ZAP-70 Regulates Autoimmune Arthritis via Alterations in T Cell Activation and Apoptosis

Cells. 2019 May 24;8(5):504. doi: 10.3390/cells8050504.

Abstract

T cells play an essential role in the pathogenesis of both human rheumatoid arthritis (RA) and its murine models. A key molecule in T cell activation is ZAP-70, therefore we aimed to investigate the effects of partial ZAP-70 deficiency on the pathogenesis of recombinant human G1(rhG1)-induced arthritis (GIA), a well-established mouse model of RA. Arthritis was induced in BALB/c and ZAP-70+/- heterozygous mice. Disease progression was monitored using a scoring system and in vivo imaging, antigen-specific proliferation, cytokine and autoantibody production was measured and T cell apoptotic pathways were analyzed. ZAP-70+/- mice developed a less severe arthritis, as shown by both clinical picture and in vitro parameters (decreased T cell proliferation, cytokine and autoantibody production). The amount of cleaved Caspase-3 increased in arthritic ZAP-70+/- T cells, with no significant changes in cleaved Caspase-8 and -9 levels; although expression of Bim, Bcl-2 and Cytochrome C showed alterations. Tyrosine phosphorylation was less pronounced in arthritic ZAP-70+/- T cells and the amount of Cbl-b-a negative regulator of T cell activation-decreased as well. We hypothesize that the less severe disease seen in the partial absence of ZAP-70 might be caused by the decreased T cell activation accompanied by increased apoptosis.

Keywords: Cbl-b; T cells; ZAP-70; apoptosis; autoimmune arthritis; intrinsic pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Aggrecans / pharmacology
  • Animals
  • Apoptosis / immunology*
  • Arthritis, Rheumatoid / chemically induced
  • Arthritis, Rheumatoid / metabolism*
  • Autoantibodies / metabolism
  • Autoimmunity*
  • Bcl-2-Like Protein 11 / metabolism
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Cytochromes c / metabolism
  • Cytokines / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Gene Knockout Techniques
  • Humans
  • Immunoglobulin Fc Fragments / pharmacology
  • Immunoglobulin G / chemistry
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Spleen / cytology
  • Spleen / pathology
  • T-Lymphocytes / immunology*
  • ZAP-70 Protein-Tyrosine Kinase / genetics
  • ZAP-70 Protein-Tyrosine Kinase / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Aggrecans
  • Autoantibodies
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Cblb protein, mouse
  • Cytokines
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Proto-Oncogene Proteins c-bcl-2
  • Bcl2 protein, mouse
  • Cytochromes c
  • Proto-Oncogene Proteins c-cbl
  • ZAP-70 Protein-Tyrosine Kinase
  • Zap70 protein, mouse
  • Casp3 protein, mouse
  • Caspase 3