T-Cell-Intrinsic Receptor Interacting Protein 2 Regulates Pathogenic T Helper 17 Cell Differentiation

Immunity. 2018 Nov 20;49(5):873-885.e7. doi: 10.1016/j.immuni.2018.08.022. Epub 2018 Oct 23.

Abstract

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.

Keywords: Chlamydia pneumoniae; IL-17; RIP2; RORα; Th17; atherosclerosis; chronic inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis
  • Biomarkers
  • Caspase Activation and Recruitment Domain
  • Cell Differentiation / genetics*
  • Encephalomyelitis, Autoimmune, Experimental / etiology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / mortality
  • Gene Expression
  • Immunophenotyping
  • Inflammation / genetics
  • Inflammation / metabolism
  • Interleukin-17 / biosynthesis
  • Interleukin-1beta
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Receptor-Interacting Protein Serine-Threonine Kinases / chemistry
  • Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Th17 Cells / cytology*
  • Th17 Cells / metabolism*

Substances

  • Biomarkers
  • IL1B protein, mouse
  • Interleukin-17
  • Interleukin-1beta
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Rora protein, mouse
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk2 protein, mouse