Colovai A I, Liu Z, Ciubotariu R, Lederman S, Cortesini R, Suciu-Foca N
Department of Pathology, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA.
Transplantation. 2000 Apr 15;69(7):1304-10. doi: 10.1097/00007890-200004150-00016.
The underlying mechanism of immune suppression mediated by regulatory T cells is not completely understood. In previous studies we have shown that antigen-specific human T suppressor cells (Ts) can be generated in vitro by multiple rounds of stimulation with allogeneic, xenogeneic, or antigen-pulsed autologous antigen-presenting cells (APC). Human Ts express the CD8+CD28- phenotype and require specific recognition of MHC class I/peptide complexes on the surface of APC to block proliferation of T helper cells (Th). The aim of the present study was to explore the activation requirements of Ts as well as the nature of Th unresponsiveness to xenogeneic (swine) antigens induced by Ts.
We investigated whether specific antigenic stimulation of Ts is required for their ability to inhibit early activation of xenoreactive Th (up-regulation of CD40 ligand). Flow cytometry studies indicated that Ts function required specific recognition of MHC class I on the surface of the stimulating APC. However, neither proliferation nor protein synthesis was required for the ability of Ts to inhibit Th. Ts drastically reduced the capacity of xenoreactive Th cells to produce interleukin (IL)-2 in response to the specific APC, without affecting their surface expression of IL-2 receptor. The suppressor effect that Ts exerted on Th proliferation could not be circumvented by CD40 ligation on the surface of the APC but could be reversed by the addition of exogenous IL-2.
These data indicate that Ts induce anergy of xenoreactive human Th cells upon specific recognition of MHC class I antigens. Hence, Ts may prevent the activation of T cell-mediated immune responses against xenogeneic transplants.
调节性T细胞介导免疫抑制的潜在机制尚未完全明确。在先前的研究中，我们已经表明，通过用同种异体、异种或抗原脉冲自体抗原呈递细胞（APC）进行多轮刺激，可以在体外产生抗原特异性人T抑制细胞（Ts）。人Ts表达CD8 + CD28 - 表型，并且需要特异性识别APC表面的MHC I类/肽复合物以阻断T辅助细胞（Th）的增殖。本研究的目的是探讨Ts的激活要求以及Ts诱导的Th对异种（猪）抗原无反应性的性质。
我们研究了Ts对异种反应性Th早期激活（CD40配体上调）的抑制能力是否需要特异性抗原刺激。流式细胞术研究表明，Ts的功能需要特异性识别刺激APC表面的MHC I类。然而，Ts抑制Th的能力既不需要增殖也不需要蛋白质合成。Ts显著降低了异种反应性Th细胞响应特异性APC产生白细胞介素（IL）-2的能力，而不影响其IL-2受体的表面表达。Ts对Th增殖施加的抑制作用不能通过APC表面的CD40连接来规避，但可以通过添加外源性IL-2来逆转。
这些数据表明，Ts在特异性识别MHC I类抗原后诱导异种反应性人Th细胞失能。因此，Ts可能会阻止针对异种移植的T细胞介导的免疫反应的激活。
