Reduction of CD18 Promotes Expansion of Inflammatory γδ T Cells Collaborating with CD4+ T Cells in Chronic Murine Psoriasiform Dermatitis
Reduction of CD18 Promotes Expansion of Inflammatory γδ T Cells Collaborating with CD4+ T Cells in Chronic Murine Psoriasiform Dermatitis
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DOI：
10.4049/jimmunol.1300976
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发表时间：
2013-12-01
影响因子：
4.4
通讯作者：
Scharffetter-Kochanek, Karin
中科院分区：
文献类型：
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作者：
Gatzka, Martina;Hainzl, Adelheid;Scharffetter-Kochanek, Karin
IL-17在银屑病和其他炎症性疾病的发病机制中起关键作用。在急性小鼠IL-23和咪喹莫特诱导的皮肤炎症中，γ-Delta T细胞是IL-17的重要来源，对人类牛皮癣的影响尚不清楚。利用多基因CD18(Subo)PL/J银屑病小鼠模型，通过CD18/β(2)整合素表达降低至野生型水平的2-16%而自发发展为慢性银屑病样皮炎小鼠模型，本研究观察了黏附分子表达对炎性γ-T细胞生成的影响，并分析了不同疾病阶段产生IL-17的gd和CD4(+)T细胞的发生情况。CD18(How O)PL/J银屑病样皮炎的严重程度与皮肤中V-Gamma 5(+)T细胞的丧失以及局部淋巴结中Vg4(+)T细胞增多的同时伴有IL-17(+)、IL-22(+)和TNF-α(+)γ-TCRlow细胞的皮肤浸润有关。在体外，CD18水平的降低促进了炎性记忆型gdT细胞对IL-7的反应。与IL-17或IL-23/p19的耗竭相似，注射CD18(Subo)PL/J小鼠的抗-Gamma Delta TCR单抗可显著减轻皮肤炎症，并在很大程度上消除病理性的Gamma Delta和CD4(+)T细胞。此外，CD18(低)gd T细胞比CD18(Wt)T细胞更有效地诱导同种异体的CD4(+)T细胞反应，并在过继转移时在易感宿主中触发银屑病样皮炎。这些结果表明，CD18水平降低在病理性GdT细胞的生成中具有新的作用，这一功能已被银屑病患者CD18(低)γ-增量T细胞的检测所证实，并可能对其他炎症性疾病具有一定的意义。
IL-17 is a critical factor in the pathogenesis of psoriasis and other inflammatory diseases. The impact of gamma delta T cells, accounting for an important source of IL-17 in acute murine IL-23- and imiquimod-induced skin inflammation, in human psoriasis is still unclear. Using the polygenic CD18(hypo) PL/J psoriasis mouse model spontaneously developing chronic psoriasiform dermatitis due to reduced CD18/beta(2) integrin expression to 2-16% of wild-type levels, we investigated in this study the influence of adhesion molecule expression on generation of inflammatory gamma delta T cells and analyzed the occurrence of IL-17-producing gd and CD4(+) T cells at different disease stages. Severity of CD18(hypo) PL/J psoriasiform dermatitis correlated with a loss of skin-resident V gamma 5(+) T cells and concurrent skin infiltration with IL-17(+), IL-22(+), and TNF-alpha(+) gamma delta TCRlow cells preceded by increases in Vg4(+) T cells in local lymph nodes. In vitro, reduced CD18 levels promoted expansion of inflammatory memory-type gd T cells in response to IL-7. Similar to IL-17 or IL-23/p19 depletion, injection of diseased CD18(hypo) PL/J mice with anti-gamma delta TCR Abs significantly reduced skin inflammation and largely eliminated pathological gamma delta and CD4(+) T cells. Moreover, CD18(hypo) gd T cells induced allogeneic CD4(+) T cell responses more potently than CD18(wt) counterparts and, upon adoptive transfer, triggered psoriasiform dermatitis in susceptible hosts. These results demonstrate a novel function of reduced CD18 levels in generation of pathological gd T cells that was confirmed by detection of increases in CD18(low) gamma delta T cells in psoriasis patients and may also have implications for other inflammatory diseases.