Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes
Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes
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DOI：
10.4049/jimmunol.1600802
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发表时间：
2017-03-15
影响因子：
4.4
通讯作者：
DeBenedette, Mark A.
中科院分区：
文献类型：
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作者：
Horvatinovich, Joe M.;Grogan, Elizabeth W.;DeBenedette, Mark A.
在apc、B细胞和T细胞上表达的跨膜蛋白CD83可以通过选择性剪接变异体和/或脱落以可溶性形式表达。可溶性CD83 （sCD83）被证明参与负性调节免疫反应。sCD83在体外抑制T细胞增殖，支持同种异体移植在体内的存活，防止角膜移植排斥反应，并减轻自身免疫性疾病和实验性结肠炎的进展和严重程度。虽然sCD83与人类PBMCs结合，但结合sCD83的特定分子尚未确定。在本文中，我们确定髓样分化因子-2 (MD-2)， TLR4/MD-2受体复合物中的辅助受体，作为高亲和力的sCD83结合伙伴。TLR4/MD-2介导细菌lps识别后的促炎信号传递。然而，改变TLR4信号可以减弱促炎级联反应，导致LPS耐受。我们的数据显示，sCD83与MD-2的结合通过快速降解il - 1r相关的激酶-1来改变这一信号级联，导致以cox -2依赖的方式诱导抗炎介质IDO、IL-10和PGE(2)。sCD83抑制T细胞增殖，阻断IL-2分泌，使T细胞对IL-2介导的进一步下游分化信号无反应。因此，我们提出sCD83的耐受性作用机制依赖于与apc的初始相互作用，改变早期细胞因子信号通路并导致T细胞无反应性。
The transmembrane protein CD83, expressed on APCs, B cells, and T cells, can be expressed as a soluble form generated by alternative splice variants and/or by shedding. Soluble CD83 (sCD83) was shown to be involved in negatively regulating the immune response. sCD83 inhibits T cell proliferation in vitro, supports allograft survival in vivo, prevents corneal transplant rejection, and attenuates the progression and severity of autoimmune diseases and experimental colitis. Although sCD83 binds to human PBMCs, the specific molecules that bind sCD83 have not been identified. In this article, we identify myeloid differentiation factor-2 (MD-2), the coreceptor within the TLR4/MD-2 receptor complex, as the high-affinity sCD83 binding partner. TLR4/MD-2 mediates proinflammatory signal delivery following recognition of bacterial LPSs. However, altering TLR4 signaling can attenuate the proinflammatory cascade, leading to LPS tolerance. Our data show that binding of sCD83 to MD-2 alters this signaling cascade by rapidly degrading IL-1R-associated kinase-1, leading to induction of the anti-inflammatory mediators IDO, IL-10, and PGE(2) in a COX-2-dependent manner. sCD83 inhibited T cell proliferation, blocked IL-2 secretion, and rendered T cells unresponsive to further downstream differentiation signals mediated by IL-2. Therefore, we propose the tolerogenic mechanism of action of sCD83 to be dependent on initial interaction with APCs, altering early cytokine signal pathways and leading to T cell unresponsiveness.