Proteasome immunosubunits protect against the development of CD8 T-cell-mediated autoimmune diseases

Zaiss, Dietmar; Bekker, Cornelis P. J.; University, Andrea GrneUtrecht; Lie, Benedicte A.; Sijts, Alice J.A.M.

doi:10.1016/j.molimm.2012.02.084

Cited by 4 publications

(6 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hence, ONX 0914 was used as the prototype LMP7-selective inhibitor in many studies. LMP7 inhibition with ONX 0914, for example, protected from immunopathological damage in the brain after virus infection [4], exacerbated the pathogenesis of experimental systemic Candida albicans infection [5], protected from colitis-associated cancer formation [6,7], and prevented several autoimmune diseases in pre-clinical mouse models [3,[8][9][10][11][12][13][14] (summarized in Ref. [13]).…”

Section: Introductionmentioning

confidence: 99%

Co‐inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity

et al. 2018

View full text Add to dashboard Cite

Cells of hematopoietic origin express high levels of the immunoproteasome, a cytokine‐inducible proteasome variant comprising the proteolytic subunits LMP2 (β1i), MECL‐1 (β2i), and LMP7 (β5i). Targeting the immunoproteasome in pre‐clinical models of autoimmune diseases with the epoxyketone inhibitor ONX 0914 has proven to be effective. ONX 0914 was previously described as a selective LMP7 inhibitor. Here, we show that PRN1126, developed as an exclusively LMP7‐specific inhibitor, has limited effects on IL‐6 secretion, experimental colitis, and experimental autoimmune encephalomyelitis (EAE). We demonstrate that prolonged exposure of cells with ONX 0914 leads to inhibition of both LMP7 and LMP2. Co‐inhibition of LMP7 and LMP2 with PRN1126 and LMP2 inhibitors LU‐001i or ML604440 impairs MHC class I cell surface expression, IL‐6 secretion, and differentiation of naïve T helper cells to T helper 17 cells, and strongly ameliorates disease in experimental colitis and EAE. Hence, co‐inhibition of LMP2 and LMP7 appears to be synergistic and advantageous for the treatment of autoimmune diseases.

show abstract

Section: Introductionmentioning

confidence: 99%

Co‐inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In hematopoietic cells and in cells stimulated with interferon (IFN)-γ or tumor necrosis factor (TNF)-α these proteolytically active subunits are replaced by β1i (low molecular mass polypeptide (LMP)2), β2i (multicatalytic endopeptidase complex-like (MECL)-1), and β5i (LMP7) forming an inducible variant of the 20S proteasome designated the immunoproteasome. The immunoproteasome is functionally involved in the generation of MHC-I ligands [4][5][6][7][8][9][10][11][12], in T cell expansion [13,14], in the protection from immunopathological damage in the brain [15,16], and in autoimmune diseases [17][18][19][20][21][22][23]. Immunoproteasome-deficient mice have been used to investigate the impact of the inducible proteasome subunits in various studies (reviewed in [24]).…”

Section: Introductionmentioning

confidence: 99%

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

2017

View full text Add to dashboard Cite

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.

show abstract

“…The key role of i-proteasomes in autoreactive CD8 + T cell response has been recently confirmed by the observation that mice lacking i-proteasome β 5i- β 2i subunits developed a multitissue autoimmune disorder mediated by CD8 + T cells via altered MHC class I-restricted self-antigen presentation [ 38 ]. The authors of the study speculated that a relatively high percentage of MHC class I molecules present “dangerous” epitopes in presence of inflammation and in the absence of i-proteasome.…”

Section: I-proteasome and Cd8 + T Cells In Msmentioning

confidence: 99%

“…These self-peptides are low-affinity binders to the MHC class I complexes (as the epitope MBP 111–119 [ 22 ]) and are better produced by s-proteasomes. Hence, in the absence of an appropriate i-proteasome activity these “dangerous” self-epitopes may be generated and targeted by autoreactive CD8 + cytotoxic T cells, thereby triggering an autoimmune response [ 38 ]. It is attractive to hypothesize that a similar mechanism is at work in MS and would imply that i-proteasome might hamper MS development by reducing the amount of “dangerous” self-peptides presented by APCs in periphery.…”

Section: I-proteasome and Cd8 + T Cells In Msmentioning

confidence: 99%

“…For instance, in transgenic mice the induction of EAE by HLA-A*03-restricted myelin epitope was hampered by the overexpression of HLA-A*02 molecules, confirming the opposite (and interacting) action of MHC class I-restricted myelin epitopes on EAE onset [ 124 ]. Furthermore, it has been hypothesized that the expression of i-proteasome limits the generation of self-epitopes associated with autoimmune responses [ 38 ] and we have proposed that a link exists between a genetic protection toward MS and an i-proteasome polymorphism that impairs the generation of a specific MBP epitope [ 22 ]. We therefore conclude that i-proteasomes could play a role in the CD8 + T cell-mediated immune response in MS, and further studies shall better define the role of CD8 + T cells in this pathology and identify which epitopes trigger a deleterious autoimmune CD8 + T cell reaction and how they are generated by different proteasome isoforms.…”

Section: Is Proteasome Inhibition a Potential Therapy Of Ms?mentioning

confidence: 99%

See 1 more Smart Citation

Current Understanding on the Role of Standard and Immunoproteasomes in Inflammatory/Immunological Pathways of Multiple Sclerosis

Bellavista

Santoro

Galimberti

et al. 2014

Autoimmune Diseases

View full text Add to dashboard Cite

The ubiquitin-proteasome system is the major intracellular molecular machinery for protein degradation and maintenance of protein homeostasis in most human cells. As ubiquitin-proteasome system plays a critical role in the regulation of the immune system, it might also influence the development and progression of multiple sclerosis (MS). Both ex vivo analyses and animal models suggest that activity and composition of ubiquitin-proteasome system are altered in MS. Proteasome isoforms endowed of immunosubunits may affect the functionality of different cell types such as CD8+ and CD4+ T cells and B cells as well as neurons during MS development. Furthermore, the study of proteasome-related biomarkers, such as proteasome antibodies and circulating proteasomes, may represent a field of interest in MS. Proteasome inhibitors are already used as treatment for cancer and the recent development of inhibitors selective for immunoproteasome subunits may soon represent novel therapeutic approaches to the different forms of MS. In this review we describe the current knowledge on the potential role of proteasomes in MS and discuss the pro et contra of possible therapies for MS targeting proteasome isoforms.

show abstract

Proteasome immunosubunits protect against the development of CD8 T-cell-mediated autoimmune diseases

Cited by 4 publications

References 19 publications

Co‐inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity

Co‐inhibition of immunoproteasome subunits LMP2 and LMP7 is required to block autoimmunity

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

Current Understanding on the Role of Standard and Immunoproteasomes in Inflammatory/Immunological Pathways of Multiple Sclerosis

Contact Info

Product

Resources

About