Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells
Immunotherapeutic targeting of LIGHT/LTβR/HVEM pathway fully recapitulates the reduced cytotoxic phenotype of LIGHT-deficient T cells
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DOI：
10.1080/19420862.2015.1132130
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发表时间：
2016-04-02
期刊：
影响因子：
5.3
通讯作者：
Rodriguez-Barbosa, Jose-Ignacio
中科院分区：
文献类型：
--
作者：
del Rio, Maria-Luisa;Fernandez-Renedo, Carlos;Rodriguez-Barbosa, Jose-Ignacio
肿瘤坏死因子(TNF)/肿瘤坏死因子受体(TNFR)超家族成员在免疫应答的不同阶段发挥重要作用。小鼠LIGH(TNFSF14)是一种具有C末端胞外肿瘤坏死因子同源结构域(THD)的II型跨膜蛋白，它以同源三聚体的形式组装，通过两种受体，即疱疹病毒进入介体(HVEM，TNFSFR14)和淋巴毒素β受体(LT beta R，TNFSFR3)，调节免疫反应的进程。LIGHT是一种膜结合蛋白，在活化的T细胞、自然杀伤(NK)细胞和未成熟的树突状细胞上瞬时表达，可被金属蛋白酶降解并释放到细胞外环境。体内评价光阻滞剂的免疫治疗潜力。给予光与其受体相互作用的拮抗剂可以减弱移植物抗宿主反应的进程，并概括了过继转移到非照射半异基因受者体内的光缺乏T细胞的细胞毒活性降低的情况。供者T细胞缺乏光表达或阻断与其受体的光相互作用会减缓T细胞的增殖速度，降低前体同种异体反应性T细胞的频率，从而延缓T细胞向效应T细胞的分化。LIGH/LTβR/HVEM途径的阻断与IL-7Rα的延迟下调和供者同种异体反应性CD8 T细胞上可诱导的共刺激分子表达的延迟上调有关，这是T细胞分化受损的典型特征。这些结果揭示了LIGH/LTβR/HVEM相互作用对同种异体反应性CD8T细胞介导的同种异体免疫反应的潜在治疗控制作用，这有助于延长同种异体移植物的存活。
Tumor necrosis factor (TNF)/TNF receptor (TNFR) superfamily members play essential roles in the development of the different phases of the immune response. Mouse LIGHT (TNFSF14) is a type II transmembrane protein with a C-terminus extracellular TNF homology domain (THD) that assembles in homotrimers and regulates the course of the immune responses by signaling through 2 receptors, the herpes virus entry mediator (HVEM, TNFSFR14) and the lymphotoxin beta receptor (LT beta R, TNFSFR3). LIGHT is a membrane-bound protein transiently expressed on activated T cells, natural killer (NK) cells and immature dendritic cells that can be proteolytically cleaved by a metalloprotease and released to the extracellular milieu. The immunotherapeutic potential of LIGHT blockade was evaluated in vivo. Administration of an antagonist of LIGHT interaction with its receptors attenuated the course of graft-versus-host reaction and recapitulated the reduced cytotoxic activity of LIGHT-deficient T cells adoptively transferred into non-irradiated semiallogeneic recipients. The lack of LIGHT expression on donor T cells or blockade of LIGHT interaction with its receptors slowed down the rate of T cell proliferation and decreased the frequency of precursor alloreactive T cells, retarding T cell differentiation toward effector T cells. The blockade of LIGHT/LT beta R/HVEM pathway was associated with delayed downregulation of interleukin-7R alpha and delayed upregulation of inducible costimulatory molecule expression on donor alloreactive CD8 T cells that are typical features of impaired T cell differentiation. These results expose the relevance of LIGHT/LT beta R/HVEM interaction for the potential therapeutic control of the allogeneic immune responses mediated by alloreactive CD8 T cells that can contribute to prolong allograft survival.