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However, upon inflammation, the sharp increase in protein production requires additional mechanisms to limit protein-associated cellular stress. Under inflammatory conditions and the release of interferons, the immunoproteasome (IP) is induced to support protein processing and recycling. In antigen-presenting cells constitutively expressing IPs, inflammation-related mechanisms contribute to the formation of MHC class I\/II-peptide complexes, which are required for the induction of T cell responses. The control of<jats:italic>Toxoplasma gondii<\/jats:italic>infection relies on Interferon-\u03b3 (IFN\u03b3)-related T cell responses. Whether and how the IP affects the course of anti-parasitic T cell responses along the infection as well as inflammation of the central nervous system is still unknown. To answer this question we used triple knockout (TKO) mice lacking the 3 catalytic subunits of the immunoproteasome (\u03b21i\/LMP2, \u03b22i\/MECL-1 and \u03b25i\/LMP7). Here we show that the numbers of dendritic cells, monocytes and CD8<jats:sup>+<\/jats:sup>T cells were reduced in<jats:italic>Toxoplasma gondii<\/jats:italic>-infected TKO mice. Furthermore, impaired IFN\u03b3, TNF and iNOS production was accompanied by dysregulated chemokine expression and altered immune cell recruitment to the brain. T cell differentiation was altered, apoptosis rates of microglia and monocytes were elevated and STAT3 downstream signaling was diminished. Consequently, anti-parasitic immune responses were impaired in TKO mice leading to elevated<jats:italic>T. gondii<\/jats:italic>burden and prolonged neuroinflammation. In summary we provide evidence for a critical role of the IP subunits \u03b21i\/LMP2, \u03b22i\/MECL-1 and \u03b25i\/LMP7 for the control of cerebral<jats:italic>Toxoplasma gondii<\/jats:italic>infection and subsequent neuroinflammation.<\/jats:p>","DOI":"10.3389\/fimmu.2021.619465","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T17:38:55Z","timestamp":1619026735000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis"],"prefix":"10.3389","volume":"12","author":[{"given":"Timothy","family":"French","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Israel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henning 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