SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms
SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms
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DOI：
10.1016/j.immuni.2006.08.026
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发表时间：
2006-11-01
期刊：
影响因子：
32.4
通讯作者：
Blumberg, Richard S.
中科院分区：
文献类型：
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作者：
Nagaishi, Takashi;Pao, Lily;Blumberg, Richard S.
通过T细胞受体(TCR)激活的T细胞随后被刺激或抑制的次级信号所改变。我们发现，由于TCR连接，含有长胞浆结构域的CEACAM1黏附分子亚型抑制了多种T细胞功能。CEACAM1的过表达在体外导致细胞增殖、同种异体反应性和细胞因子产生减少，并在体内导致小鼠迟发性超敏反应和炎症性肠病。T细胞中CEACAM1的条件性缺失导致TCR-CD3复合体信号增强。这种T细胞调节依赖于CEACAM1胞浆结构域中基于免疫受体酪氨酸的抑制基序(ITIM)和T细胞中含有Src同源2结构域的蛋白酪氨酸磷酸酶1(SHP1)。因此，CEACAM1在T细胞中的过度表达或缺失分别导致T细胞的抑制或激活，揭示了CEACAM1作为一类潜在的可用于治疗的抑制性受体的作用。
T cell activation through the T cell receptor (TCR) is subsequently modified by secondary signals that are either stimulatory or inhibitory. We show that CEACAM1 adhesion molecule isoforms containing a long cytoplasmic domain inhibited multiple T cell functions as a consequence of TCR ligation. Overexpression of CEACAM1 resulted in decreased proliferation, allogeneic reactivity, and cytokine production in vitro and delayed type hypersensitivity and inflammatory bowel disease in mouse models in vivo. Conditioned deletion of CEACAM1 in T cells caused increased TCR-CD3 complex signaling. This T cell regulation was dependent upon the presence of immunoreceptor tyrosine-based inhibition motifs (ITIM) within the cytoplasmic domain of CEACAM1 and the Src homology 2 domain-containing protein tyrosine-phosphatase 1 (SHP1) in the T cell. Thus, CEACAM1 overexpression or deletion in T cells resulted in T cell inhibition or activation, respectively, revealing a role for CEACAM1 as a class of inhibitory receptors potentially amenable to therapeutic manipulation.