Yamazaki Sayuri, Iyoda Tomonori, Tarbell Kristin, Olson Kara, Velinzon Klara, Inaba Kayo, Steinman Ralph M
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, NY 10021, USA.
J Exp Med. 2003 Jul 21;198(2):235-47. doi: 10.1084/jem.20030422.
An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T cells that suppress other CD25- autoimmune disease-inducing T cells. The antigen-presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells remain to be identified, hampering their study in experimental and clinical situations. CD25+ CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can proliferate in the absence of added cytokines in culture and in vivo when stimulated by antigen-loaded dendritic cells (DCs), especially mature DCs. With high doses of DCs in culture, CD25+ CD4+ and CD25- CD4+ populations initially proliferate to a comparable extent. With current methods, one third of the antigen-reactive T cell receptor transgenic T cells enter into cycle for an average of three divisions in 3 d. The expansion of CD25+ CD4+ T cells stops by day 5, in the absence or presence of exogenous interleukin (IL)-2, whereas CD25- CD4+ T cells continue to grow. CD25+ CD4+ T cell growth requires DC-T cell contact and is partially dependent upon the production of small amounts of IL-2 by the T cells and B7 costimulation by the DCs. After antigen-specific expansion, the CD25+ CD4+ T cells retain their known surface features and actively suppress CD25- CD4+ T cell proliferation to splenic APCs. DCs also can expand CD25+ CD4+ T cells in the absence of specific antigen but in the presence of exogenous IL-2. In vivo, both steady state and mature antigen-processing DCs induce proliferation of adoptively transferred CD25+ CD4+ T cells. The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses.
胸腺来源的CD25⁺ CD4⁺ T细胞提供了一条重要的免疫耐受途径，这些细胞可抑制其他CD25⁻ 诱导自身免疫疾病的T细胞。控制CD25⁺ CD4⁺ 抑制性T细胞所需的抗原呈递细胞（APC）仍有待确定，这阻碍了它们在实验和临床情况下的研究。经典的CD25⁺ CD4⁺ T细胞处于无反应状态，无法因针对T细胞受体复合物的促有丝分裂抗体而增殖。我们现在发现，当受到负载抗原的树突状细胞（DC）刺激时，尤其是成熟DC，CD25⁺ CD4⁺ T细胞在培养物中以及体内无添加细胞因子的情况下能够增殖。在培养物中使用高剂量的DC时，CD25⁺ CD4⁺ 和CD25⁻ CD4⁺ 群体最初增殖程度相当。使用当前方法，三分之一的抗原反应性T细胞受体转基因T细胞进入细胞周期，在3天内平均分裂三次。在不存在或存在外源性白细胞介素（IL）-2的情况下，CD25⁺ CD4⁺ T细胞的扩增在第5天停止，而CD25⁻ CD4⁺ T细胞则继续生长。CD25⁺ CD4⁺ T细胞生长需要DC与T细胞接触，并且部分依赖于T细胞产生少量IL-2以及DC提供的B7共刺激。抗原特异性扩增后，CD25⁺ CD4⁺ T细胞保留其已知的表面特征，并积极抑制CD25⁻ CD4⁺ T细胞对脾APC的增殖。DC在无特异性抗原但存在外源性IL-2的情况下也能扩增CD25⁺ CD4⁺ T细胞。在体内，稳态和成熟的抗原处理DC均可诱导过继转移的CD25⁺ CD4⁺ T细胞增殖。扩增CD25⁺ CD4⁺ T细胞的能力为DC提供了一种调节自身免疫和其他免疫反应的额外机制。
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