Dendritic cell expression of ADAM23 governs T cell proliferation and cytokine production through the α(v)β(3) integrin receptor
Dendritic cell expression of ADAM23 governs T cell proliferation and cytokine production through the α(v)β(3) integrin receptor
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DOI：
10.1189/jlb.2hi1115-525r
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发表时间：
2016-11-01
影响因子：
5.5
通讯作者：
Lipscomb, M. W.
中科院分区：
文献类型：
--
作者：
Elizondo, D. M.;Andargie, T. E.;Lipscomb, M. W.
ADAM23是脑巨噬细胞来源的趋化因子家族的一员。ADAM蛋白的结构同源性表明它们具有整合素受体的功能。先前的研究已经将ADAM23与大脑发育和癌症转移联系起来。目前的研究表明，dc上ADAM23的表达部分地控制了应答CD4(+) T细胞的抗原呈递能力。使用RNAi方法，在小鼠bmdc中敲低ADAM23导致T细胞活化、增殖和细胞因子产生受损。敲低不改变dc的成熟特征（即共刺激分子表达或促炎细胞因子的产生），但明显损害同源T细胞反应。抗原特异性克隆扩增显著减少，Th细胞因子的产生也随之减少。与对照dc相比，ADAM23敲低诱导的CD4(+) T细胞中IL-2、ifn - γ、IL-4和IL-17细胞因子的总水平显著降低，而早期激活和增殖受损并未改变/扭曲Th极化的平衡。最后，针对α (v) β(3)整合素受体的中和抗体导致CD4(+) T细胞反应受损的相似表型。综上所述，这些研究表明ADAM23在控制DC抗原呈递到同源CD4(+) T细胞中的新作用。
ADAM23 is a member of the brain macrophage-derived chemokine family. Structural homology of ADAM proteins suggests their function as integrin receptors. Previous studies have linked ADAM23 as a dominant contributor to brain development and cancer metastasis. The present studies now show that ADAM23 expression on DCs partially governs antigen-presentation capacities to responder CD4(+) T cells. With the use of RNAi approaches, knockdown of ADAM23 in murine BMDCs resulted in impaired T cell activation, proliferation, and cytokine production. Knockdown did not alter the maturation profile of DCs (i.e., costimulatory molecule expression or production of proinflammatory cytokines) but markedly impaired cognate T cell responses. There was a significant decrease in antigen-specific clonal expansion coupled with a global decrease in Th cytokine production. Impaired early activation and proliferation did not alter/skew the balance of Th polarization but significantly depressed total levels of IL-2, IFN-gamma, IL-4, and IL-17 cytokine production in CD4(+) T cells primed by ADAM23 knockdown versus control DCs. Finally, neutralizing antibodies targeting the alpha(v)beta(3) integrin receptors resulted in similar phenotypes of impaired CD4(+) T cell responses. Taken together, these studies show a novel role of ADAM23 in governing DC antigen presentation to cognate CD4(+) T cells.