Do Natural T Regulatory Cells become Activated to Antigen Specific T Regulatory Cells in Transplantation and in Autoimmunity?
Do Natural T Regulatory Cells become Activated to Antigen Specific T Regulatory Cells in Transplantation and in Autoimmunity?
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DOI：
10.3389/fimmu.2013.00208
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发表时间：
2013
影响因子：
7.3
通讯作者：
Hodgkinson SJ
中科院分区：
文献类型：
--
作者：
Hall BM;Tran GT;Verma ND;Plain KM;Robinson CM;Nomura M;Hodgkinson SJ
抗原特异性 T 调节细胞 (Treg) 通常是 CD4+CD25+FoxP3+ T 细胞，其表型与天然 Treg (nTreg) 相似。据推测，随着与IL-2的重复培养，nTreg不能发育成抗原特异性Treg，并且特异性抗原不会增加nTreg在体外促进免疫耐受或抑制的能力或效力。这导致了一种假设，即抗原特异性 Treg 主要由 CD4+CD25−FoxP3− T 细胞在不存在炎症细胞因子（例如 IL-6 和 IL-1β）的情况下通过抗原和 TGF-β 激活而形成。我们对来自对同种异体移植物具有耐受性的动物的抗原特异性 CD4+CD25+ T 细胞进行的研究发现，抗原特异性 Treg 细胞正在分裂，并且需要用特异性抗原 T 细胞衍生的细胞因子进行持续刺激。我们发现多种细胞因子，特别是 IL-5 和 IFN-γ，但不促进抗原特异性 CD4+CD25+FoxP3+ Treg 的存活，但不包括 IL-2 或 IL-4。为了检查 nTreg 是否可以被激活为抗原特异性 Treg，我们用 IL-2 或 IL-4 激活培养物中的 nTreg。 3 天内，抗原特异性 Treg 被激活，并且这些细胞上会诱导新的细胞因子受体。具体而言，由 IL-2 和抗原激活的 nTreg 表达干扰素 γ 受体 (IFNGR) 和 IL-12p70 (IL-12Rβ2) 受体，但不表达 IL-5 受体 (IL-5Rα)。这些细胞对 IFN-γ 或 IL-12p70 有反应。被 IL-4 和同种抗原激活的 nTreg 表达 IL-5Rα，而不是 IFNGR 或 IL-12p70Rβ2，并对 IL-5 产生反应。这些早期激活的抗原特异性 Treg 细胞分别被命名为 Ts1 和 Ts2 细胞，因为它们依赖于 Th1 或 Th2 反应。用 IL-12p70 进一步培养 Ts1 细胞诱导 Th1 样 Treg，表达 IFN-γ、T-bet 以及 FoxP3。我们的研究表明，Th1 或 Th2 反应激活 nTreg 会诱导抗原特异性 Treg 的不同谱系，这些谱系依赖于晚期 Th1 和 Th2 细胞因子，而不是早期细胞因子 IL-2 和 IL-4。
Antigen specific T regulatory cells (Treg) are often CD4+CD25+FoxP3+ T cells, with a phenotype similar to natural Treg (nTreg). It is assumed that nTreg cannot develop into an antigen specific Treg as repeated culture with IL-2 and a specific antigen does not increase the capacity or potency of nTreg to promote immune tolerance or suppress in vitro. This has led to an assumption that antigen specific Treg mainly develop from CD4+CD25−FoxP3− T cells, by activation with antigen and TGF-β in the absence of inflammatory cytokines such as IL-6 and IL-1β. Our studies on antigen specific CD4+CD25+ T cells from animals with tolerance to an allograft, identified that the antigen specific and Treg are dividing, and need continuous stimulation with specific antigen T cell derived cytokines. We identified that a variety of cytokines, especially IL-5 and IFN-γ but not IL-2 or IL-4 promoted survival of antigen specific CD4+CD25+FoxP3+ Treg. To examine if nTreg could be activated to antigen specific Treg, we activated nTreg in culture with either IL-2 or IL-4. Within 3 days, antigen specific Treg are activated and there is induction of new cytokine receptors on these cells. Specifically nTreg activated by IL-2 and antigen express the interferon-γ receptor (IFNGR) and IL-12p70 (IL-12Rβ2) receptor but not the IL-5 receptor (IL-5Rα). These cells were responsive to IFN-γ or IL-12p70. nTreg activated by IL-4 and alloantigen express IL-5Rα not IFNGR or IL-12p70Rβ2 and become responsive to IL-5. These early activated antigen specific Treg, were respectively named Ts1 and Ts2 cells, as they depend on Th1 or Th2 responses. Further culture of Ts1 cells with IL-12p70 induced Th1-like Treg, expressing IFN-γ, and T-bet as well as FoxP3. Our studies suggest that activation of nTreg with Th1 or Th2 responses induced separate lineages of antigen specific Treg, that are dependent on late Th1 and Th2 cytokines, not the early cytokines IL-2 and IL-4.