Namekawa T, Wagner U G, Goronzy J J, Weyand C M
Mayo Clinic, Rochester, Minnesota 55905, USA.
Arthritis Rheum. 1998 Dec;41(12):2108-16. doi: 10.1002/1529-0131(199812)41:12<2108::AID-ART5>3.0.CO;2-Q.
To identify the functional properties of CD4+ CD28- T cells, which accumulate and clonally expand in patients with rheumatoid arthritis (RA).
The gene expression of molecules involved in T cell effector functions was compared in CD4+ CD28- and CD4+ CD28+ T cell clones. The expression of differentially up-regulated genes was confirmed by flow cytometry of T cells and by 2-color immunohistochemistry of rheumatoid synovial tissue. Cytotoxicity of CD4+ CD28- T cells was tested by anti-CD3 redirected lysis of Fc receptor-positive target cells.
CD4+ CD28- T cell clones lacked messenger RNA for the CD40 ligand (CD40L) but transcribed the perforin gene. Perforin was also found in freshly isolated CD4+ CD28- peripheral blood lymphocytes from RA patients. CD4+ CD28-, but not CD4+ CD28+, T cell clones lysed Fc receptor-bearing target cells. CD4+ perforin-positive T cells were present in the synovial tissue, where their frequency correlated with the expansion of the CD4+ CD28- compartment in the periphery. Among tissue-infiltrating CD4+ T cells, only the CD40L-negative subset expressed perforin transcripts.
Clonally expanded CD4+ CD28- T cells are functionally specialized for killing, while they lack the ability to provide B cell help. Tissue-infiltrating CD4+ T cells can be subdivided phenotypically and functionally into at least 2 distinct subsets based on their expression of perforin and CD40L. Because the expansion of CD4+ CD28- T cells is associated with extraarticular RA, T cell-mediated cytotoxicity may be particularly important in these most severe complications of RA.
鉴定类风湿关节炎（RA）患者体内积聚并克隆性扩增的CD4+ CD28- T细胞的功能特性。
比较CD4+ CD28-和CD4+ CD28+ T细胞克隆中参与T细胞效应功能的分子的基因表达。通过T细胞的流式细胞术和类风湿滑膜组织的双色免疫组织化学确认差异上调基因的表达。通过抗CD3重定向裂解Fc受体阳性靶细胞来测试CD4+ CD28- T细胞的细胞毒性。
CD4+ CD28- T细胞克隆缺乏CD40配体（CD40L）的信使RNA，但转录穿孔素基因。在RA患者新鲜分离的CD4+ CD28-外周血淋巴细胞中也发现了穿孔素。CD4+ CD28- T细胞克隆而非CD4+ CD28+ T细胞克隆裂解带有Fc受体的靶细胞。滑膜组织中存在CD4+穿孔素阳性T细胞，其频率与外周血中CD4+ CD28-亚群的扩增相关。在组织浸润的CD4+ T细胞中，只有CD40L阴性亚群表达穿孔素转录本。
克隆性扩增的CD4+ CD28- T细胞在功能上专门用于杀伤，而缺乏为B细胞提供帮助的能力。基于穿孔素和CD40L的表达，组织浸润的CD4+ T细胞在表型和功能上可至少分为2个不同的亚群。由于CD4+ CD28- T细胞的扩增与关节外RA相关，T细胞介导的细胞毒性在RA这些最严重的并发症中可能特别重要。
