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東京理科大学 野田校舎 生命科学研究所 2F大講義室

Dynamic Regulation of T-cell Activation by TCR Microclusters

理化学研究所 免疫・アレルギー科学総合研究センター 横須賀忠先生

The immunological synapse is an activation structure formed at the
T-cell-antigen-presenting cell (APC) interface. Current imaging studies
using planar bilayers and a TIRFM demonstrate that an immunological synapse
is constructed by the signalosomes based on T-cell receptors (TCRs)&s_comma; “TCR
microclusters”. During the initial T-cell-bilayer contact&s_comma; TCR
microclusters are generated at the entire interface and soon translocated
toward the center to form a central-supramolecular activation cluster
(c-SMAC). Later&s_comma; they are continuously formed at the nascent contact regions
in the periphery and sequentially migrate toward the center. Since TCR
microclusters&s_comma; not the c-SMAC&s_comma; contain kinases&s_comma; adaptors&s_comma; and
phospho-proteins&s_comma; they are considered as a minimal unit for T-cell
activation (Nat. Immunol. 6:1253-1262. 2005).
T-cell activation requires both TCR and costimulatory signals. There are
sets of costimulatory receptors as positive and negative regulators&s_comma; all
which cooperatively modulate T-cell activation. CD28&s_comma; a predominant positive
costimulatory receptor&s_comma; is colocalized at TCR microclusters in the presence
of its ligands&s_comma; CD80/CD86. CD28 initially forms microclusters with TCRs.
CD28 microclusters specifically recruit the unique kinase PKCθ and sooner
forms a novel subregion in the c-SMAC&s_comma; the “signaling c-SMAC”&s_comma; with PKCθ
and the scaffolding protein CARMA1 (Immunity 29:589-601. 2008). The negative
costimulatory receptor CTLA-4&s_comma; which shares the common ligands with CD28&s_comma; is
expressed after T-cell activation and stored in the secretary lysosomes.
After T-cell-bilayer contact&s_comma; CTLA-4 quickly appears at the interface and
forms CTLA-4 microclusters. CTLA-4 microclusters are accumulated at the
center and exclude the CD28-PKCθ clusters from the signaling c-SMAC to
terminate the CD28-mediated T-cell activation (Immunity 33:326-339. 2010).
From these imaging analyses&s_comma; we propose a model for T-cell activation by TCR
microclusters and&s_comma; importantly&s_comma; a spatial difference in T-cell activation
signals. TCR microclusters at the entire activating interface generate the
initial signals and the peripheral TCR microclusters maintain the continuing
signals after c-SMAC formation. In the presence of T-cell costimulation&s_comma;
CD28 microclusters form the signaling c-SMAC and generate another sustained
signal through PKCθ/CARMA1-mediated NF-κB activation. Furthermore&s_comma; the
CD28-mediated signal is regulated by the CD28-CTLA-4 competition for ligand
binding at the signaling c-SMAC. Together&s_comma; these results demonstrate the
dynamism of the T-cell activation by TCR microclusters and the c-SMAC in the
immunological synapse.

Yokosuka T et al. Curr. Top. Microbiol. Immunol. 340:81-107. (2010)
Yokosuka T et al. Immunol. Rev. 229:27-40. (2009)

つくばエクスプレス 流山おおたかの森駅(北千住から13分;つくばから19分)乗り換え、東武野田線 運河駅下車

東京理科大学 生命科学研究所
生命工学技術部門 教授
理化学研究所 免疫・アレルギー科学総合研究センター
シグナル・ネットワーク研究チーム チームリーダー
久保 允人

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