cis interaction of CD153 with TCR/CD3 is crucial for the pathogenic activation of senescence-associated T cells
cis interaction of CD153 with TCR/CD3 is crucial for the pathogenic activation of senescence-associated T cells
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DOI：
10.1016/j.celrep.2022.111373
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发表时间：
2022-09-20
期刊：
影响因子：
8.8
通讯作者：
Hattori, Masakazu
中科院分区：
文献类型：
--
作者：
Fukushima, Yuji;Sakamoto, Keiko;Hattori, Masakazu
随着年龄的增长，对T细胞受体(TCR)刺激不敏感的衰老相关(SA)CD4+T细胞随着自发生发中心(SPT-GC)的发育而增加，容易产生自身抗体。我们证明CD153及其受体CD30分别在SA-T和SPT-GC B细胞中表达，CD153或CD30的缺失会导致这两种细胞类型的折衷增加。在TCR刺激下，CD153与SA-T细胞结合导致CD153与TCR/CD3复合体结合并恢复TCR信号，而CD30与GC B细胞结合则诱导其增殖。应用抗CD153抗体阻断与CD30的相互作用，可抑制SA-T和SPT-GC B细胞随增龄而增加，并改善狼疮易感小鼠的狼疮。这些结果表明，CD153和CD30的分子相互作用在SA-T和SPT-GC B细胞的相互激活中起核心作用，从而导致免疫衰老表型和自身免疫。
With age, senescence-associated (SA) CD4+ T cells that are refractory to T cell receptor (TCR) stimulation are increased along with spontaneous germinal center (Spt-GC) development prone to autoantibody production. We demonstrate that CD153 and its receptor CD30 are expressed in SA-T and Spt-GC B cells, respectively, and deficiency of either CD153 or CD30 results in the compromised increase of both cell types. CD153 engagement on SA-T cells upon TCR stimulation causes association of CD153 with the TCR/CD3 complex and restores TCR signaling, whereas CD30 engagement on GC B cells induces their expansion. Administra-tion of an anti-CD153 antibody blocking the interaction with CD30 suppresses the increase in both SA-T and Spt-GC B cells with age and ameliorates lupus in lupus-prone mice. These results suggest that the molecular interaction of CD153 and CD30 plays a central role in the reciprocal activation of SA-T and Spt-GC B cells, leading to immunosenescent phenotypes and autoimmunity.