Kawano Mitsuko, Nakayama Masafumi, Aoshima Yusuke, Nakamura Kyohei, Ono Mizuho, Nishiya Tadashi, Nakamura Syou, Takeda Yuri, Dobashi Akira, Takahashi Akiko, Endo Misato, Ito Akiyo, Ueda Kyosuke, Sato Naoki, Higuchi Shigehito, Kondo Takeru, Hashimoto Suguru, Watanabe Masamichi, Watanabe Makoto, Takahashi Tetsu, Sasaki Keiichi, Nakamura Masanori, Sasazuki Takehiko, Narushima Takayuki, Suzuki Ryuji, Ogasawara Kouetsu
Department of Immunobiology, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.
Department of Immunobiology, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan ; Department of Materials Processing, Graduate School of Engineering, Tohoku University, Aramakiaza, Aoba-ku, Sendai, Miyagi, Japan.
PLoS One. 2014 Feb 12;9(2):e86810. doi: 10.1371/journal.pone.0086810. eCollection 2014.
Nickel, cobalt, and chromium are well known to be causal agents of allergic contact dermatitis. Palladium (Pd) can also cause allergic disease and exposure results from wide use of this metal in dental restorations and jewelry. Metal allergy is categorized as a delayed-type hypersensitivity, and metal-responsive T cell clones have been isolated from allergic patients. However, compared to nickel, little is known about the pathology of allergic disease mediated by Pd, and pathogenic T cells are poorly understood. To identify the pathogenic T cells that are responsible for onset of Pd allergy, we enriched metal-responsive lymphocytes by sequential adoptive transfer of involved lymph node cells. Here we show that sequential adoptive transfer gradually increased the incidence and the intensity of Pd allergy, and CD8⁺ T cells are responsible for the disease as CD8⁺ T cell-depleted mice and β2-microglobulin-deficient mice did not develop Pd allergy. In addition, we found that draining lymph node cells skewed toward CD8⁺ T cells in response to Pd challenge in 8th adoptive transferred recipient mice. The CD8⁺ T cells expressed NKG2D, a costimulatory molecule involved in the production of IFN-γ. NKG2D ligand was also induced in Pd-injected tissues. Furthermore, both NKG2D ligand-transgenic mice, where NKG2D is downmodulated, and IFN-γ-deficient mice showed impaired Pd allergy. Taken together, these results indicate that IFN-γ-producing NKG2D⁺ CD8⁺ T cells are responsible for Pd allergy and suggest that NKG2D is a potential therapeutic target for treatment of metal allergy.
众所周知，镍、钴和铬是过敏性接触性皮炎的致病因素。钯（Pd）也可引发过敏性疾病，其接触源于该金属在牙科修复体和珠宝中的广泛使用。金属过敏被归类为迟发型超敏反应，并且已从过敏患者中分离出金属反应性T细胞克隆。然而，与镍相比，人们对由钯介导的过敏性疾病的病理学知之甚少，对致病T细胞也了解不足。为了鉴定导致钯过敏发病的致病T细胞，我们通过连续过继转移受累淋巴结细胞来富集金属反应性淋巴细胞。在此我们表明，连续过继转移逐渐增加了钯过敏的发生率和强度，并且CD8⁺T细胞是该疾病的病因，因为CD8⁺T细胞耗竭的小鼠和β2-微球蛋白缺陷小鼠未发生钯过敏。此外，我们发现，在第8次过继转移的受体小鼠中，引流淋巴结细胞在受到钯攻击后偏向CD8⁺T细胞。CD8⁺T细胞表达NKG2D，这是一种参与干扰素-γ产生的共刺激分子。在注射钯的组织中也诱导了NKG2D配体。此外，NKG2D下调的NKG2D配体转基因小鼠和干扰素-γ缺陷小鼠的钯过敏均受损。综上所述，这些结果表明产生干扰素-γ的NKG2D⁺CD8⁺T细胞是钯过敏的病因，并提示NKG2D是治疗金属过敏的潜在治疗靶点。
