KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells
KLRG1 signaling induces defective Akt (ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells
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DOI：
10.1182/blood-2009-01-199588
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发表时间：
2009-06-25
期刊：
影响因子：
20.3
通讯作者：
Akbar, Arne N.
中科院分区：
文献类型：
--
作者：
Henson, Sian M.;Franzese, Ornella;Akbar, Arne N.
高度分化的CD 8（+）CD 28（-）CD 27（-）T细胞端粒短，端粒酶活性缺陷，增殖能力降低，表明它们接近复制性衰老。此外，这些细胞表达增加水平的衰老相关抑制性受体KLRG 1，并且在活化后具有较差的IL-2合成能力和缺陷的Akt（ser（473））磷酸化。目前尚不清楚通过KLRG 1的信号传导是否有助于CD 8（+）T细胞中任何减弱的分化相关功能变化。为了解决这个问题，我们使用针对其主要配体E-cadherin的抗体在T细胞受体活化期间阻断KLRG 1信号传导。这导致Akt（ser 473）磷酸化和T细胞受体诱导的CD 8（+）CD 28（-）CD 27（-）T细胞增殖活性显著增强。此外，增殖的增加与Akt介导的细胞周期蛋白D和E的诱导以及细胞周期蛋白抑制剂p27表达的减少直接相关。相反，在高度分化的CD 8（+）CD 28（-）CD 27（-）T细胞中，端粒酶活性的降低并没有被KLRG 1阻断所改变，这表明了其他机制的参与。这是KLRG 1在原代人CD 8（+）T细胞中的功能作用的首次证明，并强调了在T细胞向复制性衰老的渐进性分化过程中出现的某些功能缺陷通过抑制性受体信号传导积极维持。（血。2009; 113：6619-6628）
Highly differentiated CD8(+)CD28(-)CD27(-) T cells have short telomeres, defective telomerase activity, and reduced capacity for proliferation, indicating that they are close to replicative senescence. In addition, these cells express increased levels of the senescence-associated inhibitory receptor KLRG1 and have poor capacity for IL-2 synthesis and defective Akt (ser(473)) phosphorylation after activation. It is not known whether signaling via KLRG1 contributes to any of the attenuated differentiation-related functional changes in CD8(+) T cells. To address this, we blocked KLRG1 signaling during T-cell receptor activation using antibodies against its major ligand, E-cadherin. This resulted in a significant enhancement of Akt (ser473) phosphorylation and T-cell receptor-induced proliferative activity of CD8(+)CD28(-)CD27(-) T cells. Furthermore, the increase of proliferation was directly linked to the Akt-mediated induction of cyclin D and E and reduction in the cyclin inhibitor p27 expression. In contrast, the reduced telomerase activity in highly differentiated CD8(+)CD28(-)CD27(-) T cells was not altered by KLRG1 blockade, indicating the involvement of other mechanisms. This is the first demonstration of a functional role for KLRG1 in primary human CD8(+) T cells and highlights that certain functional defects that arise during progressive T-cell differentiation toward replicative senescence are maintained actively by inhibitory receptor signaling. (Blood. 2009; 113: 6619-6628)