p21CIP1/WAF1 controls proliferation of activated/memory T cells and affects homeostasis and memory T cell responses
p21CIP1/WAF1 controls proliferation of activated/memory T cells and affects homeostasis and memory T cell responses
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DOI：
10.4049/jimmunol.178.4.2296
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发表时间：
2007-02-15
影响因子：
4.4
通讯作者：
Balomenos, Dimitrios
中科院分区：
文献类型：
--
作者：
Arias, Cristina F.;Ballesteros-Tato, Andre;Balomenos, Dimitrios
129/Sv x C57BL/6 p21(-/-) 小鼠产生的自身抗体和狼疮样自身免疫已证实细胞周期失调是导致耐受性破坏的缺陷途径之一。记忆 T 细胞积累被认为与小鼠狼疮模型中的耐受性丧失有关。我们研究了出现狼疮样疾病表现的 C57BL/6 p21(-/-) 小鼠的 T 细胞记忆反应。 p21 不影响初始 T 细胞的原代增殖，并且是循环控制所必需的，但不影响激活/记忆 T 细胞的凋亡。当我们通过二次 TCR 攻击诱导细胞凋亡时，存活的记忆 T 细胞依赖于 p21 来控制增殖。在不引起细胞凋亡的二次 T 细胞刺激条件下，p21 也需要调节激活/记忆 T 细胞的扩增。 p21 控制激活/记忆 T 细胞的 T 细胞增殖的需要表明，除了凋亡之外，p21 的循环调节构成了 T 细胞稳态的新途径。与这一观点一致的是，我们发现p21(-/-)小鼠中记忆CD4(+) T细胞的积累在TCR刺激后显示出增殖潜力的增加。此外，p21(-/-)小鼠的OVA免疫产生了高反应性OVA特异性T细胞。总体而言，数据显示 p21 仅控制激活/记忆 T 细胞的增殖，并表明 p21 形成记忆 T 细胞稳态机制的一部分，有助于维持耐受性。
Development of autoantibodies and lupus-like autoimmunity by 129/Sv x C57BL/6 p21(-/-) mice has established that cell cycle deregulation is one the defective pathways leading to break of tolerance. Memory T cell accumulation is thought to be related to tolerance loss in murine lupus models. We studied T cell memory responses in C57BL/6 p21(-/-) mice that develop lupus-like disease manifestations. p21 did not affect primary proliferation of naive T cells, and was required for cycling control, but not for apoptosis of activated/memory T cells. When we induced apoptosis by secondary TCR challenge, surviving memory T cells depended on p21 for proliferation control. Under conditions of secondary T cell stimulation that did not cause apoptosis, p21 was also needed for regulation of activated/memory T cell expansion. The requirement for p21 in the control of T cell proliferation of activated/memory T cells suggests that in addition to apoptosis, cycling regulation by p21 constitutes a new pathway for T cell homeostasis. Concurring with this view, we found accumulation in p21(-/-) mice of memory CD4(+) T cells that showed increased proliferative potential after TCR stimulation. Furthermore, OVA immunization of p21(-/-) mice generated hyperresponsive OVA-specific T cells. Overall, the data show that p21 controls the proliferation of only activated/memory T cells, and suggest that p21 forms part of the memory T cell homeostasis mechanism, contributing to maintenance of tolerance.