期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 217, 期 12, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20192275
关键词
-
资金
- Wellcome Trust Single Cell Gene Expression Atlas [108437/Z/15/Z]
- Agence Nationale de la Recherche [ANR-11-LABX0070_TRANSPLANTEX, ANR-11-IDEX-000402]
- Institut National de la Sante et de la Recherche Medicale [UMR_S 110 9]
- Institut Universitaire de France
- MSD-Avenir
The Nck-associated protein 1-like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage-specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4(+) and CD8(+) cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients' T cells displayed impaired early activation, immune synapse morphology, and leading edge formation. Moreover, knockdown of nckap1l in zebrafish led to defects in neutrophil migration. Hence, NCKAP1L mutations lead to broad immune dysregulation in humans, which could be classified within actinopathies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据