Bourgeois Elvire A, Subramaniam Sumithra, Cheng Tan-Yun, De Jong Annemieke, Layre Emilie, Ly Dalam, Salimi Maryam, Legaspi Annaliza, Modlin Robert L, Salio Mariolina, Cerundolo Vincenzo, Moody D Branch, Ogg Graham
Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02114.
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine and University of Oxford NIHR Biomedical Research Centre, Oxford, Oxfordshire OX3 9DS, England, UK MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine and University of Oxford NIHR Biomedical Research Centre, Oxford, Oxfordshire OX3 9DS, England, UK.
J Exp Med. 2015 Feb 9;212(2):149-63. doi: 10.1084/jem.20141505. Epub 2015 Jan 12.
Venoms frequently co-opt host immune responses, so study of their mode of action can provide insight into novel inflammatory pathways. Using bee and wasp venom responses as a model system, we investigated whether venoms contain CD1-presented antigens. Here, we show that venoms activate human T cells via CD1a proteins. Whereas CD1 proteins typically present lipids, chromatographic separation of venoms unexpectedly showed that stimulatory factors partition into protein-containing fractions. This finding was explained by demonstrating that bee venom-derived phospholipase A2 (PLA2) activates T cells through generation of small neoantigens, such as free fatty acids and lysophospholipids, from common phosphodiacylglycerides. Patient studies showed that injected PLA2 generates lysophospholipids within human skin in vivo, and polyclonal T cell responses are dependent on CD1a protein and PLA2. These findings support a previously unknown skin immune response based on T cell recognition of CD1a proteins and lipid neoantigen generated in vivo by phospholipases. The findings have implications for skin barrier sensing by T cells and mechanisms underlying phospholipase-dependent inflammatory skin disease.
毒液常常会利用宿主的免疫反应，因此对其作用方式的研究能够为新型炎症途径提供见解。我们以蜜蜂和黄蜂毒液反应作为模型系统，研究了毒液中是否含有由CD1呈递的抗原。在此，我们表明毒液可通过CD1a蛋白激活人类T细胞。虽然CD1蛋白通常呈递脂质，但对毒液进行色谱分离时意外发现，刺激因子会分配到含蛋白质的组分中。通过证明蜜蜂毒液来源的磷脂酶A2（PLA2）通过从常见的磷酸二酰甘油生成游离脂肪酸和溶血磷脂等小的新抗原从而激活T细胞，这一发现得到了解释。患者研究表明，注射的PLA2在人体皮肤内会在体内生成溶血磷脂，多克隆T细胞反应依赖于CD1a蛋白和PLA2。这些发现支持了一种基于T细胞对CD1a蛋白和磷脂酶在体内生成的脂质新抗原的识别而产生的此前未知的皮肤免疫反应。这些发现对T细胞的皮肤屏障感知以及磷脂酶依赖性炎症性皮肤病的潜在机制具有重要意义。
