noitilazacooCThe objective of our team is to determine the molecular mechanisms of T 30BAlcell activation, differentiation and function. Ultimately, we wish to eluci-date the onset of immune diseases and to modulate T cell function/activation to prevent immune diseases such as autoimmunity and allergic inflammation. For this purpose, we have analyzed the regulation of T cell activation/function from a signaling perspective.Our finding that TCR-microclusters (MC) initiate T cell activation led us to analyze the dynamics of signaling molecules at the immune synapse. Similar to our previous studies of CTLA4 and PD-1, we have analyzed the dynamic regulation of another inhibitory co-stimulation receptor, LAG3. This inhibi-tory receptor was also colocalized with the TCR-MC upon TCR stimulation to mediate inhibition of T cell activation. Since this association is critical for the inhibitory function, a LAG3 mAb induced separation of the LAG3 cluster from the TCR-MC and, consequently, enhancement of T cell activation. Our analyses provide a dynamic view of signal regulation to define inhibitory mechanisms (Figure).We have analyzed negative regulation of T cell activation, particularly by the autoimmune-related protein tyrosine phosphatase PTPN22. Its deficiency resulted in enhanced activation and an increase in effector/memory T cells. Analysis of the associated proteins revealed that PTPN22 was recruited to the TCR-MC to comprise an “inhibitory complex” with other inhibitory molecules to inhibit activation. A PTPN22 mutant causing susceptibility to autoimmune diseases was defective in recruitment to the TCR-MC. These studies help define the autoimmune susceptibility caused by the mutation.We have also analyzed the modulation of T cell function by innate-like signals. During this analyses, we found that Receptor-interacting serine/threo-nine-protein kinase 1 (RIPK1) plays a critical role in T cell function and differ-entiation. We are analyzing T cell-specific RIPK1-deficient mice to determine its role in T cells on metabolism and aging.anti-Lag3anti-Lag3LAG3Ab ‐Ab +TCRMergeFigure: Negative regulation of T cell activation through LAG3 colocalized with TCR microclustersA. LAG3 generates clusters colocalized with TCR-microcluster (MC) upon T cell activation. The LAG3 mAb inhibited the colocalization between TCR-MC and LAG3 clusters while enhancing IL-2 production. B. Schematic illustration showing that colocalization of LAG3 clusters with a TCR-MC is critical for LAG3 to suppress T cell acti-vation, which is inhibited by the LAG3 mAb.Recent Major PublicationsKumagai A, Nara T, Uematsu M, Kakinuma Y, Saito T, Ma-suda K. Development and characterization of a unique anti-IgE monoclonal antibody cross-reactive between human and canine IgE. Immun Inflamm Dis 9, 1740-1748 (2021)Imanishi T, Unno M, Kobayashi W, Yoneda N, Akira S, Saito T. mTORC1 signaling controls TLR2-mediated T cell activation by inducing TIRAP expression. Cell Reports 32, 107911 (2020)Imanishi T, Saito T. T cell co-stimulation and functional modulation by innate signals. Trends Immunol 41, 200-212 (2020)Invited presentationsSaito T. “Regulation of adhesion and activation of T cells at Immune synapse” The 44th Annual Meeting of Molecular Biology Society of Japan 2021 (Yokohama, Japan/Online) December 2021Saito T. “Inhibition of T cell activation through PD-1/LAG-3 clusters and their modulation by checkpoint inhibitors” OIST Conference (Okinawa, Japan/Online) February 2021Laboratory for Cell SignalingTeam Leader: Takashi Saito
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