Signal transduction of the T cell receptor in T cell anergy

1)单靠TCR刺激产生的信号不足以激活IL2基因，从而导致静息淋巴细胞的无能。2)SAPK/JNK和p38/CSBP通路形成冗余通路，MAPK/ERK通路与SAPK/JNK和p38/CSBP通路协同激活IL-2基因。3)SAPK/JNK和p38/CSBP通路的激活对环孢素A敏感。在TCR/CD28和SAPK/JNK和p38/CSBP途径的激活之间可能存在一个敏感的环孢素A步骤。4)对CD3zeta膜近端基于酪氨酸的免疫受体激活基序(ITAM)的功能分析表明，ITAM N端YxxL片段的酪氨酸或亮氨酸残基突变取消了该ITAM的所有信号转导功能。相反，C端YxxL片段的酪氨酸或亮氨酸残基突变抑制了IL-2的产生信号，但不阻止钙动员。含有C端YxxL亮氨酸突变的嵌合受体的交联会诱导ZAP7O的酪氨酸磷酸化，但不能稳定地与磷酸化的ITAM结合。这些结果表明，ITAM中的两个YxxL片段在功能上是不同的，都是ZAP7O结合和IL-2产生所必需的。

1)Signals generated by TCR stimulation alone is not sufficient to activate IL2 gene and thus induces anergy in resting lymphocytes. We found that TCR stimulation alone induces activation of MAPK/ERK but not SAPK/JNK and p38/CSBP.In constrast, when T cells were stimulated through both TCR and CD28 to produce IL-2, all three MAPK superfamily members were activated.2)SAPK/JNK arid p38/CSBP pathways form redundant pathways and MAPK/ERK pathway synergistically function with SAPK/JNK and p38/CSBP pathways in activation of IL2 gene.3)Activation of SAPK/JNK and p38/CSBP pathways but not MAPK/ERK pathway is sensitive to cyclosporin A.Since activation of SAPK/JNK and p38/CSBP pathways by osmotic shock is not inhibited by cyclosporin A, it is likely that there is a cyclosporin A sensitive step between TCR/CD28 and activation of SAPK/JNK and p38/CSBP pathways.4)Functional analysis of the immunoreceptor tyrosine-based activation motif (ITAM) derived from the membrane proximal ITAM of CD3zeta demonstrates that mutations at either the tyrosine or leucine residues in the N-terminal YxxL segment of the ITAM abolish all signal transduction functions of this ITAM.In contrast, mutations at the tyrosine or leucine residues in the C-terminal YxxL segment abrogate signals for IL-2 production but do not prevent calcium mobilization. Crosslinking of chimeric receptors containing a C-terminal YxxL leucine mutation induces tyrosine phosphorylation of ZAP7O but without stable binding to the phosphorylated ITAM.These results indicate that the two YxxL segments in an ITAM are functionally distinct and that both are essential for ZAP7O binding and IL-2 production.