Critical Role for TNF in the Induction of Human Antigen-Specific Regulatory T Cells by Tolerogenic Dendritic Cells
Critical Role for TNF in the Induction of Human Antigen-Specific Regulatory T Cells by Tolerogenic Dendritic Cells
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DOI：
10.4049/jimmunol.1000560
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发表时间：
2010-08-01
影响因子：
4.4
通讯作者：
Roep, Bart O.
中科院分区：
文献类型：
--
作者：
Kleijwegt, Fleur S.;Laban, Sandra;Roep, Bart O.
TNF是一种多效性细胞因子，对免疫细胞和疾病具有不同的作用。抗TNF治疗在类风湿性关节炎中被证明是有效的，但在其他自身免疫性疾病中被证明是无效的甚至是有害的。我们研究了TNF在致耐受性维生素D3调节的人树突状细胞（VD 3-DCs）诱导Ag特异性调节性T细胞（TCLs）中的作用，该细胞在LPS成熟后释放大量可溶性TNF（sTNF）。首先，在用LPS或CD 40 L成熟后，分析经调节的VD 3-DC的TNF产生，涉及分泌的（切割的）TNF（sTNF）和膜结合的（未切割的）形式的TNF（mTNF）的表达。接下来，测试TNF拮抗剂对通过经调节的DC诱导Ag特异性Tcl 3的作用以及这些Tcl 3的后续功能。VD 3-DC表达的mTNF量比对照DC（未处理的DC）更大，与成熟方案无关。在用VD 3-DCs致敏TcM的过程中，用抗TNF Ab抑制TNF（阻断sTNF和mTNF）阻止了TcM的产生及其对CD 4（+）T细胞增殖的抑制。相反，sTNF受体II（sTNFRII），主要是阻断sTNF，没有改变抑制能力的TGFAP。在Treg诱导期间通过抗CD 120 b Ab阻断TNFRII类似地消除了其随后的抑制功能。这些数据表明VD 3-DC上的mTNF在诱导Ag特异性T细胞活化中的特异性作用。mTNF和TNFRII之间的相互作用指导VD 3-DC诱导抑制性TcR。因此，抗TNF治疗可能在不同患者或疾病途径中产生不良作用。免疫学杂志，2010，185：1412-1418。
TNF is a pleiotropic cytokine with differential effects on immune cells and diseases. Anti-TNF therapy was shown to be effective in rheumatoid arthritis but proved inefficient or even detrimental in other autoimmune diseases. We studied the role of TNF in the induction of Ag-specific regulatory T cells (Tregs) by tolerogenic vitamin D3-modulated human dendritic cells (VD3-DCs), which previously were shown to release high amounts of soluble TNF (sTNF) upon maturation with LPS. First, production of TNF by modulated VD3-DCs was analyzed upon maturation with LPS or CD40L with respect to both secreted (cleaved) TNF (sTNF) and expression of the membrane-bound (uncleaved) form of TNF (mTNF). Next, TNF antagonists were tested for their effect on induction of Ag-specific Tregs by modulated DCs and the subsequent functionality of these Tregs. VD3-DCs expressed greater amounts of mTNF than did control DCs (nontreated DCs), independent of the maturation protocol. Inhibition of TNF with anti-TNF Ab (blocking both sTNF and mTNF) during the priming of Tregs with VD3-DCs prevented generation of Tregs and their suppression of proliferation of CD4(+) T cells. In contrast, sTNF receptor II (sTNFRII), mainly blocking sTNF, did not change the suppressive capacity of Tregs. Blocking of TNFRII by anti-CD120b Ab during Treg induction similarly abrogated their subsequent suppressive function. These data point to a specific role for mTNF on VD3-DCs in the induction of Ag-specific Tregs. Interaction between mTNF and TNFRII instructs the induction of suppressive Tregs by VD3-DCs. Anti-TNF therapy may therefore act adversely in different patients or disease pathways. The Journal of Immunology, 2010, 185: 1412-1418.