Age-Dependent Effects of Immunoproteasome Deficiency on Mouse Adenovirus Type 1 Pathogenesis

ABSTRACT Acute respiratory infection with mouse adenovirus type 1 (MAV-1) induces activity of the immunoproteasome, an inducible form of the proteasome that shapes CD8 T cell responses by enhancing peptide presentation by major histocompatibility complex (MHC) class I. We used mice deficient in all three immunoproteasome subunits (triple-knockout [TKO] mice) to determine whether immunoproteasome activity is essential for control of MAV-1 replication or inflammatory responses to acute infection. Complete immunoproteasome deficiency in adult TKO mice had no effect on MAV-1 replication, virus-induced lung inflammation, or adaptive immunity compared to C57BL/6 (B6) controls. In contrast, immunoproteasome deficiency in neonatal TKO mice was associated with decreased survival and decreased lung gamma interferon (IFN-γ) expression compared to B6 controls, although without substantial effects on viral replication, histological evidence of inflammation, or expression of the proinflammatory cytokines tumor necrosis factor alpha and interleukin-1β in lungs or other organs. T cell recruitment and IFN-γ production was similar in lungs of infected B6 and TKO mice. In lungs of uninfected B6 mice, we detected low levels of immunoproteasome subunit mRNA and protein that increased with age. Immunoproteasome subunit expression was lower in lungs of adult IFN-γ-deficient mice compared to B6 controls. Together, these results demonstrate developmental regulation of the immunoproteasome that is associated with age-dependent differences in MAV-1 pathogenesis. IMPORTANCE MAV-1 infection is a useful model to study the pathogenesis of an adenovirus in its natural host. Host factors that control MAV-1 replication and contribute to inflammation and disease are not fully understood. The immunoproteasome is an inducible component of the ubiquitin proteasome system that shapes the repertoire of peptides presented by MHC class I to CD8 T cells, influences other aspects of T cell survival and activation, and promotes production of proinflammatory cytokines. We found that immunoproteasome activity is dispensable in adult mice. However, immunoproteasome deficiency in neonatal mice increased mortality and impaired IFN-γ responses in the lungs. Baseline immunoproteasome subunit expression in lungs of uninfected mice increased with age. Our findings suggest the existence of developmental regulation of the immunoproteasome, like other aspects of host immune function, and indicate that immunoproteasome activity is a critical protective factor early in life.

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T Cells Cause Acute Immunopathology and Are Required for Long-Term Survival in Mouse Adenovirus Type 1-Induced Encephalomyelitis

Journal of Virology ◽

10.1128/jvi.77.18.10060-10070.2003 ◽

2003 ◽

Vol 77 (18) ◽

pp. 10060-10070 ◽

Cited By ~ 27

Author(s):

Martin L. Moore ◽

Corrie C. Brown ◽

Katherine R. Spindler

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class I ◽

Adenovirus Type ◽

T Cell Subsets ◽

Class I ◽

Term Survival ◽

Immunodeficient Mice

ABSTRACT Infection of adult C57BL/6 (B6) mice with mouse adenovirus type 1 (MAV-1) results in dose-dependent encephalomyelitis. Utilizing immunodeficient mice, we analyzed the roles of T cells, T-cell subsets, and T-cell-related functions in MAV-1-induced encephalomyelitis. T cells, major histocompatibility complex (MHC) class I, and perforin contributed to acute disease signs at 8 days postinfection (p.i.). Acute MAV-1-induced encephalomyelitis was absent in mice lacking T cells and in mice lacking perforin. Mice lacking α/β T cells had higher levels of infectious MAV-1 at 8 days, 21 days, and 12 weeks p.i., and these mice succumbed to MAV-1-induced encephalomyelitis at 9 to 16 weeks p.i. Thus, α/β T cells were required for clearance of MAV-1. MAV-1 was cleared in mice lacking perforin, MHC class I or II, CD4+ T cells, or CD8+ T cells. Our results are consistent with a model in which either CD8+ or CD4+ T cells are sufficient for clearance of MAV-1. Furthermore, perforin contributed to MAV-1 disease but not viral clearance. We have established two critical roles for T cells in MAV-1-induced encephalomyelitis. T cells caused acute immunopathology and were required for long-term host survival of MAV-1 infection.

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Characterization of Novel Multiantigenic Vaccine Candidates with Pan-HLA Coverage against Mycobacterium tuberculosis

Clinical and Vaccine Immunology ◽

10.1128/cvi.00586-12 ◽

2013 ◽

Vol 20 (3) ◽

pp. 328-340 ◽

Cited By ~ 8

Author(s):

Riva Kovjazin ◽

David Shitrit ◽

Rachel Preiss ◽

Ilanit Haim ◽

Lev Triezer ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

T Cell ◽

Mhc Class I ◽

Cell Lines ◽

Class I ◽

Content Type ◽

Tuberculosis Patients ◽

Vaccine Candidates ◽

Ifn Γ ◽

T Cell Lines

ABSTRACTThe low protection by the bacillus Calmette-Guérin (BCG) vaccine and existence of drug-resistant strains require better anti-Mycobacterium tuberculosisvaccines with a broad, long-lasting, antigen-specific response. Using bioinformatics tools, we identified five 19- to 40-mer signal peptide (SP) domain vaccine candidates (VCs) derived fromM. tuberculosisantigens. All VCs were predicted to have promiscuous binding to major histocompatibility complex (MHC) class I and II alleles in large geographic territories worldwide. Peripheral mononuclear cells (PBMC) from healthy naïve donors and tuberculosis patients exhibited strong proliferation that correlated positively with Th1 cytokine secretion only in healthy naïve donors. Proliferation to SP VCs was superior to that to antigen-matched control peptides with similar length and various MHC class I and II binding properties. T-cell lines induced to SP VCs from healthy naïve donors had increased CD44high/CD62L+activation/effector memory markers and gamma interferon (IFN-γ), but not interleukin-4 (IL-4), production in both CD4+and CD8+T-cell subpopulations. T-cell lines from healthy naïve donors and tuberculosis patients also manifested strong, dose-dependent, antigen-specific cytotoxicity against autologous VC-loaded orM. tuberculosis-infected macrophages. Lysis ofM. tuberculosis-infected targets was accompanied by high IFN-γ secretion. Various combinations of these five VCs manifested synergic proliferation of PBMC from selected healthy naïve donors. Immunogenicity of the best three combinations, termed Mix1, Mix2, and Mix3 and consisting of 2 to 5 of the VCs, was then evaluated in mice. Each mixture manifested strong cytotoxicity againstM. tuberculosis-infected macrophages, while Mix3 also manifested a VC-specific humoral immune response. Based on these results, we plan to evaluate the protection properties of these combinations as an improved tuberculosis subunit vaccine.

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The popliteal lymph node response to streptozotocin is under type 1, MHC class-I restricted, CD8+ T-cell control

Toxicology ◽

10.1016/s0300-483x(00)00155-4 ◽

2000 ◽

Vol 146 (1) ◽

pp. 73-82 ◽

Cited By ~ 11

Author(s):

G Choquet-Kastylevsky ◽

R Tedone ◽

M.-T Ducluzeau ◽

J Kehren ◽

J.-F Nicolas ◽

...

Keyword(s):

Lymph Node ◽

T Cell ◽

Mhc Class I ◽

Cd8 T Cell ◽

Popliteal Lymph Node ◽

Class I ◽

Cell Control

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Human papillomavirus 16-encoded E7 protein inhibits IFN-γ-mediated MHC class I antigen presentation and CTL-induced lysis by blocking IRF-1 expression in mouse keratinocytes

Journal of General Virology ◽

10.1099/vir.0.054486-0 ◽

2013 ◽

Vol 94 (11) ◽

pp. 2504-2514 ◽

Cited By ~ 32

Author(s):

Fang Zhou ◽

JieZhong Chen ◽

Kong-Nan Zhao

Keyword(s):

Human Papillomavirus ◽

T Cell ◽

Antigen Presentation ◽

Mhc Class I ◽

Antigen Processing ◽

Class I ◽

Human Papillomavirus 16 ◽

Mhc Class I Antigen ◽

Ifn Γ ◽

Mouse Keratinocytes

Human papillomavirus 16 (HPV16) infection causes 50 % or more of cervical cancers in women. The HPV16 E7 oncogene is continuously expressed in infected epithelium with its oncogenicity linked to cervical cancer. The E7 protein is an ideal target in control of HPV infection through T-cell-mediated immunity. Using HPV16 E7-transgenic mouse keratinocytes (KCs–E7) to investigate T-cell-mediated immune responses, we have shown previously that HPV16-encoded E7 protein inhibits IFN-γ-mediated enhancement of MHC class I antigen processing and T-cell-induced target cell lysis. In this study, we found that HPV16 E7 suppresses IFN-γ-induced phosphorylation of STAT1(Tyr701), leading to the blockade of interferon regulatory factor-1 (IRF-1) and transporter associated antigen processing subunit 1 (TAP-1) expression in KCs–E7. The results of a 51Cr release assay demonstrated that IFN-γ-treated KCs–E7 escaped from CTL recognition because HPV16 E7 downregulated MHC class I antigen presentation on KCs. Restoration of IRF-1 expression in KCs–E7 overcame the inhibitory effect of E7 protein on IFN-γ-mediated CTL lysis and MHC class I antigen presentation on KCs. Our results suggest that HPV16 E7 interferes with the IFN-γ-mediated JAK1/JAK2/STAT1/IRF-1 signal transduction pathway and reduces the efficiency of peptide loading and MHC class I antigen presentation on KCs–E7. These results may reveal a new mechanism whereby HPV16 escapes from immune surveillance in vivo.

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Class I-Restricted T Cell-Associated Molecule Is a Marker for IFN-γ-Producing iNKT Cells in Healthy Subjects and Patients with Type 1 Diabetes

Journal of Interferon & Cytokine Research ◽

10.1089/jir.2016.0006 ◽

2017 ◽

Vol 37 (1) ◽

pp. 39-49 ◽

Cited By ~ 4

Author(s):

Nonantzin Beristain-Covarrubias ◽

Elsy B. Canche-Pool ◽

Carlos Ramirez-Velazquez ◽

Juan Carlos Barragan-Galvez ◽

Rita A. Gomez-Diaz ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Healthy Subjects ◽

Class I ◽

Inkt Cells ◽

Ifn Γ

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cIAP1/2 antagonism eliminates MHC class I–negative tumors through T cell–dependent reprogramming of mononuclear phagocytes

Science Translational Medicine ◽

10.1126/scitranslmed.abf5058 ◽

2021 ◽

Vol 13 (594) ◽

pp. eabf5058

Author(s):

Kevin Roehle ◽

Li Qiang ◽

Katherine S. Ventre ◽

Daniel Heid ◽

Lestat R. Ali ◽

...

Keyword(s):

T Cell ◽

Mhc Class I ◽

Treatment Options ◽

Acquired Resistance ◽

Nuclear Factor Κb ◽

Additional Treatment ◽

Mononuclear Phagocytes ◽

Checkpoint Blockade ◽

Class I ◽

Ifn Γ

Loss of major histocompatibility complex (MHC) class I and interferon-γ (IFN-γ) sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classical and alternative nuclear factor κB (NF-κB) signaling. Induction of noncanonical NF-κB signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-κB signaling induces T cell–dependent immune responses, even in β2-microglobulin (β2M)–deficient tumors, demonstrating that direct CD8 T cell recognition of tumor cell–expressed MHC class I is not required. Instead, T cell–produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild-type mice, but not mice incapable of antigen-specific T cell responses, cIAP1/2 antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Thus, activation of noncanonical NF-κB stimulates a T cell–macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade because of loss of MHC class I or IFN-γ sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.

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CD8+ T-Cell Priming against a NonsecretedListeria monocytogenes Antigen Is Independent of the Antimicrobial Activities of Gamma Interferon

Infection and Immunity ◽

10.1128/iai.68.4.2196-2204.2000 ◽

2000 ◽

Vol 68 (4) ◽

pp. 2196-2204 ◽

Cited By ~ 14

Author(s):

Amy R. Tvinnereim ◽

John T. Harty

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class I ◽

T Cell Responses ◽

Class I ◽

Cell Responses ◽

Presentation Pathway ◽

Exogenous Antigen ◽

Ifn Γ ◽

T Cell Priming

ABSTRACT Sublethal infection of mice with recombinant Listeria monocytogenes expressing a model epitope in either secreted or nonsecreted form results in similar CD8+ T-cell priming. Since nonsecreted bacterial proteins have no obvious access to the endogenous major histocompatibility complex (MHC) class I presentation pathway, presentation of these antigens requires destruction of the bacterium to reveal the nonsecreted molecules to an exogenous MHC class I presentation pathway. Gamma interferon (IFN-γ), a cytokine made by multiple cell types in response to L. monocytogenesinfection, could be required for exogenous presentation of nonsecreted bacterial antigens via its capacity to upregulate the expression of molecules involved in antigen presentation, its capacity to activate macrophages to kill bacteria to expose nonsecreted molecules or both. IFN-γ knockout (KO) mice were used to address the requirement for IFN-γ in CD8+ T-cell priming against (i) a model exogenous antigen and (ii) secreted and nonsecreted L. monocytogenes antigens. We demonstrate that IFN-γ KO mice are capable of cross-presenting the model exogenous antigen ovalbumin to prime CD8+ T-cell responses that are only slightly weaker than that in wild-type (WT) mice. Despite their extreme susceptibility to primary L. monocytogenes infection, previously immunized and naive IFN-γ KO mice were able to generate CD8+ T-cell responses against both secreted and nonsecreted L. monocytogenes antigens which were similar to responses of WT mice. Interestingly, IFN-γ KO mice were as capable as WT mice in mediating the characteristic drop in bacterial load in the liver at 4 h postinfection, although the IFN-γ KO mice have exacerbated bacterial loads as early as 24 h postinfection. These results demonstrate that the regulatory functions of IFN-γ are not required for priming of CD8+ T cells by cross-presentation of a model exogenous antigen or in response to a nonsecreted L. monocytogenes antigen. In addition, the capacity of IFN-γ to activate the microbicidal activities of macrophages is not required for the very early innate immune response to L. monocytogenesor priming of CD8+ T cells against a nonsecreted bacterial antigen.

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