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31ACHIEVEMENTPUBLICATIONShimizu K, Sugiura D, Okazaki IM, Maruhashi T, Takegami Y, Cheng C, Ozaki S, Okazaki T. PD-1 Imposes Qualitative Control of Cellular Transcriptomes in Response to T Cell Activation. Mol Cell. 2020 Mar 5;77(5):937-950.e6. DOI:10.1016/j.molcel.2019.12.012Sugiura D, Maruhashi T, Okazaki IM, Shimizu K, Maeda TK, Takemoto T, Okazaki T. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science. 2019 May 10;364(6440):558-566. DOI:10.1126/science.aav7062Maruhashi T, Okazaki IM, Sugiura D, Takahashi S, Maeda TK, Shimizu K, and Okazaki T. LAG-3 inhibits the activation of CD4+ T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII. Nat Immunol. 2018 Dec;19(12):1415-1426. DOI: 10.1038/s41590-018-0217-9OKAZAKITAKUPH.D. (2003) KYOTO UNIVERSITYASSISTANT PROFESSOR (2003) KYOTO UNIVERSITY21COE ASSOCIATE PROFESSOR (2004) KYOTO UNIVERSITYPROFESSOR (2008) TOKUSHIMA UNIVERSITYPROFESSOR (2019) IQB / INSTITUTE FOR QUANTITATIVE BIOSCIENCES, THE UNIVERSITY OF TOKYO●MEMBER■ PROFESSOR :OKAZAKI TAKU■ ASSOCIATE PROFESSOR :OKAZAKI IL-MI■ RESEARCH ASSOCIATE : SUGIURA DAISUKE■ RESEARCH ASSOCIATE : MARUHASHI TAKUMI■ PROJECT RESEARCHASSOCIATE : SHIMIZU KENJI■ PROJECT RESEARCHER :MAEDA NATSUMI ■ TECHNICAL SPECIALIST :TSUEDA JUNKO■ PROJECT ACADEMICSUPPORT STAFF :SAITO MASAYO■ PROJECT ACADEMICSUPPORT STAFF :MIKUNIYA AINAPUBLICATIONPUBLICATIONhe 2018 Nobel Prize in Physiology or Medicine was awarded to Drs. Tasuku Honjo and James P. Allison for their discovery of cancer therapy by inhibition of negative immune regulation. They demonstrated that the targeted blockade of inhibitory co-receptors, PD-1 and CTLA-4 can destroy tumors by activating tumor-specific T cells. I have engaged in researches such as the identifica-tion of PD-1 ligands, elucidation of the inhibitory mechanism of PD-1, dissection of the pathomechanisms of autoimmune diseases that PD-1KO mice develop, and treatments of cancer by PD-1 blockade in Dr. Honjo's laboratory. Through these researches, PD-1 has been established as an inhibitory co-receptor of lymphocytes and proposed to be a promising target of cancer immunotherapy.Stimulatory and inhibitory co-receptors tightly control the activation of lymphocytes by regulating the quality and the quantity of the antigen receptor signaling to optimize beneficial immune responses while avoiding autoimmunity and excess immune responses. In addition to PD-1 and CTLA-4, many other co-receptors have been identified and regard-ed as potential drug targets. Although these co-receptors are supposed to have unique function and cooperate each other, their functional differences and coordination remain to be clarified. The primary aim of our laboratory is to elucidate the molecular and cellular mechanisms of PD-1 as well as other co-receptors in the regulation of immune responses. By fully understanding the regula-tory mechanisms of immune system, we believe we can manipulate immune responses precisely to control various diseases such as cancer and autoimmune diseases. T(1) T cell activation is tightly regulated by various stimulatory and inhibitory co-receptors. (2) PD-1 deficient mice develop various types of autoimmune diseases depending on the genetic background. (3) PD-1 function is restricted at the activation phase by cis-PD-L1/CD80 interactions. (4) LAG-3 preferentially inhibits activation of T cells recognizing stable pMHCII.