Abnormal polarization of CD4^+ T cell subsets in autoimmune-Prone New Zealand mice.

自身免疫倾向新西兰小鼠中 CD4+ T 细胞亚群的异常极化。

• 批准号: 07670383
• 负责人: NISHIMURA Hiroyuki
• 金额: $ 1.54万
• 依托单位: TOIN UNIVERSITY OF YOKOHAMA TOIN HUMAN SCIENCE AND TECHNOLOGY CENTER
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670383/
• 关键词: SLE; CD4^+ T cells; activated T cells; NZB mice; (NZB*NZW) F1 mice; Th1; Th2; CD69; 活性化; 自己免疫疾患; 全身性エリテマトーデス; New Zealand マウス; (NZB×NZW)F1

Abnormal polarization of CD4^+ T cell subsets in autoimmune-Prone New Zealand mice.High frequencies of CD4^+ T cells bearing activation antigens such as HLA-DR and -DP in blood of patients with systemic lupus erythematosus (SLE) suggest that a continuous activation of autoreactive CD4^+ T cells occurs in this disease condition. In the present stidies, we analyzed spontaneously activated CD4^+ T cells in spleens of SLE-Prone NZB and (NZB*NZW) F1 mice, using two distinct early T cell activation markers, CD69 and NTA204. A marked age-associated increase in the proportion of each CD69^+ and NTA204^+ activated CD4^+ T cells was observed in NZB and (NZB*NZW) F1, but not in non-autoimmune NZW and BALB/c mice. Interestingly, there were phenotypically separate, three types of activated T cells ; one with CD69 alone, one with NTA204, and one with both CD69 and NTA204, Studies of T cell receptor (TCR) V bata repertoire showed that these activated T cells had no skewed TCR V beta repertoire usages. Murine CD4^+ T cells could be subdivided into 4 distinct subsets, either positive or negative for CD62L (L-selectin) and NTA260, an antigendefined by a hybridoma monoclonal autoantibody from autoimmune NZB mice. It was found that all three activated CD4^+ T cell subpopulations were included in the CD62L-NTA260-CD4^+ T cell subset. This subset was unique because it belonged to neither naive nor memory CD4^+ T cells. It also did not functioon as either Th1 or Th2, based on its cytokine production patterns. As such CD62L-NTA260-CD4^+ T cell subset became the major population of CD4^+ T cells in aged NZB and (NZB*NZW) F1 mice, further phenotypical and functional analysis of this subset may provide insightsinto the mechanisms of the generation of autoreactive T cells responsible for the pathogenesis of SLE.

系统性红斑狼疮(SLE)患者血液中携带人类白细胞抗原DR和-DP等活化抗原的CD4^+T细胞的高频率提示，在这种疾病状态下，自身反应性的CD4^+T细胞持续激活。在本研究中，我们使用两个不同的早期T细胞激活标志物CD69和NTA204分析了易患SLE的NZB和(NZB*NZW)F1小鼠脾中自发激活的CD4^+T细胞。在NZB和(NZB*NZW)F1小鼠中，CD69^+和NTA204^+活化的CD4^+T细胞的比例随着年龄的增长而显著增加，而在非自身免疫的NZW和BALB/c小鼠中则不显著。有趣的是，有三种表型分离的活化T细胞；一种只有CD69，一种有NTA204，还有一种既有CD69又有NTA204。T细胞受体(TCR)V BATA谱的研究表明，这些激活的T细胞没有TCR Vβ谱的偏斜使用。小鼠CD_4~+T细胞可分为4个不同的亚群，CD62L(L-选择素)阳性或阴性，NTA260是由来自自身免疫性NZB小鼠的杂交瘤自身抗体所定义的抗原。研究发现，CD62L-NTA260-CD4^+T细胞亚群中存在三个活化的CD4^+T细胞亚群。这个亚群是独一无二的，因为它既不属于幼稚的也不属于记忆的CD4^+T细胞。根据其细胞因子的产生模式，它也不能发挥Th1或Th2的功能。因此，CD62L-NTA260-CD4^+T细胞亚群成为老年NZB和(NZB*NZW)F1小鼠主要的CD4^+T细胞亚群，对这一亚群的进一步表型和功能分析可能为揭示自身反应性T细胞在SLE发病机制中的作用提供依据。

项目成果

Hiroyuki Nishimura 他: "Effects of transgenic mixed-haplotype MHC class II molecules Aα^dAβ^z on autoimmune diseases in New Zealand mice." International Immunology. 8. 967-976 (1996)

Hiroyuki Nishimura 等人：“转基因混合单倍型 MHC II 类分子 Aα^dAβ^z 对新西兰小鼠自身免疫性疾病的影响”，8. 967-976 (1996)。

Nishimura H, et al.: "Functional CD4+ T cell subsets defined by expression of CD45RC and NTA260 antigens and age-associated polarization in murine lupus." Int. Immunol.7:. 1115-1123 (1995)

Nishimura H 等人：“通过小鼠狼疮中 CD45RC 和 NTA260 抗原的表达以及年龄相关的极化来定义功能性 CD4 T 细胞亚群。”

Nishimura H.et al.: "Effects of transgenic mixed-haplotype MHC class II molecules AadAbz on autoimmune disease in New Zealand mice." Internat. Immunol.8. 7-976 (1996)

Nishimura H.等人：“转基因混合单倍型 MHC II 类分子 AadAbz 对新西兰小鼠自身免疫性疾病的影响。”

Nishimura H,Ishikawa S,Nozawa S,Awaji M,Saito J,Abe M and Shirai T: "Effects of transgenic mixed-haplotype MHC class II molecules AadAbz on autoimmune disease in New Zealand mice." Internat.Immunol. 8. 967-976 (1996)

Nishimura H、Ishikawa S、Nozawa S、Awaji M、Saito J、Abe M 和 Shirai T：“转基因混合单倍型 MHC II 类分子 AadAbz 对新西兰小鼠自身免疫性疾病的影响。”

赤倉新、西村裕之他: "全身性エリテマトーデス(SLE)モデルに発見された新しい早期活性化CD^+T細胞亜集団" 順天堂医学. (発表予定). (1997)

Arata Akakura、Hiroyuki Nishimura 等人：“在系统性红斑狼疮 (SLE) 模型中发现了一种新的早期激活的 CD^+ T 细胞亚群”Juntendo Medical Sciences（即将出版）。