Immunoproteasome Subunits Are Required for CD8 ⁺ T Cell Function and Host Resistance to Brucella abortus Infection in Mice

Abstract

The immunoproteasome is a specific proteasome isoform composed of three subunits, termed β1i, β2i, and β5i. Its proteolytic activity enhances the quantity and quality of peptides to be presented by major histocompatibility complex class I (MHC-I) molecules to CD8 T cells. However, the role of the combined deficiency of the three immunoproteasome subunits in protective immunity against bacterial pathogens has not been investigated. In this study, we addressed the role of the immunoproteasome during infection by , an intracellular bacterium that requires CD8 T cell responses for the control of infection. Here, we demonstrate that immunoproteasome triple-knockout (TKO) mice were more susceptible to infection. This observed susceptibility was accompanied by reduced interferon gamma (IFN-γ) production by mouse CD4 and CD8 T lymphocytes. Moreover, the absence of the immunoproteasome had an impact on MHC-I surface expression and antigen presentation by dendritic cells. CD8 T cell function, which plays a pivotal role in immunity, also presented a partial impairment of granzyme B expression and, consequently, reduced cytotoxic activity. In conclusion, these results strongly suggest that immunoproteasome subunits are important components in host resistance to infection by impacting both the magnitude and quality of CD8 T cell responses.

The Immunoproteasome Subunits LMP2, LMP7 and MECL-1 Are Crucial Along the Induction of Cerebral Toxoplasmosis

“…Infection with Brucella abortus in TKO mice led to an increased bacterial burden. This was associated with an impaired MHC I presentation of CD11c + cells and a reduced percentage of both CD4 + and CD8 + IFNg producing T cells as well as fewer Granzyme B producing CD8 + T cells (37). Similarly, infection with the protozaon Trypanosoma cruzi in TKO mice resulted in reduced MHC I expression and altered CD8 + effector T cell function, in both quantity and quality as there were fewer overall CD8 + effector cells and fewer IFNg producers (36).…”

CD8+ T Cell Co-Expressed Genes Correlate With Clinical Phenotype and Microenvironments of Urothelial Cancer

“…The antigen peptide which combined with MHC class I, hydrolyzed by immunoproteasome, has stronger CTL activation effect than that in constitutive proteasome (41,47,48). Gabriela et al demonstrated a negatively impact on MHC-I surface expression and antigen presentation process in immunoproteasome triple knockout mice, and cytotoxic activity of CD8 + T cell showed a consequently reduced tendency (49). Nagayama et al suggested that Th1 235 and Th17 differentiation was inhibited by a selective inhibitor of immunoproteasome in the murine model (50).…”

Proteomic Analysis of Human Immune Responses to Live-Attenuated Tularemia Vaccine

“…To our knowledge, this is the first report linking these proteins to human immune responses except for PMSA2 and COTL1. PMSA2 is a subunit of the immunoproteasome which is known to be able to enhance the repertoire of peptides presented by MHC-I molecules [ 41 ]. In line with this observation, an increase in PSME1 and PSME2 (Proteasome activator complex subunit 1 and 2) protein following AS03 adjuvanted H5N1 influenza vaccination was observed in monocytes at Day 3, predicting later seroprotection status (based on protective levels of HAI titter) [ 42 ].…”