Signal transduction of the T cell receptor in T cell anergy

T 细胞无反应性中 T 细胞受体的信号转导

• 批准号: 09044332
• 负责人: KOYASU Shigeo
• 金额: $ 0.7万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044332/
• 关键词: tolerance; cyclosporin A; ITAM; T cell receptor; MAP kinase superfamily; ITAM; チロシンキナーゼ; キメラ分子; カルシウムイオン

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.

1)单独由TCR刺激产生的信号不足以激活IL 2基因，从而在静息淋巴细胞中诱导无反应性。我们发现，单独刺激TCR可诱导MAPK/ERK的活化，但不诱导SAPK/JNK和p38/CSBP的活化。2）MAPK/ERK通路与SAPK/JNK通路和p38/CSBP通路在IL 2基因的激活过程中存在协同作用，而SAPK/JNK通路和p38/CSBP通路在IL 2基因的激活过程中存在冗余通路。SAPK/JNK和p38/CSBP通路的激活而不是MAPK/ERK通路对环孢菌素A敏感。由于通过渗透压休克激活SAPK/JNK和p38/CSBP通路不被环孢菌素A抑制，在TCR/CD 28与SAPK/JNK和p38/CSBP通路的激活之间可能存在环孢菌素A敏感步骤。来自CD 3 ζ的膜近端ITAM的基于ITAM的激活基序（ITAM）证明ITAM的N-末端YxxL区段中的酪氨酸或亮氨酸残基处的突变消除了该ITAM的所有信号转导功能。在C-末端YxxL片段中酪氨酸或亮氨酸残基的突变消除了IL-2产生的信号，但不阻止钙动员。含有C-末端YxxL亮氨酸突变的嵌合受体的交联诱导ZAP 7 O的酪氨酸磷酸化，但没有稳定的结合到磷酸化的ITAM.These结果表明，在ITAM中的两个YxxL片段在功能上是不同的，并且都是必不可少的ZAP 7 O结合和IL-2的生产。

项目成果

Ghendler,Y.,et al.: "Double positive TCRhigh thymocytes are resistant to peptide/MHC ligand-induced negative selection." Eur.J.Immunol.27. 2279-2289 (1997)

Ghendler,Y.,et al.：“双阳性 TCRhigh 胸腺细胞对肽/MHC 配体诱导的阴性选择具有抵抗力。”

Sunder-Plassmann, R., et al.: "Functional analysis of immunoreceptor tyrosine-activated motif (ITAM)-mediated signal transduction:the two YxxL segments within a single CD3ζ-ITAM are functionally distinct." Eur.J.Immunol.27. 2001-2009 (1997)

Sunder-Plassmann, R. 等人：“免疫受体酪氨酸激活基序 (ITAM) 介导的信号转导的功能分析：单个 CD3z-ITAM 内的两个 YxxL 片段在功能上是不同的。”Eur.J.Immunol.27 .2001-2009 (1997)

Katamura,K.,et al.: "Existence of activated and memory CD4^+ T cells in peripheral blood and their skin infiltration in CD8 deficiency." Clin.Exp.Immunol.115. 124-130 (1999)

Katamura,K.,et al.：“外周血中存在活化和记忆 CD4^ T 细胞及其在 CD8 缺乏症中的皮肤浸润。”

Nishizawa, K., and Koyasu, S.: "IL2 and IL7 differentially induce CD4^-CD8^-αβTCR^+NK1.1^+ large granular lymphocytes and IL4 producing dells from CD4^-CD8^-αβTCR^+NK1.1^- cells : implications for the regulation of Th1 and Th2 type responses." Int.Immunol

Nishizawa, K. 和 Koyasu, S.：“IL2 和 IL7 差异性地诱导 CD4^-CD8^-αβTCR^+NK1.1^+ 大颗粒淋巴细胞和 CD4^-CD8^-αβTCR^+NK1 产生的 IL4。 1^- 细胞：对 Th1 和 Th2 型反应调节的影响。” Int.Immunol

Sunder-Plassmann, R.et al.: "Functional analysis of immunoreceptor tyrosine-activated motif (ITAM) -mediated signal transduction : the two YxxL segments within a single CD3zeta-ITAM are functionally distinct." Eur.J.Immunol.27. 2001-2009 (1997)

Sunder-Plassmann, R.等人：“免疫受体酪氨酸激活基序 (ITAM) 介导的信号转导的功能分析：单个 CD3zeta-ITAM 内的两个 YxxL 片段在功能上是不同的。”