Leslie David S, Dascher Christopher C, Cembrola Katherine, Townes Maria A, Hava David L, Hugendubler Lynne C, Mueller Elisabetta, Fox Lisa, Roura-Mir Carme, Moody D Branch, Vincent Michael S, Gumperz Jenny E, Illarionov Petr A, Besra Gurdyal S, Reynolds Carol G, Brenner Michael B
Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
Immunology. 2008 Nov;125(3):289-301. doi: 10.1111/j.1365-2567.2008.02842.x. Epub 2008 Apr 28.
Dendritic cells (DCs) are highly potent antigen-presenting cells (APCs) and play a vital role in stimulating naïve T cells. Treatment of human blood monocytes with the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 stimulates them to develop into immature dendritic cells (iDCs) in vitro. DCs generated by this pathway have a high capacity to prime and activate resting T cells and prominently express CD1 antigen-presenting molecules on the cell surface. The presence of human serum during the differentiation of iDCs from monocytes inhibits the expression of CD1a, CD1b and CD1c, but not CD1d. Correspondingly, T cells that are restricted by CD1c showed poor responses to DCs that were generated in the presence of human serum, while the responses of CD1d-restricted T cells were enhanced. We chemically fractionated human serum to isolate the bioactive factors that modulate surface expression of CD1 proteins during monocyte to DC differentiation. The human serum components that affected CD1 expression partitioned with polar organic soluble fractions. Lysophosphatidic acid and cardiolipin were identified as lipids present in normal human serum that potently modulate CD1 expression. Control of CD1 expression was mediated at the level of gene transcription and correlated with activation of the peroxisome proliferator-activated receptor (PPAR) nuclear hormone receptors. These findings indicate that the ability of human DCs to present lipid antigens to T cells through expression of CD1 molecules is sensitively regulated by lysophosphatidic acid and cardiolipin in serum, which are ligands that can activate PPAR transcription factors.
树突状细胞（DCs）是高效的抗原呈递细胞（APCs），在刺激初始T细胞方面发挥着至关重要的作用。用人粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白细胞介素（IL）-4细胞因子处理人血单核细胞，可刺激它们在体外发育成未成熟树突状细胞（iDCs）。通过该途径产生的DCs具有高效启动和激活静息T细胞的能力，并在细胞表面显著表达CD1抗原呈递分子。在从单核细胞分化iDCs的过程中，人血清的存在会抑制CD1a、CD1b和CD1c的表达，但不影响CD1d的表达。相应地，受CD1c限制的T细胞对在人血清存在下产生的DCs反应较差，而受CD1d限制的T细胞的反应则增强。我们对人血清进行化学分级分离，以分离出在单核细胞向DC分化过程中调节CD1蛋白表面表达的生物活性因子。影响CD1表达的人血清成分与极性有机可溶级分一起分离。溶血磷脂酸和心磷脂被鉴定为正常人血清中存在的能有效调节CD1表达的脂质。CD1表达的调控是在基因转录水平介导的，并且与过氧化物酶体增殖物激活受体（PPAR）核激素受体的激活相关。这些发现表明，人DCs通过CD1分子表达向T细胞呈递脂质抗原的能力受到血清中溶血磷脂酸和心磷脂的敏感调节，它们是能够激活PPAR转录因子的配体。
