title: Enhanced inflammatory potential of CD4+ T-cells that lack proteasome immunosubunit expression, in a T-cell transfer-based colitis model.
abstract: Proteasomes play a fundamental role in intracellular protein degradation and therewith regulate a variety of cellular processes. Exposure of cells to (pro)inflammatory cytokines upregulates the expression of three inducible catalytic proteasome subunits, the immunosubunits, which incorporate into newly assembled proteasome complexes and alter the catalytic activity of the cellular proteasome population. Single gene-deficient mice lacking one of the three immunosubunits are resistant to dextran sulfate sodium (DSS)-induced colitis development and, likewise, inhibition of one single immunosubunit protects mice against the development of DSS-induced colitis. The observed diminished disease susceptibility has been attributed to altered cytokine production and CD4+ T-cell differentiation in the absence of immunosubunits. To further test whether the catalytic activity conferred by immunosubunits plays an essential role in CD4+ T-cell function and to distinguish between the role of immunosubunits in effector T-cells versus inflamed tissue, we used a T-cell transfer-induced colitis model. Naïve wt or immunosubunit-deficient CD4+ T-cells were adoptively transferred into RAG1-/- and immunosubunit-deficient RAG1-/- mice and colitis development was determined six weeks later. While immunosubunit expression in recipient mice had no effect on colitis development, transferred immunosubunit-deficient T- cells were more potent in inducing colitis and produced more proinflammatory IL17 than wt T-cells. Taken together, our data show that modifications in proteasome-mediated proteolysis in T-cells, conferred by lack of immunosubunit incorporation, do not attenuate but enhance CD4+ T-cell-induced inflammation.
authors.affiliation: Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Orhan
authors.initials: O
authors.lastname: Rasid
authors.affiliation: Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Chantal
authors.initials: C
authors.lastname: Meulenbroeks
authors.affiliation: Department of Pathology, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gröne
authors.affiliation: Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Zaiss
authors.affiliation: Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Alice
authors.initials: A
authors.lastname: Sijts
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology*; D021122:Protein Subunits / Q000235:genetics / Q000276:immunology*
chemical_list: D018398:Homeodomain Proteins; D020381:Interleukin-17; D021122:Protein Subunits; C064658:RAG-1 protein; D016264:Dextran Sulfate; D046988:Proteasome Endopeptidase Complex
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