RIKEN IMS AnnualReport 2020
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The objective of our team is to determine the molecular mechanisms of T 29cell activation, differentiation and function. Ultimately, we wish to eluci-date the onset of and to modulate T cell function/activation to prevent immune diseases such as autoimmunity and allergic inflammation. For this purpose, we have analyzed regulation of T cell activation/function from a signaling perspec-tive.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 are analyzing the dynamic regula-tion of other inhibitory co-stimulation receptors such as LAG3. These inhibi-tory receptors were colocalized with the TCR-MC to mediate inhibition of T cell activation. Our analyses provide a dynamic view of signal regulation and also define inhibitory mechanisms.We have analyzed negative regulation of T cell activation, particularly by autoimmune-related 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 “inhibi-tory complex” with other inhibitory molecules to inhibit activation. A PTPN22 mutant causing susceptibility to autoimmune diseases was defective in recruit-ment 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 signals. We previously found that T cells are activated by co-stimulation of TCR and TLRs. TLR2 in particular activates effector T cells (as Th1) but not naïve T cells without TCR stimulation. We found that naïve T cells failed to respond to TLR2 stimulation due to the defective expression of TIRAP. TIRAP is expressed upon stimulation through mTORC1 activation via TCR or IL-2 signaling (Figure).Figure: TLR2-mediated T-cell activation is de-pendent on TIRAP expression in T cells and regulated by mTORC1 signalingEffector T cells are activated by TLR2 signals in the ab-sence of TCR signals. TLR2-mediated activation is medi-ated through TIRAP, whose expression is induced by mTOR signals through TCR or IL-2 signals, whereas naïve T cells are not activated by TLR2 due to the lack of TIRAP expression.Recent Major PublicationsImanishi 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)Sasaki T, Yajima T, Shimaoka T, Ogawa S, Saito T, Ya-maoka K, Takeuchi T, Kubo M. Synergistic effect of IgG4 antibody and CTLs causes tissue inflammation in IgG4-related disease. Int Immunol 32, 163-174 (2020)Invited presentationsSaito T. “Regulation of adhesion and activation of T cells at Immune synapse” The 43rd Annual Meeting of Molecular Biology Society of Japan 2020 (Kobe, Japan/Online) December 2020Saito T. “Regulation of T cell activation and function by innate signaling” OIST Conference (Okinawa, Japan/Online) February 2020Saito T. “Negative regulation of T cell activation by phosphatases” Seminar at Hokkaido University (Sapporo, Japan/Online) January 2020Laboratory for Cell SignalingTeam Leader: Takashi Saito

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