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

• 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
• 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

 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（由适用提供）：人类T细胞库的很大一部分不能识别肽-MHC复合物，而是被复合到CD1抗原呈现分子的脂质激活。 CD1a是人类中表达的四个表面表达的脂质抗原分子之一，在表皮langerhans细胞上始终以高水平表达。 CD1AHIGH LANGERHANS细胞在皮肤免疫系统和皮肤微生物组之间的界面上的定位表明，CD1A脂质抗原呈递系统在皮肤免疫史地中的重要作用。我们最近的发现进一步支持了这一观念，即CD1A限制的T细胞在健康个体的血液和皮肤中很常见，并且人皮肤中存在的某些疏水性脂质可以作为这些T细胞的抗原。在我们确定的脂质抗原中，有游离脂肪酸，蜡剂，甘油三酸酯和小矛烯，都是人皮脂的所有成分。这表明除了提供屏障功能的皮肤脂质的新作用，即作为T细胞抗原。此外，我们的皮肤是大量微生物种群的所在地，我们识别为CD1A抗原的哺乳动物脂质的类似物，仅在烷基链立体化学（CIS/Trans Insrysations）或精细结构（例如甲基分支，环形植物）中有所不同。先前的研究表明，脂质链中的较小结构变化会影响CD1限制的T细胞激活的强度，现在我们计划从系统上解决以下方面的问题：1）如果CD1A限制的TCR与使用乳腺类类似物的baciepriany-lip-2）（Biacsical Modect op foperigant）（BIAC）（biackorsical Modect）（biackiors of）（biackiors of）（biack）（biack）（biack）（biace）（biack）（biack）（biack）（biack）（biack）（biack）（biack）（biack）（biack）（biack）（biack），则与较高的CD1A分子结合（通过通过LC/MS分析CD1A，与结构相关的脂质的定义混合物共结合后，从CD1A中洗脱的脂质，3）确定使用哺乳动物脂质和微生物类似物的皮肤居民T细胞的精细特异性。最后，由于已显示出特应性皮炎患者的皮肤会显示出微生物菌群的变化以及脂质组成的变化，因此我们将确定使用CD1A四聚体的非特应性皮肤炎患者的非特应性皮肤炎患者的非经济性皮肤比较中CD1A限制的T细胞的频率。这项研究与申请人成为成为独立研究者的目标是直接的 该提案的结果将在皮肤中脂质抗原调节T细胞激活T细胞激活以及脂质组成中的变化可能影响T细胞激活时提供有价值的见解。这与皮肤免疫学领域高度相关，并通向新的基于脂质的皮肤疾病的方式。