Namekawa T, Snyder M R, Yen J H, Goehring B E, Leibson P J, Weyand C M, Goronzy J J
Department of Medicine/Rheumatology and Immunology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
J Immunol. 2000 Jul 15;165(2):1138-45. doi: 10.4049/jimmunol.165.2.1138.
Expansion of CD4+CD28null T cells is a characteristic finding in patients with rheumatoid arthritis. Despite lacking CD28 molecules, these unusual CD4 T cells undergo clonal proliferation and form large and long-lived clonal populations. They produce high levels of IFN-gamma, exhibit autoreactivity, and have cytolytic function. The mechanisms facilitating the expansion and longevity of CD4+CD28null T cell clones in vivo are unknown. Here, we report that CD4+CD28null, but not CD4+CD28+, T cells express MHC class I-recognizing receptors normally found on NK cells. CD4+CD28null T cells preferentially expressed killer cell activating receptors (KAR), often in the absence of killer cell inhibitory receptors. Cross-linking of KAR molecules enhanced the proliferative response to TCR-mediated stimulation, but not the cytolytic function of CD4+CD28null T cells, suggesting different signaling pathways in CD4 T cells and NK cells. Triggering of KAR signaling led to the phosphorylation of several cellular targets, although the pattern of phosphorylation differed from that induced by the TCR. Aberrant expression of KAR molecules in the absence of inhibitory receptors and in the appropriate HLA setting may lead to the clonal outgrowth of autoreactive CD4+CD28null T cells commonly seen in rheumatoid arthritis.
CD4+CD28null T细胞的扩增是类风湿性关节炎患者的一个特征性表现。尽管缺乏CD28分子，但这些异常的CD4 T细胞仍会发生克隆增殖，形成大量且长寿的克隆群体。它们产生高水平的干扰素-γ，表现出自反应性，并具有细胞溶解功能。促进CD4+CD28null T细胞克隆在体内扩增和长寿的机制尚不清楚。在此，我们报告CD4+CD28null T细胞（而非CD4+CD28+ T细胞）表达通常在自然杀伤细胞上发现的MHC I类识别受体。CD4+CD28null T细胞优先表达杀伤细胞激活受体（KAR），且通常缺乏杀伤细胞抑制受体。KAR分子的交联增强了对TCR介导刺激的增殖反应，但未增强CD4+CD28null T细胞的细胞溶解功能，这表明CD4 T细胞和自然杀伤细胞中的信号通路不同。KAR信号的触发导致多个细胞靶点的磷酸化，尽管磷酸化模式与TCR诱导的不同。在缺乏抑制受体且处于合适的HLA环境中，KAR分子的异常表达可能导致类风湿性关节炎中常见的自身反应性CD4+CD28null T细胞的克隆性生长。
