Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Exp Med. 2011 Aug 29;208(9):1741-7. doi: 10.1084/jem.20110665. Epub 2011 Aug 1.
Microbial lipids activate T cells by binding directly to CD1 and T cell receptors (TCRs) or by indirect effects on antigen-presenting cells involving induction of lipid autoantigens, CD1 transcription, or cytokine release. To distinguish among direct and indirect mechanisms, we developed fluorescent human CD1b tetramers and measured T cell staining. CD1b tetramer staining of T cells requires glucose monomycolate (GMM) antigens, is specific for TCR structure, and is blocked by a recombinant clonotypic TCR comprised of TRAV17 and TRBV4-1, proving that CD1b-glycolipid complexes bind the TCR. GMM-loaded tetramers brightly stain a small subpopulation of blood-derived cells from humans infected with Mycobacterium tuberculosis, providing direct detection of a CD1b-reactive T cell repertoire. Polyclonal T cells from patients sorted with tetramers are activated by GMM antigens presented by CD1b. Whereas prior studies emphasized CD8(+) and CD4(-)CD8(-) CD1b-restricted clones, CD1b tetramer-based studies show that nearly all cells express the CD4 co-receptor. These findings prove a cognate mechanism whereby CD1b-glycolipid complexes bind to TCRs. CD1b tetramers detect a natural CD1b-restricted T cell repertoire ex vivo with unexpected features, opening a new investigative path to study the human CD1 system.
微生物脂质通过直接与 CD1 和 T 细胞受体 (TCR) 结合，或通过涉及诱导脂质自身抗原、CD1 转录或细胞因子释放的抗原呈递细胞的间接作用来激活 T 细胞。为了区分直接和间接机制，我们开发了荧光人源 CD1b 四聚体并测量了 T 细胞染色。CD1b 四聚体染色 T 细胞需要葡萄糖单酰基甘油 (GMM) 抗原，特异性针对 TCR 结构，并被由 TRAV17 和 TRBV4-1 组成的重组克隆型 TCR 阻断，证明 CD1b-糖脂复合物结合 TCR。负载 GMM 的四聚体可强烈染色来自感染结核分枝杆菌的人类血液衍生细胞的一小部分亚群，提供了对 CD1b 反应性 T 细胞库的直接检测。用四聚体分选的患者的多克隆 T 细胞被 CD1b 呈递的 GMM 抗原激活。虽然先前的研究强调了 CD8(+)和 CD4(-)CD8(-) CD1b 限制性克隆，但基于 CD1b 四聚体的研究表明，几乎所有细胞都表达 CD4 共受体。这些发现证明了一种同源机制，即 CD1b-糖脂复合物与 TCR 结合。CD1b 四聚体以意想不到的特征检测天然 CD1b 限制性 T 细胞库，为研究人类 CD1 系统开辟了新的研究途径。
