Enhanced inflammatory potential of [CD4.sup.+] T-cells that lack proteasome immunosubunit expression, in a T-cell transfer-based colitis model

• Published in: PloS one 2014-04, Vol.9 (4)
• Main Authors: Rasid, Orhan, Meulenbroeks, Chantal, Grone, Andrea, Zaiss, Dietmar, Sijts, Alice
• Format: Article
• Language: English
• Subjects: Analysis; Cell differentiation; Colitis; Cytokines; Physiological aspects; Proteolysis; T cells
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0095378

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.sup.+] T-cell differentiation in the absence of immunosubunits. To further test whether the catalytic activity conferred by immunosubunits plays an essential role in [CD4.sup.+] 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. Naive wt or immunosubunit-deficient [CD4.sup.+] T-cells were adoptively transferred into [RAG1.sup.-/-] and immunosubunit-deficient [RAG1.sup.-/-] mice and colitis development was determined six weeks later. While immunosubunit expression in recipient mice had no effect on colitis development, transferred immunosubunit-deficient Tcells 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.sup.+] T-cell-induced inflammation.