Zhang Ruan, Zhang Na, Mueller Daniel L
Department of Medicine and the Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
J Immunol. 2008 Oct 15;181(8):5331-9. doi: 10.4049/jimmunol.181.8.5331.
Optimal clonal expansion of CD4(+) T cells during the primary response to Ag requires prolonged TCR recognition of peptide Ag/MHC complexes. In this study, we investigated the capacity of Casitas B-lineage lymphoma b (Cbl-b) to counter-regulate late TCR signals necessary for continued cell division in vivo. During the first 24 h of a primary response to Ag, Cblb(-/-) 5C.C7 CD4(+) T cells demonstrated no alteration in CD69, CD25, and CD71 up-regulation or cell growth as compared with wild-type cells. Nevertheless, beyond 24 h, both the expression of CD71 and the rate of cell division were increased in the genetic absence of Cbl-b, leading to an augmented clonal expansion. This deregulation of late T cell proliferation in the absence of Cbl-b resulted in part from an inability of Cblb(-/-) T cells to desensitize Akt, PLCgamma-1, and ERK phosphorylation events downstream of the TCR/CD3 complex, in addition to their failure to undergo a growth arrest in the absence of Ag. These observations now suggest a novel role for Cbl-b in triggering the exit from cell cycle at the end of a CD4(+) T cell clonal expansion.
在对抗原的初次应答过程中，CD4(+) T细胞的最佳克隆扩增需要TCR对肽抗原/MHC复合物进行长时间识别。在本研究中，我们调查了Casitas B系淋巴瘤b（Cbl-b）对抗调节体内持续细胞分裂所需的晚期TCR信号的能力。在对抗原的初次应答的最初24小时内，与野生型细胞相比，Cblb(-/-) 5C.C7 CD4(+) T细胞在CD69、CD25和CD71上调或细胞生长方面没有变化。然而，超过24小时后，在基因缺失Cbl-b的情况下，CD71的表达和细胞分裂速率均增加，导致克隆扩增增强。在没有Cbl-b的情况下，晚期T细胞增殖的这种失调部分是由于Cblb(-/-) T细胞无法使TCR/CD3复合物下游的Akt、PLCγ-1和ERK磷酸化事件脱敏，此外还由于它们在没有抗原的情况下无法进入生长停滞状态。这些观察结果现在表明Cbl-b在CD4(+) T细胞克隆扩增结束时触发细胞周期退出方面具有新作用。
