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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：
9770555
负责人：
Annemieke de Jong
金额：
$ 8.04万
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 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9770555
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 Clone Cells Complex Disease Environment Epithelial Epithelium Fatty Acids Follow-Up Studies Frequencies Goals Home environment Human Hydrophobicity Immune system Immunity Immunobiology Immunology Incubated Individual Infection Inflammation Institutes Intervention Investigation Knowledge Label Laboratories Langerhans cell Length Lesion Letters Ligands Lipid Binding Lipids Malignant Neoplasms Mammalian Cell Measurement Measures Mentors Methods Microbe Minor Molecular Conformation Nature Nonesterified Fatty Acids Pathogenesis Patients Peptide/MHC Complex Physiological Play Population Proteins Psoriasis Recombinants Regulation Research Research Personnel Role Rosacea Sebum Skin Specificity Squalene Stains Stratum corneum Structure Surface Surface Plasmon Resonance Surveys System T cell regulation T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Time Translational Research Triglycerides Work X-Ray Crystallography alpha-galactosylceramide analog autoreactive T cell base biophysical techniques cytokine fungus human disease insight liquid chromatography mass spectrometry microbial microbiota novel novel therapeutics preference public health relevance receptor binding response skin disorder skin microbiome 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)：相当大一部分人类T细胞谱系不识别多肽-MHC复合体，而是被与CD1抗原递呈分子络合的脂类激活。CD1a是人类表面表达的四种脂类抗原递呈分子之一，在表皮朗格汉斯细胞上高水平结构性表达。CD1a高表达的朗格汉斯细胞定位于皮肤免疫系统与皮肤微生物组的交界处，提示CD1a脂类抗原提呈系统在皮肤免疫中的重要作用。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，而且人体皮肤中存在的某些疏水脂质可以作为这些T细胞的抗原。在我们确定的脂肪抗原中有游离脂肪酸、蜡酯、甘油三酯和角鲨烯，这些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，还有一个新的作用，即作为T细胞抗原。此外，我们的皮肤是大量微生物的家园，这些微生物与我们确认为CD1a抗原的哺乳动物脂类非常相似，只是在烷链立体化学(顺式/反式不饱和)或精细结构(例如甲基支化、环丙化)上有所不同。先前的研究表明，脂链上微小的结构变化可以影响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与负载微生物脂结构的CD1a分子结合比负载哺乳动物类似物的CD1a分子具有更高的亲和力，那么使用生物物理方法(Biaccore)，2)通过LC/MS分析CD1a与特定的结构相关脂的混合物共同孵育后CD1a的洗脱脂类，确定CD1a的脂结合偏好，3)使用哺乳动物脂类和微生物类似物来确定皮肤驻留T细胞的精细特异性。最后，由于特应性皮炎患者的受影响皮肤已经显示出微生物菌群的变化和脂质成分的变化，我们将确定使用CD1a四聚体的特应性皮炎患者皮损中CD1a限制性T细胞的频率是否高于非皮损皮肤。这项研究与申请者成为一名独立调查员的目标直接一致皮肤免疫生物学领域。这一建议的结果将为皮肤中脂类抗原调节T细胞活化以及脂类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，并为以脂质为基础的皮肤病干预新模式开辟了道路。