Cutting Edge: Processing of Oxidized Peptides in Macrophages Regulates T Cell Activation and Development of Autoimmune Arthritis

Min Yang; Claus Haase; Johan Viljanen; Bingze Xu; Changrong Ge; Jan Kihlberg; Rikard Holmdahl

doi:10.4049/jimmunol.1700774

Cutting Edge: Processing of Oxidized Peptides in Macrophages Regulates T Cell Activation and Development of Autoimmune Arthritis

J Immunol. 2017 Dec 15;199(12):3937-3942. doi: 10.4049/jimmunol.1700774. Epub 2017 Nov 10.

Authors

Min Yang¹, Claus Haase², Johan Viljanen³, Bingze Xu¹, Changrong Ge¹, Jan Kihlberg³, Rikard Holmdahl^{4

5}

Affiliations

¹ Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden.
² Global Research, Novo Nordisk A/S, 2880 Bagsvaerd, Denmark.
³ Department of Chemistry-Biomedical Centre, Uppsala University, 751 23 Uppsala, Sweden; and.
⁴ Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden; [email protected].
⁵ Center for Medical Immunopharmacology Research, Southern Medical University, 510515 Guangzhou, China.

PMID: 29127146
DOI: 10.4049/jimmunol.1700774

Abstract

APCs are known to produce NADPH oxidase (NOX) 2-derived reactive oxygen species; however, whether and how NOX2-mediated oxidation affects redox-sensitive immunogenic peptides remains elusive. In this study, we investigated a major immunogenic peptide in glucose-6-phosphate isomerase (G6PI), a potential autoantigen in rheumatoid arthritis, which can form internal disulfide bonds. Ag presentation assays showed that presentation of this G6PI peptide was more efficient in NOX2-deficient (Ncf1^m1J/m1J mutant) mice, compared with wild-type controls. IFN-γ-inducible lysosomal thiol reductase (GILT), which facilitates disulfide bond-containing Ag processing, was found to be upregulated in macrophages from Ncf1 mutant mice. Ncf1 mutant mice exhibited more severe G6PI peptide-induced arthritis, which was accompanied by the increased GILT expression in macrophages and enhanced Ag-specific T cell responses. Our results show that NOX2-dependent processing of the redox-sensitive autoantigens by APCs modify T cell activity and development of autoimmune arthritis.

MeSH terms

Amino Acid Motifs
Amino Acid Sequence
Animals
Antigen Presentation*
Arthritis, Experimental / genetics
Arthritis, Experimental / immunology*
Arthritis, Experimental / metabolism
Autoantigens / chemistry
Autoantigens / immunology*
Autoimmune Diseases / genetics
Autoimmune Diseases / immunology*
Autoimmune Diseases / metabolism
Cysteine / metabolism
Cystine / metabolism
Cytokines / chemistry
Cytokines / immunology
Glucose-6-Phosphate Isomerase / chemistry
Glucose-6-Phosphate Isomerase / immunology*
Humans
Immune Tolerance
Lymphocyte Activation*
Macrophages / enzymology
Macrophages / immunology*
Mice
Mice, Knockout
Models, Molecular
NADPH Oxidase 2 / metabolism
NADPH Oxidases / deficiency*
Oxidation-Reduction
Oxidoreductases / physiology
Oxidoreductases Acting on Sulfur Group Donors
Peptide Fragments / chemistry
Peptide Fragments / immunology*
Protein Conformation
Reactive Oxygen Species / immunology*
Reactive Oxygen Species / metabolism
T-Lymphocyte Subsets / immunology*

Substances

Autoantigens
Cytokines
Peptide Fragments
Reactive Oxygen Species
Cystine
Oxidoreductases
Cybb protein, mouse
NADPH Oxidase 2
NADPH Oxidases
neutrophil cytosolic factor 1
Ifi30 protein, mouse
Oxidoreductases Acting on Sulfur Group Donors
GPI protein, human
Glucose-6-Phosphate Isomerase
Cysteine