Functional islet-specific Treg can be generated from CD4+CD25- T cells of healthy and type 1 diabetic subjects
Functional islet-specific Treg can be generated from CD4+CD25- T cells of healthy and type 1 diabetic subjects
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DOI：
10.1002/eji.200838819
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发表时间：
2009-02-01
影响因子：
5.4
通讯作者：
Buckner, Jane H.
中科院分区：
文献类型：
--
作者：
Long, S. Alice;Walker, Mindi R.;Buckner, Jane H.
CD4(+)CD25(+)FOXP3(+) Treg细胞需要TCR参与抑制功能，从而确保仅在特定抗原存在时才发生抑制；然而，到目前为止，还没有研究涉及人类自身抗原特异性Treg的功能。这些研究旨在确定1型糖尿病（T1D）患者胰岛抗原特异性适应性Treg的外周生成和功能是否存在缺陷。通过谷氨酸脱羧酶和胰岛特异性葡萄糖-6-磷酸催化亚基相关蛋白肽在t1d相关HLA-DR β等位基因背景下激活CD4(+) FOXP3(-) T细胞，体外诱导胰岛抗原特异性适应性Treg。采用流式细胞术检测FOXP3和II类四聚体的抗原特异性Treg，并评估其抑制增殖的能力。然后将这些适应性Treg与来自同一研究人群的流感特异性Treg进行比较。表达FOXP3的四聚体（+）细胞对来自对照和T1D受试者的流感和胰岛抗原的功能相似。事实上，抑制的效力与FOXP3的表达有关，而不是抗原特异性。因此，这些数据表明，功能适应性Treg的发育可以在胰岛抗原的反应中发生，激活胰岛特异性Treg可能被用作T1D的靶向免疫治疗。
CD4(+)CD25(+)FOXP3(+) Treg cells require TCR engagement for suppressive function, thus ensuring that suppression occurs only in the presence of specific antigens; however, to date no studies have addressed the function of self-antigen-specific Treg in humans. These studies were designed to determine whether peripheral generation and function of islet antigen-specific adaptive Treg are defective in human subjects with type 1 diabetes (T1D). Islet antigen-specific adaptive Treg were induced in vitro by activation of CD4(+) FOXP3(-) T cells with glutamic acid decarboxylase and islet-specific glucose-6-phosphate catalytic subunit-related protein peptides in the context of T1D-associated HLA-DR beta alleles. Antigen-specific Treg were characterized using flow cytometry for FOXP3 and class II tetramer and assessed for the ability to inhibit proliferation. These adaptive Treg were then compared with influenza-specific Treg from the same study population. The function of tetramer(+) cells that expressed FOXP3 was similar for both influenza and islet antigens generated from control and T1D subjects. in fact, the potency of suppression correlated with FOXP3 expression, not antigen specificity. Thus, these data suggest that development of functional adaptive Treg can occur in response to islet antigens and activation of islet-specific Treg may potentially be used as a targeted immunotherapy in T1D.