The immunoproteasome subunit LMP7 is required in the murine thymus for filling up a hole in the T cell repertoire

Abstract

Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine-inducible variant of the proteasome which has been implicated in regulating inflammatory responses and antigen presentation. In the thymus, medullary thymic epithelial cells (mTECs) and cortical thymic epithelial cells (cTECs) do express different proteasome subunits exerting chymotrypsin-like activities suggesting distinct functions in thymic T cell selection. Employing the lymphocytic choriomeningitis virus (LCMV) infection model, we could show that the immunoproteasome subunit LMP7 was absolutely required for the generation of LCMV GP -specific T cells although the class I mediated presentation of GP was not dependent on LMP7. Using bone marrow chimeras and adoptive transfer of LMP7-deficient CD8 T cells into RAG1-deficient mice we show that LMP7-deficient mice lacked GP -specific T cell precursors and that LMP7 was required in radioresistant cells - most likely thymic epithelial cells - to enable their selection. Since LMP7 is strongly expressed in negatively selecting mTECs but barely in positively selecting cTECs our data suggest that LMP7 was required to avoid excessive negative selection of GP -specific T cell precursors. Taken together, this study demonstrates that the immunoproteasome is a crucial factor for filling up holes within the cytotoxic T cell repertoire.

Targeted Transcriptomic Analysis of C57BL/6 and BALB/c Mice During Progressive Chronic Toxoplasma gondii Infection Reveals Changes in Host and Parasite Gene Expression Relating to Neuropathology and Resolution

“…IFTIM3 plays a role in viral infections through IFN signaling, indicating possible novel anti-parasitic functions of this gene during T. gondii infection. PSMB8 is involved in the degradation of cytoplasmic antigen processing to generate MHC I binding proteins via stimulation by IFNg production, provides instructions to make one subunit of immunoproteasomes responsible for helping in response to infections, and also regulates glioma cell migration proliferation and apoptosis (Agarwal et al, 2010;Basler et al, 2018a;Basler et al, 2018b;Yang et al, 2018). While previous work on PSMB8 has produced minimal data in relation to Toxoplasma infection (Agarwal et al, 2010), further research specifically relating to chronic infection could elaborate on anti-parasitic functions in the CNS.…”

On the Role of the Immunoproteasome in Protein Homeostasis

“…This leads to the generation of peptides with hydrophobic C-terminal residues, which are suitable for MHC-I presentation [4]. The involvement of the immunoproteasome in antigen processing influences the pathogen-induced cytotoxic T lymphocyte (CTL) responses, pathogen clearance, and shapes the CTL repertoire [5][6][7][8][9][10]. Apart from MHC-I antigen processing, immunoproteasomes are involved in T cell expansion [7,11,12], T helper cell differentiation [13,14], macrophage polarisation [15,16], in protection from immunopathological damage in the brain [17,18], lung-associated diseases [19][20][21][22], neurodegenerative diseases [23][24][25][26][27][28][29][30][31], and inflammatory diseases [14,[32][33][34][35][36][37][38][39] (summarized in [40]).…”

Immunoproteasome Inhibition Selectively Kills Human CD14+ Monocytes and as a Result Dampens IL-23 Secretion

“…The catalytically active subunits b1c, b2c, and b5c in the inner two rings are replaced by b1i (low molecular mass polypeptide [LMP] 2), b2i (multicatalytic endopeptidase complex-like [MECL]-1), and b5i (LMP7) in hematopoietic cells and in cells stimulated with IFN-g forming the immunoproteasome (IP) (1). Apart from the long-known function in the generation of MHC class I ligands (2)(3)(4)(5)(6)(7), the IP is involved in T cell expansion (8)(9)(10), in protection from immunopathological damage in the brain (11,12), and in autoimmune diseases (13,14). Targeting the IP alleviated disease symptoms in different animal models for autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, Hashimoto thyroiditis, Sjögren syndrome (15), systemic lupus erythematosus, neuritis (16), and multiple sclerosis (summarized in Ref.…”