未经刺激的静止CD4^+ T细胞与克隆CD4^+ T细胞在抗原特异的及主要组织相容性抗原限制的无能诱导中的差异及其意义(英文)

Differential susceptibility of naive versus cloned CD4^+ T cells to antigen-specific and MHC-restricted anergy induction

在体外克隆T细胞中,T细胞无能可在多种条件下诱导产生,但T细胞在体内条件下的无能诱导仍有很多疑问和争议。由于正常动物体内对单一抗原特异应答的T细胞频率太低,从体内新提取未经刺激的T细胞进行无能诱导研究一直存在技术上的困难。本文利用HNT-TCR转基因小鼠高度单一的针对HA多肽抗原的CD4+T细胞群体,以T细胞增殖反应作为检测方法,比较研究了克隆CD4+T细胞和新提取未经刺激的CD4+T细胞对无能诱导的反应。结果表明,经化学交联剂1-ethyl-3-3(3-dimethylaminopropyl)carbodiimide(ECDI)处理的抗原提呈细胞(APC)与流感病毒血细胞凝集素(HA)多肽诱导在克隆CD4+T细胞中产生了无能,这种无能是依赖于特异抗原和主要组织相容性抗原(MHC)的;而在同样条件下,新提取未经刺激的CD4+T细胞则不能被诱导产生无能。结果提示,体内T细胞与克隆T细胞存在功能上的不同,体内T细胞的无能诱导可能需要不同的条件。这对体内T细胞免疫耐受产生的机制研究和临床应用都有重要意义。

T cell anergy has been successfully induced under different conditions in cloned CD4 + T cells, but induction of T cell anergy in vivo has been difficult and controversial. Due to the low frequency of naturally occurring T cell population with specificity to a defined antigen, it is very difficult to study anergy of nai've T cells without prior in vivo priming which complicates the interpretation of experimental data. To solve this problem, we adopted the HNT-TCR transgenic mice which have homogenous antigen specific CD4 + T cell population. In this study, we generated an influenza virus hemagglutinin (HA) pep-tide-specific CD4 + T cell clone from the HNT-TCR transgenic mice and induced anergy using APCs which were treated with the crosslinker, ECDI (1-ethyl-3-3(3-dimethylaminopropyl) carbodiimide). The proliferative response of the cloned or freshly purified nai've CD4 + transgenic T cells after treatment with ECDI-treated APCs and the HA peptide antigen was monitored as the index of anergy induction. The results showed that anergy was successfully induced in the cloned HNT-TCR transgenic CD4+ T cells. It was determined that the induced anergy was antigen- and MHC-specific. By contrast, anergy was not observed in freshly purified nai've CD4 + transgenic T cells under the same conditions. The results suggest that nai've CD4 + T cells may have different anergy inducing requirements, or that cloned CD4 + T cells may have certain priming or in vitro cloning artifact which makes them more susceptible to anergy induction. We propose that induction of T cell anergy may depend on the T cell growth, activation and differentiation state or cloning conditions. The results from the present study may have important implications for the study of the mechanism(s) underlying T cell anergy induction in vivo and for applications of immune tolerance based therapy.