Okkenhaug K, Wu L, Garza K M, La Rose J, Khoo W, Odermatt B, Mak T W, Ohashi P S, Rottapel R
Department of Immunology, University of Toronto, Ontario M5S 1A2, Canada.
Nat Immunol. 2001 Apr;2(4):325-32. doi: 10.1038/86327.
Upon interaction with its ligand, B7, CD28 becomes phosphorylated on tyrosines. One tyrosine in particular (Y170 in mouse CD28, Y173 in human CD28) has received much attention. This is because it permits CD28 to recruit SH2-containing signaling molecules, including phosphoinositide 3 kinase, Grb2 and Gads. Using mice we employed a transgenic approach to express a tyrosine-->phenylalanine mutant form of CD28 that uncouples these SH2-mediated interactions from CD28. The CD28 mutant is unable to up-regulate expression of the prosurvival protein Bcl-xL, rendering the T cells more susceptible to radiation-induced death. Nonetheless, this mutated form of CD28 still prevents the induction of anergy and promotes T cell proliferation, interleukin 2 secretion and B cell help. Thus, we describe a single point mutation within the CD28 cytoplasmic domain that uncouples signals required for proliferation and survival.
与配体B7相互作用时，CD28的酪氨酸会发生磷酸化。其中一个特定的酪氨酸（小鼠CD28中的Y170，人类CD28中的Y173）受到了广泛关注。这是因为它使CD28能够招募含SH2的信号分子，包括磷酸肌醇3激酶、Grb2和Gads。我们利用小鼠采用转基因方法表达一种酪氨酸突变为苯丙氨酸的CD28突变形式，从而使这些由SH2介导的与CD28的相互作用解偶联。CD28突变体无法上调抗凋亡蛋白Bcl-xL的表达，使T细胞更容易受到辐射诱导的死亡。尽管如此，这种突变形式的CD28仍然能够阻止无反应性的诱导，并促进T细胞增殖、白细胞介素2分泌以及B细胞辅助。因此，我们描述了CD28胞质结构域内的一个单点突变，该突变使增殖和存活所需的信号解偶联。
