Human autoreactive CD4+ T cells from naive CD45RA+ and memory CD45RO+ subsets differ with respect to epitope specificity and functional antigen avidity
Human autoreactive CD4+ T cells from naive CD45RA+ and memory CD45RO+ subsets differ with respect to epitope specificity and functional antigen avidity
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DOI：
10.4049/jimmunol.164.10.5474
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发表时间：
2000-05-15
影响因子：
4.4
通讯作者：
Martin, R
中科院分区：
文献类型：
--
作者：
Muraro, PA;Pette, M;Martin, R
对自身抗原具有特异性的 T 细胞通常存在于外周血中，并且在激活后可能会靶向组织抗原并参与自身免疫过程的发病机制。在多发性硬化症（一种中枢神经系统脱髓鞘疾病）中，假定炎症损伤是由与髓磷脂抗原反应的 CD4(+) T 细胞引发的。为了研究循环髓磷脂反应细胞的潜在幼稚与记忆起源，我们从 CD45RA(+)/RO- 和 CD45RO(+)/RA(-) CD4(+) 中产生了髓磷脂碱性蛋白 (MBP) 和破伤风环形特异性 T 细胞克隆来自多发性硬化症患者和对照者外周血的 T 细胞亚群。我们的结果表明 1) 对 MBP 的反应与对 TT 的反应不同，主要来自 CD45RA(+) 子集； 2) 对免疫显性MBP表位的反应主要存在于CD45RA(+)子集中； 3) 在每个个体中，单个 MBP 表位的识别偏向任一子集，Ag 精细特异性没有重叠； 4) 尽管共刺激分子和粘附分子的表达较低，但 CD45RA(+) 子集衍生的克隆识别具有更高功能性 Ag 亲和力的表位。这些发现表明，初始 CD45RA(+) T 细胞亚群作为人类免疫显性、潜在致病性效应 CD4(+) T 细胞反应的来源，发挥着核心作用。
T cells with specificity for self-Ags are normally present in the peripheral blood, and, upon activation, may target tissue Ags and become involved in the pathogenesis of autoimmune processes. In multiple sclerosis, a demyelinating disease of the CNS, it is postulated that inflammatory damage is initiated by CD4(+) T cells reactive to myelin Ags, To investigate the potential naive vs memory origin of circulating myelin-reactive cells, we have generated myelin basic protein (MBP)- and tetanus toroid-specific T cell clones from CD45RA(+)/RO- and CD45RO(+)/RA(-) CD4(+) T cell subsets from the peripheral blood of multiple sclerosis patients and controls. Our results show that 1) the response to MBP, different from that to TT, predominantly emerges from the CD45RA(+) subset; 2) the reactivity to immunodominant MBP epitopes mostly resides in the CD45RA(+) subset; 3) in each individual, the recognition of single MBP epitopes is skewed to either subset, with no overlap in the Ag fine specificity; and 4) in spite of a lower expression of costimulatory and adhesion molecules, CD45RA(+) subset-derived clones recognize epitopes with higher functional Ag avidity. These findings point to a central role of the naive CD45RA(+) T cell subset as the source for immunodominant, potentially pathogenic effector CD4(+) T cell responses in humans.