Department of Pediatrics, Division of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Infectious and Immunologic Disease Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Science, Research Division of Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Department of Pediatrics, Division of Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Immunity. 2018 Nov 20;49(5):873-885.e7. doi: 10.1016/j.immuni.2018.08.022. Epub 2018 Oct 23.
Receptor interacting protein 2 (RIP2) plays a role in sensing intracellular pathogens, but its function in T cells is unclear. We show that RIP2 deficiency in CD4 T cells resulted in chronic and severe interleukin-17A-mediated inflammation during Chlamydia pneumoniae lung infection, increased T helper 17 (Th17) cell formation in lungs of infected mice, accelerated atherosclerosis, and more severe experimental autoimmune encephalomyelitis. While RIP2 deficiency resulted in reduced conventional Th17 cell differentiation, it led to significantly enhanced differentiation of pathogenic (p)Th17 cells, which was dependent on RORα transcription factor and interleukin-1 but independent of nucleotide oligomerization domain (NOD) 1 and 2. Overexpression of RIP2 resulted in suppression of pTh17 cell differentiation, an effect mediated by its CARD domain, and phenocopied by a cell-permeable RIP2 CARD peptide. Our data suggest that RIP2 has a T cell-intrinsic role in determining the balance between homeostatic and pathogenic Th17 cell responses.
受体相互作用蛋白 2（RIP2）在感知细胞内病原体方面发挥作用，但它在 T 细胞中的功能尚不清楚。我们发现，CD4 T 细胞中 RIP2 的缺失导致肺炎衣原体肺部感染期间慢性和严重的白细胞介素 17A 介导的炎症，感染小鼠肺部的辅助性 T 细胞 17（Th17）细胞形成增加，动脉粥样硬化加速，实验性自身免疫性脑脊髓炎更严重。虽然 RIP2 的缺乏导致常规 Th17 细胞分化减少，但它导致致病性（p）Th17 细胞的分化显著增强，这依赖于 RORα 转录因子和白细胞介素 1，但不依赖于核苷酸寡聚化结构域（NOD）1 和 2。RIP2 的过表达导致 pTh17 细胞分化受到抑制，这种作用是由其 CARD 结构域介导的，可被细胞通透性的 RIP2 CARD 肽模拟。我们的数据表明，RIP2 在决定稳态和致病性 Th17 细胞反应之间的平衡方面具有 T 细胞内在作用。
