Dianzani U, Shaw A, al-Ramadi B K, Kubo R T, Janeway C A
Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
J Immunol. 1992 Feb 1;148(3):678-88.
The coreceptor hypothesis postulates that physical association of CD4 with the TCR is required for effective signaling for T cell activation. A variety of studies has suggested that the coreceptor function of CD4 allows responses to 10- to 100-fold lower levels of peptide:self MHC class II ligand. We test the hypothesis of CD4 physical association with the TCR in two different ways. First, we use a panel of soluble antibodies directed at different TCR epitopes to activate a cloned T cell line, and show that activation by antibodies directed at a particular TCR epitope can be inhibited by anti-CD4 antibodies binding to a certain CD4 epitope. These effects establish that the interaction of CD4 and the TCR occurs in a specific orientation. Second, we use the same system to provide evidence that the physical association of CD4 with the TCR is required for effective tyrosine phosphorylation of the TCR zeta-chain subunit, presumably reflecting delivery of p56lck (lck) to the TCR. Only anti-TCR antibodies that induce physical association of CD4 with the TCR as monitored by cocapping can induce efficient tyrosine-phosphorylation of the TCR zeta-chain, unless second antibodies are used to force CD4 and the TCR to associate. Furthermore, the phosphorylation of the TCR zeta-chain exactly parallesl physical association in time and drug sensitivity. We conclude from these studies that stimuli that drive physical association of CD4 and the TCR strongly favor T cell activation, supporting the coreceptor hypothesis of CD4 function.
共受体假说假定，CD4与T细胞受体（TCR）的物理缔合是T细胞激活有效信号传导所必需的。各种研究表明，CD4的共受体功能使T细胞对低10至100倍水平的肽：自身MHC II类配体产生应答。我们用两种不同的方法检验CD4与TCR物理缔合的假说。首先，我们使用一组针对不同TCR表位的可溶性抗体来激活一个克隆的T细胞系，并表明针对特定TCR表位的抗体激活可被结合到某个CD4表位的抗CD4抗体所抑制。这些效应证实CD4与TCR的相互作用以特定方向发生。其次，我们使用同一系统来提供证据，即CD4与TCR的物理缔合是TCR ζ链亚基有效酪氨酸磷酸化所必需的，这大概反映了p56lck（lck）向TCR的传递。只有那些如通过共帽作用监测到的能诱导CD4与TCR发生物理缔合的抗TCR抗体才能诱导TCR ζ链的有效酪氨酸磷酸化，除非使用二抗迫使CD4与TCR缔合。此外，TCR ζ链的磷酸化在时间和药物敏感性方面与物理缔合完全平行。我们从这些研究得出结论，驱动CD4与TCR物理缔合的刺激强烈有利于T细胞激活，支持CD4功能的共受体假说。
