Vignali D A, Vignali K M
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38101, USA.
J Immunol. 1999 Feb 1;162(3):1431-9.
CD4 plays an important role in the activation and development of CD4+ T cells. This is mediated via its bivalent interaction with MHC class II molecules and the TCR:CD3 complex through p56lck. Recent studies have implicated a third site of interaction between the membrane-proximal extracellular domains of CD4 and the TCR. Due to these multiple interactions, direct evidence for the functional importance of this extracellular association has remained elusive. Furthermore, the residues that mediate this interaction are unknown. In this study, we analyzed the function of 61 CD4 mutants. Alanine substitution of just 2 residues, either Q114/F182 or F182/F201, which are partially buried and located close to the D2/D3 interface, completely abrogated CD4 function. Direct evidence for the functional importance of TCR:CD4.D3 interaction was obtained using an anti-CD3fos:anti-CD4jun-bispecific Ab. Surprisingly, it induced strong T cell activation in hybridomas transfected with cytoplasmic-tailless CD4, despite the lack of association with either p56lck or MHC class II molecules. However, this effect was completely abrogated with the CD4 mutants Q114A/F182A or F182A/F201A. These data demonstrate that TCR:CD4.D3 interaction can have a profound effect on T cell activation and obviates the need for receptor oligomerization.
CD4在CD4+ T细胞的激活和发育中发挥重要作用。这是通过其与MHC II类分子以及通过p56lck的TCR:CD3复合物的二价相互作用介导的。最近的研究表明，CD4的膜近端胞外结构域与TCR之间存在第三个相互作用位点。由于这些多重相互作用，这种胞外关联功能重要性的直接证据仍然难以捉摸。此外，介导这种相互作用的残基尚不清楚。在本研究中，我们分析了61个CD4突变体的功能。仅对部分埋藏且位于D2/D3界面附近的2个残基Q114/F182或F182/F201进行丙氨酸替换，就完全消除了CD4的功能。使用抗CD3fos:抗CD4jun双特异性抗体获得了TCR:CD4.D3相互作用功能重要性的直接证据。令人惊讶的是，尽管与p56lck或MHC II类分子均无关联，但它在转染了无胞质尾CD4的杂交瘤中诱导了强烈的T细胞激活。然而，这种效应在CD4突变体Q114A/F182A或F182A/F201A中完全消除。这些数据表明，TCR:CD4.D3相互作用可对T细胞激活产生深远影响，并且无需受体寡聚化。
