Activation of Human Skin T Cells by Mammalian and Microbial Lipids Presented by CD1a

CD1a 呈递的哺乳动物和微生物脂质对人类皮肤 T 细胞的激活

基本信息

批准号：
8950769
负责人：
Annemieke de Jong
金额：
$ 11.51万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8950769
关键词：
Address Affect Affinity Antibodies Antigen-Presenting Cells Antigens Atopic Dermatitis Autoimmune Diseases Autoimmune Process Bacteria Binding Biological Markers Blood CD1 Antigens CD1a antigen CD1d antigen Cell Line Chemicals Clinical Research Complex Crystallography Disease Environment Epithelial Epithelium Fatty Acids Frequencies Galactosylceramides Goals Home environment Human Immune system Immunity Immunobiology Immunology Incubated Individual Infection Inflammation Institutes Intervention Investigation Knowledge Label Laboratories Langerhans cell Length Letters Ligands Lipid Binding Lipids Malignant Neoplasms Measurement Measures Mentors Methods Microbe Minor Nature Nonesterified Fatty Acids Pathogenesis Patients Peptide/MHC Complex Physiological Play Population Proteins Psoriasis Recombinant Proteins Recombinants Regulation Research Research Personnel Role Rosacea Sebum Skin Specificity Squalene Staining method Stains Stratum corneum Structure Surface Surface Plasmon Resonance Surveys System T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Time Translational Research Triglycerides Work analog autoreactive T cell base biophysical techniques cytokine follow-up fungus insight liquid chromatography mass spectrometry microbial microbiome novel preference public health relevance response skin disorder stereochemistry tool

项目摘要

DESCRIPTION (provided by applicant): A significant fraction of the human T cell repertoire does not recognize peptide-MHC complexes, but instead is activated by lipids complexed to CD1 antigen presenting molecules. CD1a, which is one of four surface-expressed lipid antigen presenting molecules in humans, is constitutively expressed at high levels on epidermal Langerhans cells. The localization of CD1ahigh Langerhans cells at the interface between skin immune system and skin microbiome, suggests an important role for the CD1a lipid antigen presenting system in skin immunity. This notion is further supported by our recent findings that CD1a-restricted T cells are common in blood and skin of healthy individuals, and that certain hydrophobic lipids present in human skin can act as antigens for these T cells. Among the lipid antigens we identified are free fatty acids, waxesters, triglycerides and squalene, all components of human sebum. This indicates a novel role for skin lipids beyond providing barrier function, namely as T cell antigens. Moreover, our skin is home to a large microbial population, which harbor close analogs of the mammalian lipids we identified as CD1a antigens, differing only in alkyl chain stereochemistry (cis/trans unsaturations) or fine structure (e.g. methyl branching, cyclopropanation). Prior studies have shown that minor structural changes in lipid chains can affect the strength of activation of CD1-restricted T cells, and we now plan to systemically address the following: 1) if CD1a-restricted TCRs bind with higher affinity to CD1a molecules loaded with microbial lipid structures than those loaded with mammalian analogs, using biophysical methods (Biacore), 2) determine the lipid binding preference of CD1a, by analyzing by LC/MS the eluted lipids from CD1a after co-incubation with defined mixtures of structurally related lipids, 3) determine the fine-specificity of skin-resident T cells using mammalian lipids and microbial analogs. Last, because affected skin in atopic dermatitis patients has been shown to display a shift in microbial flora as well as changes in lipid composition, we will determine if the frequency of CD1a-restricted T cells is increased in lesional compared to non-lesional skin of atopic dermatitis patients using CD1a tetramers. This research is in direct line with the applicant's goal of becoming an independent investigator in the field of skin immunobiology. The results of this proposal will provide valuable insights in the regulation of T cell activation by lipid antigens in the skin, and how shifts in lipid composition may affect T cell activation. This is highly relevant to the field of skin immunology, and opens the way to new lipid-based modes of intervention in skin diseases.

描述（由申请人提供）：人类 T 细胞库的很大一部分不识别肽-MHC 复合物，而是被与 CD1 抗原呈递分子复合的脂质激活，CD1a 是四种表面表达的脂质抗原呈递分子之一。 CD1ahigh 朗格汉斯细胞在人体的表皮朗格汉斯细胞上以高水平表达。CD1ahigh 朗格汉斯细胞位于皮肤免疫系统和皮肤微生物组之间的界面，表明 CD1a 脂质抗原呈递系统在皮肤免疫中发挥重要作用，我们最近的发现进一步支持了这一观点，即 CD1a 限制性 T 细胞在健康人的血液和皮肤中很常见，并且人类皮肤个体中存在的某些疏水性脂质可以。我们鉴定出的脂质抗原包括游离脂肪酸、蜡酯、甘油三酯和角鲨烯，它们都是人类皮脂的成分，这表明皮肤脂质除了提供屏障功能外还具有新的作用。此外，我们的皮肤是大量微生物群的家园，它们与我们鉴定为 CD1a 抗原的哺乳动物脂质密切类似，仅在烷基链立体化学（顺式/反式不饱和度）或精细结构（例如甲基支化、环丙烷化）方面有所不同。之前的研究表明，脂质链的微小结构变化会影响 CD1 限制性 T 细胞的激活强度，我们现在计划系统地解决以下问题： 1) 如果 CD1a 限制性 TCR 与负载微生物脂质结构的 CD1a 分子结合的亲和力高于负载哺乳动物类似物的 CD1a 分子，则使用生物物理方法 (Biacore)，2) 通过 LC/MS 分析，确定 CD1a 的脂质结合偏好。与结构相关脂质的确定混合物共孵育后从 CD1a 中洗脱脂质，3) 使用哺乳动物脂质确定皮肤驻留 T 细胞的精细特异性，最后，由于特应性皮炎患者受影响的皮肤已被证明表现出微生物菌群的变化以及脂质成分的变化，因此我们将确定与非病变相比，CD1a 限制性 T 细胞的频率是否增加。使用 CD1a 四聚体治疗特应性皮炎患者的病变皮肤这项研究与申请人成为独立研究者的目标直接一致。该提案的结果将为皮肤中脂质抗原调节 T 细胞活化以及脂质成分的变化如何影响 T 细胞活化提供有价值的见解，这与皮肤免疫学领域高度相关。，并为基于脂质的皮肤病干预新模式开辟了道路。