scholarly journals The Functional and Mechanistic Roles of Immunoproteasome Subunits in Cancer

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3587
Author(s):  
Satyendra Chandra Tripathi ◽  
Disha Vedpathak ◽  
Edwin Justin Ostrin
Keyword(s):  
Tumor Antigens ◽  
Proteasome Inhibition ◽  
Interferon Γ ◽  
Cell Mediated Immunity ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Inflammatory Stimuli ◽  
Tumorigenic Mechanism ◽  
Functional Relevance

Cell-mediated immunity is driven by antigenic peptide presentation on major histocompatibility complex (MHC) molecules. Specialized proteasome complexes called immunoproteasomes process viral, bacterial, and tumor antigens for presentation on MHC class I molecules, which can induce CD8 T cells to mount effective immune responses. Immunoproteasomes are distinguished by three subunits that alter the catalytic activity of the proteasome and are inducible by inflammatory stimuli such as interferon-γ (IFN-γ). This inducible activity places them in central roles in cancer, autoimmunity, and inflammation. While accelerated proteasomal degradation is an important tumorigenic mechanism deployed by several cancers, there is some ambiguity regarding the role of immunoproteasome induction in neoplastic transformation. Understanding the mechanistic and functional relevance of the immunoproteasome provides essential insights into developing targeted therapies, including overcoming resistance to standard proteasome inhibition and immunomodulation of the tumor microenvironment. In this review, we discuss the roles of the immunoproteasome in different cancers.

scholarly journals The Role of Peptides in T Cell Alloreactivity Is Determined by Self–Major Histocompatibility Complex Molecules

2000 ◽  
Vol 191 (5) ◽  
pp. 805-812 ◽  
Author(s):  
Reinhard Obst ◽  
Nikolai Netuschil ◽  
Karsten Klopfer ◽  
Stefan Stevanović ◽  
Hans-Georg Rammensee
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Target Cells ◽  
Major Histocompatibility ◽  
Complex Molecules ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Alloreactive T Cells

By analyzing T cell responses against foreign major histocompatibility complex (MHC) molecules loaded with peptide libraries and defined self- and viral peptides, we demonstrate a profound influence of self-MHC molecules on the repertoire of alloreactive T cells: the closer the foreign MHC molecule is related to the T cell's MHC, the higher is the proportion of peptide-specific, alloreactive (“allorestricted”) T cells versus T cells recognizing the foreign MHC molecule without regard to the peptide in the groove. Thus, the peptide repertoire of alloreactive T cells must be influenced by self-MHC molecules during positive or negative thymic selection or peripheral survival, much like the repertoire of the self-restricted T cells. In consequence, allorestricted, peptide-specific T cells (that are of interest for clinical applications) are easier to obtain if T cells and target cells express related MHC molecules.

scholarly journals Tolerance to parenchymal self. Regulatory role of major histocompatibility complex-restricted, OX8+ suppressor T cells specific for autologous renal tubular antigen in experimental interstitial nephritis.

1985 ◽  
Vol 162 (6) ◽  
pp. 1892-1903 ◽  
Author(s):  
C J Kelly ◽  
W K Silvers ◽  
E G Neilson
Keyword(s):  
T Cells ◽  
Interstitial Nephritis ◽  
Clonal Expansion ◽  
Delayed Type Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Suppressor T Cells ◽  
Rat Strains ◽  
Histocompatibility Complex ◽  
Renal Tubular

BN rats develop interstitial nephritis after immunization with rabbit, but not rat renal tubular antigen. Using RT1n rat strains that differentially express tubular antigen, we investigated the unresponsiveness of BN rats to BN tubular antigen (BN-TBM) using delayed-type hypersensitivity (DTH) responses to BN-TBM as a measure of cell-mediated immunity. Our results indicate that rat strains expressing tubular antigen respond to immunization with BN-TBM with the clonal expansion of antigen-specific, cyclophosphamide-sensitive, OX8+, MHC-restricted suppressor T cells. Such suppression appears to be relevant to the maintenance of tolerance to parenchymal self, since chronic cyclophosphamide therapy abrogates suppression and results in significant interstitial nephritis.

scholarly journals Central Role for Interferon-γ Receptor in the Regulation of Renal MHC Expression

2000 ◽  
Vol 11 (2) ◽  
pp. 250-261
Author(s):  
YUTAKA TAKEI ◽  
TASHA N. SIMS ◽  
JOAN URMSON ◽  
PHILIP F. HALLORAN
Keyword(s):  
Renal Injury ◽  
Class Ii ◽  
Interferon Γ ◽  
Class I ◽  
Renal Tubules ◽  
Targeted Disruption ◽  
Inflammatory Stimuli ◽  
Ifn Γ ◽  
Arterial Endothelium

The role of the interferon-γ (IFN-γ) receptor 1 (IFN-γR1) was investigated in the regulation of MHC expression in kidney in the basal state, in response to potent inflammatory stimuli, and after renal injury. In this study, MHC regulation in mice lacking IFN-γR due to targeted disruption of the IFN-γR1 gene (GRKO mice) was compared with regulation in 129Sv/J mice with wild-type IFN-γR1 genes. Basal class I expression was reduced by approximately 45% in kidneys of GRKO mice, while basal class II expression was confined to interstitial cells and was not reduced in GRKO kidneys. Recombinant IFN-γ administration induced widespread expression of class I and II in renal tubules, arterial endothelium, and glomeruli of 129Sv/J mice, but produced no change in kidneys of GRKO mice. Potent systemic inflammatory stimuli (injections of allogeneic cells, skin sensitization with oxazolone, and injection of bacterial lipopolysaccharide) significantly induced both class I and class II expression in 129Sv/J mice, but not in GRKO mice. Acute renal injury increased local expression of class I and II in both 129Sv/J and GRKO mice, but the induction in GRKO mice was reduced compared with 129Sv/J mice. Thus, the IFN-γ receptor plays a unique and nonredundant role in the regulation of renal MHC in the response to inflammation, in the response to renal injury, and in the basal state.

scholarly journals Role of BoLA-DRB3 genetic diversity against resistance to mastitis in cattle: Review

2019 ◽  
pp. 30-36 ◽  
Author(s):  
Namita Kumari ◽  
Shubham Loat ◽  
Shallu Saini ◽  
Nitika Dhilor ◽  
Anurag Kumar ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Immune Response ◽  
Major Histocompatibility Complex ◽  
Immune Regulation ◽  
Peptide Antigens ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Antigen Presenting ◽  
Jawless Fish

The major histocompatibility complex (MHC) is an organized cluster of tightly linked genes, present in all vertebrates, playing an important role in the immune system, except the jawless fish [1]. MHC was first identified during tissue transplantation studies in mice [2] and was first known for its role in histocompatibility. Consequently, the role of MHC was discovered in immune regulation [3] and several other functions [4,5]. The important function of the MHC is to code for specialized antigen-presenting receptor glycoproteins, also called as MHC molecules. The products of these genes are involved in the induction and regulation of immune response. These molecules bind processed peptide antigens and present them to T-lymphocytes, thereby triggering immune response.

scholarly journals Prevention of nephritis in major histocompatibility complex class II-deficient MRL-lpr mice.

1994 ◽  
Vol 179 (4) ◽  
pp. 1137-1143 ◽  
Author(s):  
A M Jevnikar ◽  
M J Grusby ◽  
L H Glimcher
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
De Novo ◽  
Class Ii ◽  
Systemic Lupus Erythematosis ◽  
Major Histocompatibility ◽  
Mhc Molecules ◽  
Histocompatibility Complex

MRL-lpr mice develop aggressive autoimmune kidney disease associated with increased or de novo renal expression of major histocompatibility complex (MHC) class II molecules and a massive systemic expansion of CD4-CD- double negative (DN) T cells. Whereas non-MHC linked genes can have a profound effect on the development of nephritis, lymphadenopathy, and anti-DNA antibody production in MRL-lpr mice, the role of MHC molecules has not been unequivocally established. To study the role of MHC class II in this murine model of systemic lupus erythematosis, class II-deficient MRL-lpr mice (MRL-lpr -/-) were created. MRL-lpr -/- mice developed lymphadenopathy but not autoimmune renal disease or autoantibodies. This study demonstrates that class II expression is critical for the development of autoaggressive CD4+ T cells involved in autoimmune nephritis and clearly dissociates DN T cell expansion from autoimmune disease initiation.

scholarly journals In the Absence of CD154, Administration of Interleukin-12 Restores Th1 Responses but Not Protective Immunity to Schistosoma mansoni

2007 ◽  
Vol 75 (7) ◽  
pp. 3539-3547 ◽  
Author(s):  
James P. Hewitson ◽  
Paul A. Hamblin ◽  
Adrian P. Mountford
Keyword(s):  
Lymph Nodes ◽  
Protective Immunity ◽  
Interleukin 12 ◽  
Cell Mediated Immunity ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Cellular Immune ◽  
Antigen Presenting ◽  
Induced Immunity

ABSTRACT The cytokine interplay during the development of protective immunity to the radiation-attenuated (RA) schistosome vaccine has been extensively characterized over recent years, yet the role of costimulatory molecules in the development of cell-mediated immunity is much less well understood. Here we demonstrate the importance of CD40/CD154 in vaccine-induced immunity, as CD154−/− mice exposed to RA schistosomes develop no protection to challenge infection. We showed that vaccinated CD154−/− mice have defective Th1-associated immune responses in the skin-draining lymph nodes and the lungs, with reduced or absent levels of interleukin-12p40 (IL-12p40), gamma interferon, and nitric oxide, but elevated levels of lung IL-4 and IL-5. The expression of major histocompatibility complex II (MHC-II) on antigen-presenting cells recovered from the lungs of vaccinated CD154−/− mice was also severely compromised. The administration of anti-CD40 monoclonal antibody (MAb) to CD154−/− mice did not reconstitute sustained Th1 responses in the lymph nodes or the lungs, nor did the MAb restore anti-parasite immunoglobulin G production or protective immunity. On the other hand, the administration of recombinant IL-12 (rIL-12) to CD154−/− mice shortly after vaccination caused elevated and sustained levels of Th1-associated cytokines, rescued MHC-II expression by lung CD11c+ cells, and restored the appearance of inflammatory effector foci in the lungs. However, the treatment of CD154−/− mice with rIL-12 did not restore protection. We conclude that protective immunity to the RA schistosome vaccine is CD154 dependent but is independent of IL-12-orchestrated cellular immune mechanisms in the lungs.

scholarly journals The Role of Interleukine-10 and Interferon-γ as Potential Markers of the Evolution of African Swine Fever Virus Infection in Wild Boar

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 757
Author(s):  
Sandra Barroso-Arévalo ◽  
Jose A. Barasona ◽  
Estefanía Cadenas-Fernández ◽  
José M. Sánchez-Vizcaíno
Keyword(s):  
Wild Boar ◽  
Vaccine Candidate ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Interferon Γ ◽  
Fever Virus ◽  
Control Group ◽  
Challenge Virus ◽  
Ifn Γ

African swine fever virus (ASFv) is one of the most challenging pathogens to affect both domestic and wild pigs. The disease has now spread to Europe and Asia, causing great damage to the pig industry. Although no commercial vaccine with which to control the disease is, as yet, available, some potential vaccine candidates have shown good results in terms of protection. However, little is known about the host immune mechanisms underlying that protection, especially in wild boar, which is the main reservoir of the disease in Europe. Here, we study the role played by two cytokines (IL-10 and IFN-γ) in wild boar orally inoculated with the attenuated vaccine candidate Lv17/WB/Rie1 and challenged with a virulent ASFv genotype II isolate. A group of naïve wild boar challenged with the latter isolate was also established as a control group. Our results showed that both cytokines play a key role in protecting the host against the challenge virus. While high levels of IL-10 in serum may trigger an immune system malfunctioning in challenged animals, the provision of stable levels of this cytokine over time may help to control the disease. This, together with high and timely induction of IFN-γ by the vaccine candidate, could help protect animals from fatal outcomes. Further studies should be conducted in order to support these preliminary results and confirm the role of these two cytokines as potential markers of the evolution of ASFV infection.

scholarly journals Mannoproteins from Cryptococcus neoformans Promote Dendritic Cell Maturation and Activation

2005 ◽  
Vol 73 (2) ◽  
pp. 820-827 ◽  
Author(s):  
Donatella Pietrella ◽  
Cristina Corbucci ◽  
Stefano Perito ◽  
Giovanni Bistoni ◽  
Anna Vecchiarelli
Keyword(s):  
Cryptococcus Neoformans ◽  
Nuclear Factor Κb ◽  
Dendritic Cell Maturation ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Histocompatibility Complex ◽  
Factor Alpha ◽  
Human Dendritic Cells ◽  
Mannose Receptors

ABSTRACT Our previous data show that mannoproteins (MPs) from Cryptococcus neoformans are able to induce protective responses against both C. neoformans and Candida albicans. Here we provide evidence that MPs foster maturation and activation of human dendritic cells (DCs). Maturation was evaluated by the ability of MPs to facilitate expression of costimulatory molecules such as CD40, CD86, CD83, and major histocompatibility complex classes I and II and to inhibit receptors such as CD14, CD16, and CD32. Activation of DCs was measured by the capacity of MPs to promote interleukin-12 and tumor necrosis factor alpha secretion. DC-induced maturation and interleukin-12 induction are largely mediated by engagement of mannose receptors and presume MP internalization and degradation. DC activation leads to IκBα phosphorylation, which is necessary for nuclear factor κB transmigration into the nucleus. MP-loaded DCs are efficient stimulators of T cells and show a remarkable capacity to promote CD4 and CD8 proliferation. In conclusion, we have evidenced a novel regulatory role of MPs that promotes their candidacy as a vaccine against fungi.

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