Notch controls the magnitude of T helper cell responses by promoting cellular longevity
Notch controls the magnitude of T helper cell responses by promoting cellular longevity
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DOI：
10.1073/pnas.1206044109
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发表时间：
2012-06-05
影响因子：
11.1
通讯作者：
Amsen, Derk
中科院分区：
文献类型：
--
作者：
Helbig, Christina;Gentek, Rebecca;Amsen, Derk
产生有效的免疫应答需要扩增罕见的抗原特异性CD4（+）T细胞。响应种群的规模最终由增殖和存活决定。这两个过程都受到严格控制，以限制对无害抗原的反应。只有当先天免疫传感器被微生物刺激或佐剂激活时，才会发生持续的扩增，这对疫苗接种具有重要意义。控制持续T细胞反应的信号的分子身份还不完全清楚。在这里，我们描述了Notch途径在这一过程中的重要作用。Notch的共激活允许比单独通过T细胞受体和经典共刺激刺激的刺激更大数量的活化的CD4（+）T细胞的积累。Notch不明显影响CD4（+）T细胞的细胞周期进入或进展。相反，Notch在克隆扩增的初始阶段后保护活化的CD4（+）T细胞免于凋亡。Notch诱导广泛的抗凋亡基因表达程序，保护免受内在的，以及外在的，凋亡途径。Notch1和Notch2受体以及经典效应子RBPJ（免疫球蛋白κ J区的重组信号结合蛋白）都参与了这一过程。相应地，在缺乏Notch途径的这些组分的小鼠中，对蛋白抗原免疫的CD4（+）T细胞应答强烈降低。因此，我们的研究结果表明，Notch通过促进细胞寿命来控制CD4（+）T细胞反应的大小。
Generation of effective immune responses requires expansion of rare antigen-specific CD4(+) T cells. The magnitude of the responding population is ultimately determined by proliferation and survival. Both processes are tightly controlled to limit responses to innocuous antigens. Sustained expansion occurs only when innate immune sensors are activated by microbial stimuli or by adjuvants, which has important implications for vaccination. The molecular identity of the signals controlling sustained T-cell responses is not fully clear. Here, we describe a prominent role for the Notch pathway in this process. Coactivation of Notch allows accumulation of far greater numbers of activated CD4(+) T cells than stimulation via T-cell receptor and classic costimulation alone. Notch does not overtly affect cell cycle entry or progression of CD4(+) T cells. Instead, Notch protects activated CD4(+) T cells against apoptosis after an initial phase of clonal expansion. Notch induces a broad antiapoptotic gene expression program that protects against intrinsic, as well as extrinsic, apoptosis pathways. Both Notch1 and Notch2 receptors and the canonical effector RBPJ (recombination signal binding protein for immunoglobulin kappa J region) are involved in this process. Correspondingly, CD4(+) T-cell responses to immunization with protein antigen are strongly reduced in mice lacking these components of the Notch pathway. Our findings, therefore, show that Notch controls the magnitude of CD4(+) T-cell responses by promoting cellular longevity.