APCs express substantial amount of CD80. By generating anti-CD80 antibodies that detach CD80 from the cis-PD-L1-CD80 duplex and enable PD-L1 to engage PD-1 in the presence of CD80, we demonstrated that the targeted dissociation of cis-PD-L1-CD80 duplex elicits PD-1 function in the condition where PD-1 function is otherwise restricted. We also demonstrated using murine models that the removal of PD-1 restriction is effective in alleviating autoimmune disease symptoms. Finally, we investigated the relative contribution of potential ligands to LAG-3 function and demonstrated that stable pMHCII, but not FGL1, serves as the functional ligand of LAG-3 to trigger its immuno-inhibitory function.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

抑制性免疫補助受容体PD-1を標的としたがん免疫療法の成功により、免疫補助受容体の機能が大きな関心を集めているが、各分子の機能解明は期待通りには進んでいない。PD-1やLAG-3の機能が発揮あるいは制限されるメカニズムの解明により、これらの分子を標的とした薬剤の開発が促進されると期待される。PD-1の機能制限を解除することにより自己免疫疾患を治療する方法については、臨床への応用が期待される。