Dysregulation of T lymphocyte proliferative responses in autoimmunity.
Dysregulation of T lymphocyte proliferative responses in autoimmunity.
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DOI：
10.1371/journal.pone.0106347
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Moore DJ
中科院分区：
文献类型：
--
作者：
Elizer SK;Marshall AF;Moore DJ
T细胞在很大程度上依赖于细胞的增殖才能发挥其效应功能。自身免疫性菌株通常被认为具有不受控制的T细胞增殖；然而，在自身免疫性糖尿病的小鼠模型中，先前发现T细胞增殖不足导致AICD缺陷。我们现在确定易患狼疮的小鼠品系是否也同样反应迟钝。在T淋巴细胞活化的广泛特征之后，我们观察到了三个自身免疫株-NOD、MRL和NZBxNZW F1的共同的CD4T细胞活化特征。当用多克隆有丝分裂原刺激时，与非自身免疫菌株C57BL/6相比，CD4T细胞显示细胞分裂受阻和剂量反应减弱，我们进一步追踪到这一表型依赖于B细胞介导的共刺激作用，这突显了B细胞定向免疫疗法在防止T细胞介导的组织损伤方面的成功。反过来，这些CD4T细胞的增殖能力减弱，导致对激活诱导的细胞死亡的敏感性降低，但激活是合适的。在NOD小鼠的CD8区也观察到类似的刺激反应降低；NOD CD8 T细胞与狼疮易感株的区别在于对抗CD3介导的刺激的剂量反应减弱。这种区别可能解释了糖尿病和狼疮易感小鼠品系激活的不同致病途径。
T cells are critically dependent on cellular proliferation in order to carry out their effector functions. Autoimmune strains are commonly thought to have uncontrolled T cell proliferation; however, in the murine model of autoimmune diabetes, hypo-proliferation of T cells leading to defective AICD was previously uncovered. We now determine whether lupus prone murine strains are similarly hyporesponsive. Upon extensive characterization of T lymphocyte activation, we have observed a common feature of CD4 T cell activation shared among three autoimmune strains–NOD, MRL, and NZBxNZW F1s. When stimulated with a polyclonal mitogen, CD4 T cells demonstrate arrested cell division and diminished dose responsiveness as compared to the non-autoimmune strain C57BL/6, a phenotype we further traced to a reliance on B cell mediated costimulation, which underscores the success of B cell directed immune therapies in preventing T cell mediated tissue injury. In turn, the diminished proliferative capacity of these CD4 T cells lead to a decreased, but activation appropriate, susceptibility to activation induced cell death. A similar decrement in stimulation response was observed in the CD8 compartment of NOD mice; NOD CD8 T cells were distinguished from lupus prone strains by a diminished dose-responsiveness to anti-CD3 mediated stimulation. This distinction may explain the differential pathogenetic pathways activated in diabetes and lupus prone murine strains.
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