Optimal CD8<sup>+</sup> T‐cell memory formation following subcutaneous cytomegalovirus infection requires virus replication but not early dendritic cell responses

Dimonte, Sandra; Gimeno-Brias, Silvia; Marsden, Morgan; Chapman, Lucy; Sabberwal, Pragati; Clement, Mathew; Humphreys, Ian R.

doi:10.1111/imm.13368

Cited by 4 publications

(1 citation statement)

References 49 publications

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“…Generation of z-DC/Ifitm3 −/− chimeric mice Female wt recipient mice were gamma irradiated with 550 rad for 2 min over two intervals. After 24 h, mice were intravenously (i.v) transfused with 1 × 10 6 bone marrow-derived cells from Ifitm3 −/− and wt-zDC-DTR 82 female donors. Twelve weeks later mice were administered either with or without Diptheria toxin (DT) (1 μg/ml) i.p.…”

Section: Sars-cov-2 Propagationmentioning

confidence: 99%

IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses

et al. 2022

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Interferon-induced transmembrane protein 3 (IFITM3) is a restriction factor that limits viral pathogenesis and exerts poorly understood immunoregulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 promotes MyD88-dependent, TLR-mediated IL-6 production following exposure to cytomegalovirus (CMV). IFITM3 also restricts IL-6 production in response to influenza and SARS-CoV-2. In dendritic cells, IFITM3 binds to the reticulon 4 isoform Nogo-B and promotes its proteasomal degradation. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and in the case of TLR2 responses, this process involves alteration of TLR2 cellular localization. Nogo-B deletion abrogates inflammatory cytokine responses and associated disease in virus-infected IFITM3-deficient mice. Thus, we uncover Nogo-B as a driver of viral pathogenesis and highlight an immunoregulatory pathway in which IFITM3 fine-tunes the responsiveness of myeloid cells to viral stimulation.

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Section: Sars-cov-2 Propagationmentioning

confidence: 99%

IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses

et al. 2022

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Mucosal T-cell responses to chronic viral infections: Implications for vaccine design

Al-Talib,

Dimonte,

Humphreys

2024

Cell Mol Immunol

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Mucosal surfaces that line the respiratory, gastrointestinal and genitourinary tracts are the major interfaces between the immune system and the environment. Their unique immunological landscape is characterized by the necessity of balancing tolerance to commensal microorganisms and other innocuous exposures against protection from pathogenic threats such as viruses. Numerous pathogenic viruses, including herpesviruses and retroviruses, exploit this environment to establish chronic infection. Effector and regulatory T-cell populations, including effector and resident memory T cells, play instrumental roles in mediating the transition from acute to chronic infection, where a degree of viral replication is tolerated to minimize immunopathology. Persistent antigen exposure during chronic viral infection leads to the evolution and divergence of these responses. In this review, we discuss advances in the understanding of mucosal T-cell immunity during chronic viral infections and how features of T-cell responses develop in different chronic viral infections of the mucosa. We consider how insights into T-cell immunity at mucosal surfaces could inform vaccine strategies: not only to protect hosts from chronic viral infections but also to exploit viruses that can persist within mucosal surfaces as vaccine vectors.

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IFITM3 regulates virus-induced inflammatory cytokine production by titrating Nogo-B orchestration of TLR responses

Clement

Forbester

Marsden

et al. 2021

Preprint

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Interferon induced transmembrane protein 3 (IFITM3) is an important viral restriction factor in viral pathogenesis that also exhibits poorly understood immune regulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 regulates MyD88-dependent TLR-mediated cytokine production following dendritic cell exposure to cytomegalovirus (CMV), and this process limits viral pathogenesis in vivo. IFITM3 also restricted pro-inflammatory (IL-6) cytokine production in response to influenza. IFITM3 bound to and promoted ubiquitination and proteasomal degradation of the reticulon 4 isoform Nogo-B. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and this process involved alteration of TLR dynamics. The anti-inflammatory function of IFITM3 was intrinsically linked to its ability to regulate Nogo-B. Thus, we uncover Nogo-B as an unappreciated driver of viral pathogenesis and highlight a novel immune regulatory pathway where IFITM3 fine-tunes TLR responsiveness of myeloid cells to viral stimulation.

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Optimal CD8⁺ T‐cell memory formation following subcutaneous cytomegalovirus infection requires virus replication but not early dendritic cell responses

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 4 publications

References 49 publications

IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses

IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses

Mucosal T-cell responses to chronic viral infections: Implications for vaccine design

IFITM3 regulates virus-induced inflammatory cytokine production by titrating Nogo-B orchestration of TLR responses

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Optimal CD8+ T‐cell memory formation following subcutaneous cytomegalovirus infection requires virus replication but not early dendritic cell responses

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 4 publications

References 49 publications

IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses

IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses

Mucosal T-cell responses to chronic viral infections: Implications for vaccine design

IFITM3 regulates virus-induced inflammatory cytokine production by titrating Nogo-B orchestration of TLR responses

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Optimal CD8⁺ T‐cell memory formation following subcutaneous cytomegalovirus infection requires virus replication but not early dendritic cell responses