Takumi Maruhashi, Daisuke Sugiura, Il-mi Okazaki, Kenji Shimizu, K Takeo Maeda, Jun Ikubo, Harunori Yoshikawa, Katsumi Maenaka, Naozumi Ishimaru, Hidetaka Kosako, Tatsuya Takemoto and Taku Okazaki : Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity., Immunity, 55, 5, 912-924.e8, 2022.
(Summary)
Lymphocyte activation gene-3 (LAG-3) is a potent inhibitory co-receptor; yet, its functional ligand remains elusive, with distinct potential ligands identified. Here, we investigated the relative contribution of potential ligands, stable peptide-MHC class II complexes (pMHCII) and fibrinogen-like protein 1 (FGL1), to LAG-3 activity invitro and invivo. Binding of LAG-3 to stable pMHCII but not to FGL1 induced Tcell suppression invitro. Consistently, LAG-3 mutants lacking FGL1-binding capacity but not those lacking stable pMHCII-binding capacity retained suppressive activity invitro. Accordingly, targeted disruption of stable pMHCII- but not FGL1-binding capacity of LAG-3 in NOD mice recapitulated diabetes exacerbation by LAG-3 deficiency. Additionally, the loss of stable pMHCII-binding capacity of LAG-3 augmented anti-cancer immunity comparably with LAG-3 deficiency in C57BL/6 mice. These results identify stable pMHCII as a functional ligand of LAG-3 both in autoimmunity and anti-cancer immunity. Thus, stable pMHCII-LAG-3 interaction is a potential therapeutic target in human diseases.
(Keyword)
Animals / Antigens, CD / Autoimmunity / Histocompatibility Antigens Class II / Ligands / Mice / Mice, Inbred C57BL / Mice, Inbred NOD / Neoplasms / Peptides / T-Lymphocytes
Shimizu Kenji, Daisuke Sugiura, Il-mi Okazaki, Takumi Maruhashi, Tatsuya Takemoto and Taku Okazaki : PD-1 preferentially inhibits the activation of low-affinity T cells, Proceedings of the National Academy of Sciences of the United States of America, 118, 35, e2107141118, 2021.
(Summary)
Anti-PD-1 therapies can activate tumor-specific T cells to destroy tumors. However, whether and how T cells with different antigen specificity and affinity are differentially regulated by PD-1 remain vaguely understood. Upon antigen stimulation, a variety of genes is induced in T cells. Recently, we found that T cell receptor (TCR) signal strength required for the induction of genes varies across different genes and PD-1 preferentially inhibits the induction of genes that require stronger TCR signal. As each T cell has its own response characteristics, inducibility of genes likely differs across different T cells. Accordingly, the inhibitory effects of PD-1 are also expected to differ across different T cells. In the current study, we investigated whether and how factors that modulate T cell responsiveness to antigenic stimuli influence PD-1 function. By analyzing TCRs with different affinities to peptide-MHC complexes (pMHC) and pMHCs with different affinities to TCR, we demonstrated that PD-1 inhibits the expression of TCR-inducible genes efficiently when TCR:pMHC affinity is low. In contrast, affinities of peptides to MHC and MHC expression levels did not affect PD-1 sensitivity of TCR-inducible genes although they markedly altered the dose responsiveness of T cells by changing the efficiency of pMHC formation, suggesting that the strength of individual TCR signal is the key determinant of PD-1 sensitivity. Accordingly, we observed a preferential expansion of T cells with low-affinity to tumor-antigen in PD-1-deficient mice upon inoculation of tumor cells. These results demonstrate that PD-1 imposes qualitative control of T cell responses by preferentially suppressing low-affinity T cells.
Hikari Okamura, Il-mi Okazaki, Kenji Shimizu, Takumi Maruhashi, Daisuke Sugiura, Reina Mizuno and Taku Okazaki : PD-1 aborts the activation trajectory of autoreactive CD8 T cells to prohibit their acquisition of effector functions., Journal of Autoimmunity, 102296, 2019.
(Summary)
Anti-PD-1 therapy can induce eradication of tumors and immune-related adverse events (irAEs) in humans and model animals. However, how anti-PD-1 therapy modifies cellular phenotypes of CD8 T cells to destroy tumors and damage self-tissues remains to be clarified. Here we performed single cell mRNA expression profiling of autoreactive CD8 T cells under or beyond PD-1 suppression in target tissues and reconstructed their activation trajectory. Autoreactive CD8 T cells went through four activation phases and PD-1 strongly attenuated the transition from the second- to the third-phase, where effector functions were acquired. Shifts in cluster composition of autoreactive CD8 T cells markedly reflected the severity of autoimmunity. In addition, genes up-regulated along the activation-trajectory in autoimmunity were highly expressed in responders of melanoma patients in anti-PD-1 therapy, suggesting that tumor-specific T cells need to be activated in a similar trajectory to destroy tumors in human patients upon PD-1 blockade. These findings reveal that PD-1 blockade facilitates the activation trajectory of CD8 T cells to boost their effector functions. Targeted manipulation of the trajectory could lead to new therapeutic opportunities.
Daisuke Sugiura, Takumi Maruhashi, Il-mi Okazaki, Kenji Shimizu, Takeo K. Maeda, Tatsuya Takemoto and Taku Okazaki : Restriction of PD-1 function by -PD-L1/CD80 interactions is required for optimal T cell responses., Science, 364, 6440, 558-566, 2019.
(Summary)
Targeted blockade of PD-1 with immune checkpoint inhibitors can activate T cells to destroy tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of T cell responses, yet how PD-1 function is restricted at the activation stage is currently unknown. Here we demonstrate that CD80 interacts with PD-L1 in cis on antigen-presenting cells (APCs) to disrupt PD-L1/PD-1 binding. Subsequently, PD-L1 cannot engage PD-1 to inhibit T cell activation when APCs express substantial amounts of CD80. In knock-in mice in which -PD-L1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1. These findings indicate that CD80 on APCs limits the PD-1 coinhibitory signal, while promoting CD28-mediated costimulation, and highlight critical components for induction of optimal immune responses.
Reina Mizuno, Daisuke Sugiura, Kenji Shimizu, Takumi Maruhashi, Mizuki Watada, Il-mi Okazaki and Taku Okazaki : PD-1 Primarily Targets TCR Signal in the Inhibition of Functional T Cell Activation., Frontiers in Immunology, 10, 630, 2019.
(Summary)
Cancer-immunotherapy targeting programmed cell death 1 (PD-1) activates tumor-specific T cells and provides clinical benefits in various cancers. However, the molecular basis of PD-1 function is still enigmatic. Especially, it is unclear which signaling pathway PD-1 primarily targets. Besides, the capacity of PD-1 to inhibit the T cell receptor (TCR)-dependent activation of T cells in the presence of co-stimulation is also controversial. Here we used co-culture systems of T cells and antigen-presenting cells with targeted deletion and overexpression of co-receptors and ligands and examined the inhibitory potency of PD-1 against T cell activation upon TCR stimulation with CD28 and ICOS co-stimulation. As an unambiguous criterion of T cell activation, we used the acquisition of cytokine production capacity, which represents one of the most important functions of T cells. PD-1 inhibited functional T cell activation upon TCR stimulation in the absence as well as in the presence of CD28 co-stimulation, indicating that PD-1 can directly inhibit TCR signal. Notably, CD28 co-stimulation rather attenuated the efficiency of PD-1 in inhibiting TCR-dependent functional T cell activation. In addition, PD-1 inhibited TCR-dependent functional T cell activation with ICOS co-stimulation as efficiently as that with CD28 co-stimulation. Furthermore, we found that the maintenance of antigen-induced follicular helper T (T) cells that required ICOS co-stimulation was persistently restrained by PD-1 . These findings indicate that PD-1 primarily targets TCR signal in the inhibition of functional T cell activation. Thus, PD-1 functions as the rheostat of T cell activation rather than an inhibitor of a specific stimulatory co-receptor.
Reina Mizuno, Takumi Maruhashi, Daisuke Sugiura, Kenji Shimizu, Mizuki Watada, Il-mi Okazaki and Taku Okazaki : PD-1 efficiently inhibits T cell activation even in the presence of co-stimulation through CD27 and GITR., Biochemical and Biophysical Research Communications, 511, 3, 491-497, 2019.
(Summary)
Cancer immunotherapies targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 revolutionized cancer treatment and instigated various trials to develop new cancer immunotherapies with higher therapeutic efficacy. Agonistic Abs against tumor necrosis factor receptor super family (TNFRSF) molecules are highly expected due to their high potential to enhance survival, proliferation, and effector function of T cells. To date, agonistic antibodies (Abs) against CD27, GITR, OX40, and 4-1BB have been reported to increase the efficacy of anti-PD-1 therapy in animal models and clinical trials of these combinatorial therapies are underway. However, the mechanisms how agonistic Abs against TNFRSF molecules potentiate anti-PD-1 therapy are not well understood. Here we examined the potency of PD-1 to inhibit the antigen-dependent activation of T cells in the presence of co-stimulation through CD27 and GITR by using in vitro and ex vivo co-culture systems of T cells and antigen presenting cells. The cytokine secretion from T cells upon antigen stimulation was strongly augmented by the engagement of CD27 or GITR with their corresponding ligands. Remarkably, PD-1 efficiently inhibited the activation of T cells even in the presence of co-stimulation through CD27 or GITR. Accordingly, cytokine secretion was synergistically augmented when PD-1 blockade was combined with triggering of CD27 or GITR. These results indicate that the triggering of TNFRSF molecules and PD-1 blockade can act on the same individual cells simultaneously to augment the magnitude of T cell activation, providing the rationale for the combinatorial usage of agonistic Abs against TNFRSF molecules and blocking Abs against PD-1 or PD-L1.
Takeo K. Maeda, Daisuke Sugiura, Il-mi Okazaki, Takumi Maruhashi and Taku Okazaki : Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation., The Journal of Biological Chemistry, 294, 15, 6017-6026, 2019.
(Summary)
T cell activation is tightly regulated by both stimulatory and inhibitory co-receptors and has been a focus in the development of interventions for managing cancer or autoimmune diseases. Targeting the inhibitory co-receptors programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) has successfully eradicated tumors but induced immune-related adverse events in humans and mice. The beneficial and adverse effects of targeting these co-receptors highlight their importance in cancer immunity and also autoimmunity. Although the therapeutic potencies of other inhibitory co-receptors are under extensive investigation, their inhibitory mechanisms and their functional differences are not well understood. Here we analyzed the inhibitory mechanisms of lymphocyte activation gene-3 (LAG-3), another inhibitory co-receptor, by using an T cell activation system and a high-affinity anti-LAG-3 antibody that strongly interferes with the binding of LAG-3 to its ligand. We found that the expression level of LAG-3 strongly correlates with the inhibitory function of LAG-3, suggesting that LAG-3 functions as a rheostat rather than as a breaker of T cell activation. By evaluating the inhibitory capacities of various LAG-3 variants relative to their expression levels, we found that LAG-3 transduces two independent inhibitory signals through an FL motif in the membrane-proximal region and the C-terminal E repeat. These motifs have not been reported previously for inhibitory co-receptors, suggesting that LAG-3 inhibits T cell activation through a nonredundant inhibitory mechanisms along with the other inhibitory co-receptors. Our findings provide a rationale for combinatorial targeting of LAG-3 and the other inhibitory co-receptors to improve cancer immunotherapy.
Takumi Maruhashi, Il-mi Okazaki, Daisuke Sugiura, Suzuka Takahashi, Takeo K. Maeda, Kenji Shimizu and Taku Okazaki : LAG-3 inhibits the activation of CD4 T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII., Nature Immunology, 19, 12, 1415-1426, 2018.
(Summary)
The success of tumor immunotherapy targeting the inhibitory co-receptors PD-1 and CTLA-4 has indicated that many other co-receptors might be potential druggable targets, despite limited information about their functional differences. Here we identified a unique target selectivity for the inhibitory co-receptor LAG-3 that was intrinsic to its immunoregulatory roles. Although LAG-3 has been reported to recognize major histocompatibility complex (MHC) class II, it did not recognize MHC class II universally; instead, we found that it selectively recognized stable complexes of peptide and MHC class II (pMHCII). LAG-3 did not directly interfere with interactions between the co-receptor CD4 and MHC class II or between the T cell antigen receptor and MHC class II. Instead, LAG-3 preferentially suppressed T cells responsive to stable pMHCII by transducing inhibitory signals via its intracellular region. Thus, LAG-3 might function more selectively than previously thought and thereby maintain tolerance to dominant autoantigens.
(Keyword)
Animals / Antigens, CD / CD4-Positive T-Lymphocytes / Cell Line, Tumor / Histocompatibility Antigens Class II / Humans / Lymphocyte Activation / Mice / Molecular Conformation
Taku Okazaki, Il-mi Okazaki, Jian Wang, Daisuke Sugiura, Fumio Nakaki, Taku Yoshida, Yu Kato, Sidonia Fagarasan, Masamichi Muramatsu, Tomoo Eto, Kyoji Hioki and Tasuku Honjo : PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice, The Journal of Experimental Medicine, 208, 2, 395-407, 2011.
(Summary)
Stimulatory and inhibitory co-receptors play fundamental roles in the regulation of the immune system. We describe a new mouse model of spontaneous autoimmune disease. Activation-induced cytidine deaminase-linked autoimmunity (aida) mice harbor a loss-of-function mutation in the gene encoding lymphocyte activation gene 3 (LAG-3), an inhibitory co-receptor. Although LAG-3 deficiency alone did not induce autoimmunity in nonautoimmune-prone mouse strains, it induced lethal myocarditis in BALB/c mice deficient for the gene encoding the inhibitory co-receptor programmed cell death 1 (PD-1). In addition, LAG-3 deficiency alone accelerated type 1 diabetes mellitus in nonobese diabetic mice. These results demonstrate that LAG-3 acts synergistically with PD-1 and/or other immunoregulatory genes to prevent autoimmunity in mice.
(Keyword)
Animals / Antigens, CD / Antigens, Surface / Apoptosis Regulatory Proteins / autoimmunity / DNA Primers / Diabetes Mellitus, Type 1 / Disease Models, Animal / Flow Cytometry / Lymphocyte Activation / Mice / Mice, Inbred BALB C / knockout mice / Microsatellite Repeats / Myocarditis / Polymorphism, Restriction Fragment Length / Polymorphism, Single Nucleotide / Programmed Cell Death 1 Receptor / Reverse Transcriptase Polymerase Chain Reaction / T-Lymphocytes, Regulatory
Daisuke Sugiura, Kaori Denda-Nagai, Kazuyoshi Takeda and Tatsuro Irimura : Organ microenvironment plays significant roles through Fas ligand in vaccine-induced CD4(+) T cell dependent suppression of tumor growth at the orthotopic site, Cancer Science, 101, 9, 1965-1969, 2010.
(Summary)
Growth of colon carcinoma cells transfected with mucin 1 (MUC1) was effectively suppressed by vaccination with MUC1 cDNA. The suppression was dependent on the presence of Fas ligand (FasL) in the cecum, whereas it was independent of FasL in the spleen and in the liver, as revealed by the use of gld/gld mice as the recipients of vaccination, and transplantation of tumor cells expressing MUC1. CD4(+) T cells were transferred from mice immunized with MUC1 cDNA to naive gld/gld or C57BL/6 mice, and the suppression of colon carcinoma growth in the cecum was tested. The results clearly showed that FasL in the recipient played a significant role. In the cecum, FasL was associated with intratumoral CD11b(+) cells, which are likely to be responsible for vaccine-induced tumor suppression. The T cell response to MUC1 was not influenced by the gld/gld status.
Kaori Denda-Nagai, Satoshi Aida, Kengo Saba, Kiwamu Suzuki, Saya Moriyama, Sarawut Oo-puthinan, Makoto Tsuiji, Akiko Morikawa, Yosuke Kumamoto, Daisuke Sugiura, Akihiko Kudo, Yoshihiro Akimoto, Hayato Kawakami, Nicolai V. Bovin and Tatsuro Irimura : Distribution and function of macrophage galactose-type C-type lectin 2 (MGL2/CD301b): efficient uptake and presentation of glycosylated antigens by dendritic cells, The Journal of Biological Chemistry, 285, 25, 19193-19204, 2010.
(Summary)
Dendritic cells (DCs) express cell surface lectins that are potentially involved in the recognition, uptake, and presentation of glycosylated foreign substances. A unique calcium-type (C-type) lectin, the macrophage galactose (Gal)-type C-type lectin (MGL/CD301) expressed on DCs, is thought to participate in the recognition of molecules from both altered self and pathogens due to its monosaccharide specificity for Gal and N-acetylgalactosamine (GalNAc). Although mice have two MGL genes, Mgl1 and Mgl2, their distinct roles have not been previously explored. The present report characterizes the properties of MGL2 by examining its distribution and its role in antigen presentation by DCs. We generated an MGL2-specific monoclonal antibody and examined MGL2 expression in tissues by immunohistochemistry and in isolated cells by flow cytometry. The cells reactive with this antibody were shown to be a portion of MGL1-expressing cells, mostly conventional DCs. Internalization of soluble polyacrylamide polymers (PAA) with alpha-GalNAc residues (GalNAc-PAA) by bone marrow-derived DCs (BM-DCs) was mediated by MGL2, as revealed by a comparison of Mgl1(-/-) and Mgl2(-/-) BM-DCs with wild-type BM-DCs. Biotinylated GalNAc-PAA conjugated to streptavidin (SAv) was more efficiently presented to SAv-primed T cells by BM-DCs than beta-N-acetylglucosamine-PAA conjugated to SAv or SAv alone as shown by thymidine uptake and cytokine production. This is the first report that demonstrates the involvement of GalNAc residues in antigen uptake and presentation by DCs that lead to CD4(+) T cell activation.
Yuri Yi, Mika Kamata-Sakurai, Kaori Denda-Nagai, Tomoko Itoh, Kyoko Okada, Katrin Ishii-Schrade, Akihiro Iguchi, Daisuke Sugiura and Tatsuro Irimura : Mucin 21/epiglycanin modulates cell adhesion, The Journal of Biological Chemistry, 285, 28, 21233-21240, 2010.
(Summary)
The molecular structure of mouse Mucin 21 (Muc21)/epiglycanin is proposed to have 98 tandem repeats of 15 amino acids and three exceptional repeats with 12 or 13 amino acids each, followed by a stem domain, a transmembrane domain, and a cytoplasmic tail. A cDNA of Muc21 having 84 tandem repeats of 15 amino acids was constructed and transfected using a Venus vector into HEK 293T cells. The fluorescent cells, which were considered to express Muc21, were nonadherent. This antiadhesion effect was lessened when constructs with smaller numbers of tandem repeats were used, suggesting that the tandem repeat domain plays a crucial role. Cells expressing Muc21 were significantly less adherent to each other and to extracellular matrix components than control cells. Antibody binding to the cell surface integrin subunits alpha5, alpha6, and beta1 was reduced in Muc21 transfectants in a tandem repeat-dependent manner, whereas equal amounts of proteins were detected by Western blot analysis. Muc21 was expressed as a large glycoprotein that was highly glycosylated with O-glycans at the cell surface, as detected by flow cytometry, Western blotting, and lectin blotting. Although at least a portion of Muc21 was glycosylated with sialylated glycans, removal of sialic acid did not influence the prevention of adhesion.
Daisuke Sugiura, Satoshi Aida, Kaori Denda-Nagai, Kazuyoshi Takeda, Mika Kamata-Sakurai, Hideo Yagita and Tatsuro Irimura : Differential effector mechanisms induced by vaccination with MUC1 DNA in the rejection of colon carcinoma growth at orthotopic sites and metastases, Cancer Science, 99, 12, 2477-2484, 2008.
(Summary)
The effects of MUC1 DNA vaccination on the orthotopic growth and liver metastasis of colon carcinoma cells were investigated in mice. Vaccination with MUC1 DNA resulted in immune responses that were effective in suppressing mouse colon carcinoma cells transfected with MUC1 cDNA. CD4+ T cells but not CD8+ T cells mediated this antitumor response as shown by the in vivo depletion of lymphocyte subpopulations with the use of anti-CD4 or anti-CD8 antibody. The effects of neutralizing antibodies in vivo revealed that the predominant effector molecule in preventing orthotopic tumor growth was FasL, whereas the effector molecule effective in preventing liver metastasis was tumor necrosis factor-alpha. Colon carcinoma cells isolated from tumors growing in the ceca, spleens, and livers were shown to be equally sensitive to FasL and tumor necrosis factor-alpha. The results strongly suggest that elimination of tumor cells initiated by DNA vaccination in the present protocol is mediated by antigen-specific CD4+ T cells and the effector mechanisms in the cecum and in the liver are distinct due to a unique organ microenvironment.
Takumi Maruhashi, Il-mi Okazaki, Daisuke Sugiura, Shimizu Kenji and Taku Okazaki : LAG-3 preferentially inhibits activation of CD4 T cells recognizing stable pMHCII by its conformation-dependent recognition of MHCII, 第47回日本免疫学会学術集会, Fukuoka, Dec. 2018.
2.
Mizuno Reina, Daisuke Sugiura, Shimizu Kenji, Takumi Maruhashi, Il-mi Okazaki and Taku Okazaki : PD-1 primarily targets TCR-signal in the inhibition of functional T cell activation, 第47回日本免疫学会学術集会, Fukuoka, Dec. 2018.
3.
Okamura Hikari, Il-mi Okazaki, Shimizu Kenji, Takumi Maruhashi, Daisuke Sugiura, Mizuno Reina and Taku Okazaki : Single-cell analysis of autoreactive T cells under the control of PD-1, 第47回日本免疫学会学術集会, Fukuoka, Dec. 2018.
4.
Taku Okazaki, Takumi Maruhashi, Il-mi Okazaki, Daisuke Sugiura and Shimizu Kenji : LAG-3 regulates immunodominance and autoimmunity by its conformation-dependent recognition of MHCII, 第41回日本分子生物学会年会, Yokohama, Nov. 2018.
5.
Hikari Okamura, Il-mi Okazaki, Kenji Shimizu, Takumi Maruhashi, Daisuke Sugiura and Taku Okazaki : Single-cell analysis of autoreactive T cells under the control of PD-1, 第46回日本免疫学会学術集会, 仙台市, Dec. 2017.
6.
Takumi Maruhashi, Il-mi Okazaki, Daisuke Sugiura and Taku Okazaki : Immuno-inhibitory co-receptor LAG-3 regulates immunodominance and autoimmunity by virtue of its conformation-dependent recognition of MHCII, 第46回日本免疫学会学術集会, 仙台市, Dec. 2017.
7.
Kenji Shimizu, Daisuke Sugiura, Takumi Maruhashi, Il-mi Okazaki and Taku Okazaki : Characterization of target genes of inhibitory co-receptor PD-1 by CAGE, The 11th International Symposium of the institute network, 徳島市, Jan. 2017.
8.
Kenji Shimizu, Daisuke Sugiura, Takumi Maruhashi, Il-mi Okazaki and Taku Okazaki : Characterization of target genes of inhibitory co-receptor PD-1 by CAGE, The 26th Hot spring harbor international symposium, 福岡市, Nov. 2016.
9.
Takeo Kajihara, Taku Okazaki, Il-mi Okazaki, Daisuke Sugiura and Takumi Maruhashi : Inhibition of T cell activation by human LAG-3, International Congress of Immunology 2016, Melbourne, Aug. 2016.
10.
Takumi Maruhashi, Taku Okazaki, Il-mi Okazaki and Daisuke Sugiura : Context-dependent inhibition of antigen-specific T cell activation by LAG-3, International Congress of Immunology 2016, Melbourne, Aug. 2016.
11.
Daisuke Sugiura and Taku Okazaki : Molecular analyses of an inhibitory co-receptor, LAG-3., The 3rd Bizan immunology symposium at the University of Tokushima, Feb. 2014.
12.
Il-mi Okazaki, Daisuke Sugiura, Suzuka Takahashi, Takeo Kajihara and Taku Okazaki : Identification of new therapeutic targets by genetic dissection and reconstitution of autoimmune diseases in mice, JST-CREST International Symposium, Jan. 2013.
13.
Taku Okazaki, Daisuke Sugiura, Il-mi Okazaki and Honjo Tasuku : Identification of the causal gene of aida mouse, a newly established animal model of autoimmunity, The 14th International Congress of Immunology, Aug. 2010.
14.
Taku Okazaki, Daisuke Sugiura, Il-mi Okazaki and Honjo Tasuku : Requirement of isotype-switched and somatically mutated autoantibodies for the development of autoimmune diseases in BALB/c-PD-1KO mice, The 4th International Conference on B cells and Autoimmunity, Aug. 2010.
15.
Daisuke Sugiura, Satoshi Aida, Kaori Denda-Nagai, Mika Kamata-Sakurai, Kazuyoshi Takeda, Hideo Yagita and Tatsuro Irimura : Effector mechanisms induced by vaccination with MUC1 DNA in the rejection of colon carcinoma growth at orthotopic sites and metastases, The 10th International Symposium on Dendritic Cells, Oct. 2008.
16.
Daisuke Sugiura, Satoshi Aida, Kaori Denda-Nagai, Mika Kamata, Kazuyoshi Takeda and Tatsuro Irimura : Organ-specific antitumor effector mechanisms induced by MUC1 DNA vaccination, 10th International Congress of the Metastasis Research Society, Sep. 2004.
Kenji Shimizu, Daisuke Sugiura, Takumi Maruhashi, Il-mi Okazaki and Taku Okazaki : Characterization of target genes of inhibitory co-receptor PD-1 by CAGE, 第45回日本免疫学会学術集会, Dec. 2016.
3.
Takumi Maruhashi, Il-mi Okazaki, Daisuke Sugiura and Taku Okazaki : Establishment and maintenance of immune tolerance by immuno-inhibitory receptors, 第39回日本分子生物学会年会, Dec. 2016.
4.
梶原 武雄, Daisuke Sugiura, 水野 玲奈, Deshani Chamila Ranawakage, 前田 菜摘, 清水 謙次, Il-mi Okazaki and Taku Okazaki : Comparison of human and mouse LAG-3, 第44回日本免疫学会学術集会, Oct. 2015.
5.
Takumi Maruhashi, Il-mi Okazaki, Daisuke Sugiura, 梶原 武雄 and Taku Okazaki : The strength of inhibition by LAG-3 depends on properties of APCs, 第44回日本免疫学会学術集会, Oct. 2015.
6.
Taku Okazaki, Takumi Maruhashi, Daisuke Sugiura and Il-mi Okazaki : Regulation of autoimmunity by PD-1 and LAG-3, 第44回日本免疫学会学術集会, Oct. 2015.
Il-mi Okazaki, Daisuke Sugiura, Takahashi Suzuka and Taku Okazaki : PD-1 and LAG-3 inhibitory coreceptors act synergistically to prevent autoimmunity in mice., 第10回四国免疫フォーラム, Jun. 2011.
12.
Taku Okazaki, Il-mi Okazaki and Daisuke Sugiura : Aida, a newly established animal model of autoimmunity, The Japanese Society for Immunology 2010 Symposium for Cutting edge of immunology; innate immunity and immune regulation, Dec. 2010.
Daisuke Sugiura, Kaori Denda-Nagai, Kazuyoshi Takeda, Hideo Yagita and Tatsuro Irimura : Antigen-specific regulatory T cells in MUC1 transgenic mice, 日本免疫学会, Dec. 2009.
15.
Daisuke Sugiura, Satoshi Aida, Kaori Denda-Nagai, Mika Sakurai, Kazuyoshi Takeda, Hideo Yagita and Tatsuro Irimura : Unique effector mechanism in the rejection of colon carcinoma growth and metastasis induced by DNA vaccination with MUC1, 日本免疫学会, Dec. 2006.