Doyle Hester A, Gee Renelle J, Mamula Mark J
Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
J Immunol. 2003 Sep 15;171(6):2840-7. doi: 10.4049/jimmunol.171.6.2840.
It is clear that many factors can perturb T cell homeostasis that is critical in the maintenance of immune tolerance. Defects in the molecules that regulate homeostasis can lead to autoimmune pathology. This simple immunologic concept is complicated by the fact that many self-proteins undergo spontaneous posttranslational modifications that affect their biological functions. This is the case in the spontaneous conversion of aspartyl residues to isoaspartyl residues, a modification occurring at physiological pH and under conditions of cell stress and aging. We have examined the effect of isoaspartyl modifications on the effector functions of T lymphocytes in vivo using mice lacking the isoaspartyl repair enzyme protein carboxyl methyltransferase (PCMT). PCMT(-/-) CD4(+) T cells exhibit increased proliferation in response to mitogen and Ag receptor stimulation as compared with wild-type CD4(+) T cells. Hyperproliferation is marked by increased phosphorylation of members of both the TCR and CD28 signaling pathways. Wild-type mice reconstituted with PCMT(-/-) bone marrow develop high titers of anti-DNA autoantibodies and kidney pathology typical of that found in systemic lupus erythematosus. These observations, coupled with the fact that humans have polymorphisms in the pcmt gene, suggest that isoaspartyl self-proteins may alter the maintenance of peripheral immune tolerance.
显然，许多因素可扰乱对维持免疫耐受至关重要的T细胞稳态。调节稳态的分子缺陷可导致自身免疫性病理。这一简单的免疫学概念因许多自身蛋白会发生影响其生物学功能的自发翻译后修饰这一事实而变得复杂。天冬氨酰残基向异天冬氨酰残基的自发转化就是这种情况，这种修饰发生在生理pH值以及细胞应激和衰老条件下。我们使用缺乏异天冬氨酰修复酶蛋白羧甲基转移酶（PCMT）的小鼠，研究了异天冬氨酰修饰对体内T淋巴细胞效应功能的影响。与野生型CD4⁺ T细胞相比，PCMT（-/-）CD4⁺ T细胞在有丝分裂原和抗原受体刺激下表现出增殖增加。增殖过度的特征是TCR和CD28信号通路成员的磷酸化增加。用PCMT（-/-）骨髓重建的野生型小鼠会产生高滴度的抗DNA自身抗体以及系统性红斑狼疮中典型的肾脏病理。这些观察结果，再加上人类pcmt基因存在多态性这一事实，表明异天冬氨酰自身蛋白可能会改变外周免疫耐受的维持。
