Parween Farhat, Singh Satya P, Kathuria Nausheen, Zhang Hongwei H, Ashida Shinji, Otaizo-Carrasquero Francisco A, Shamsaddini Amirhossein, Gardina Paul J, Ganesan Sundar, Kabat Juraj, Lorenzi Hernan A, Riley Deanna J, Myers Timothy G, Pittaluga Stefania, Bielekova Bibiana, Farber Joshua M
Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Neuroimmunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Nat Commun. 2025 Feb 26;16(1):1978. doi: 10.1038/s41467-025-57002-6.
Human Th17/type 17 cells express the chemokine receptor CCR6, but the functions of CCR6 and other chemokine receptors in human type 17 Th cell extravasation have not been fully delineated. Here we show that human peripheral blood CD4CCR6 T cells co-expressing CCR2 have a pathogenic Th17 signature, can produce inflammatory cytokines without T cell receptor activation, and show enhanced expression of pathogenicity-associated and activation-associated genes in the cerebrospinal fluid of patients with multiple sclerosis as compared to controls. In flow chambers with activated endothelial cell (EC) monolayers, CD4CCR6CCR2 T cells are efficient at transendothelial migration (TEM). Ligands for CCR5, CCR6 and CXCR3 localize to EC surfaces and mediate only arrest, whereas CCR2 ligands fail to bind well to ECs and mediate only TEM. Conversely, expressing a chimeric CCR2 ligand engineered to bind glycosaminoglycans on ECs results in CCR2-mediated arrest but blocks TEM induction. Our results from human pathogenic-like type 17 cells thus suggest that T cell migration arrest requires chemokine bound to EC surfaces, whereas TEM requires a transendothelial chemokine gradient.
人类Th17/17型细胞表达趋化因子受体CCR6，但CCR6和其他趋化因子受体在人类17型Th细胞外渗中的功能尚未完全阐明。在此我们表明，共表达CCR2的人类外周血CD4⁺CCR6⁺ T细胞具有致病性Th17特征，能够在无T细胞受体激活的情况下产生炎性细胞因子，并且与对照组相比，在多发性硬化症患者的脑脊液中显示出致病性相关基因和激活相关基因的表达增强。在具有激活的内皮细胞（EC）单层的流动小室中，CD4⁺CCR6⁺CCR2⁺ T细胞在内皮迁移（TEM）方面效率很高。CCR5、CCR6和CXCR3的配体定位于EC表面且仅介导停滞，而CCR2配体与EC结合不佳且仅介导TEM。相反，表达一种经工程改造以结合EC上糖胺聚糖的嵌合CCR2配体，会导致CCR2介导的停滞，但会阻断TEM诱导。因此，我们从人类致病性类似17型细胞得出的结果表明，T细胞迁移停滞需要趋化因子结合到EC表面，而TEM需要跨内皮趋化因子梯度。
