Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells

Sumida, Tomokazu; Dulberg, Shai; Schupp, Jonas C.; Lincoln, Matthew R.; Stillwell, Helen; Axisa, Pierre-Paul; Comi, Michela; Unterman, Avraham; Kaminski, Naftali; Madi, Asaf; Kuchroo, Vijay K.; Hafler, David A.

doi:10.1038/s41590-022-01152-y

Cited by 71 publications

(50 citation statements)

References 69 publications

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“…Our findings indicate that type I IFN signaling is critical for maintaining immune tolerance. Studies with mice and human CD4+ T cells reported an IFN gene signature in Tregs, corroborating our single cell sequencing data on gut Tregs (Miragaia et al, 2019; Szabo et al, 2019; Sumida et al, 2022). Consistent with this, the locus containing IFNAR, the receptor of type I IFNs, was identified as a susceptibility region for IBD (Jostins et al, 2012).…”

Section: Discussionsupporting

confidence: 88%

Commensal bacteria promote type I interferon signaling to maintain immune tolerance

Ayala

Matsuo

Hsü

et al. 2021

Preprint

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Type I interferons (IFN) play essential roles in numerous physiological processes, acting as central coordinators in the host response against pathogens. Upon sensing of microbial ligands, host cells rapidly activate the type I IFN response to prime innate and adaptive immune responses. Recent studies suggest tonic IFN are maintained by commensal microbes and critical in mounting an effective immune response to viral pathogens. Further, emerging developments have extended an immunoregulatory role of type I IFN in the maintenance of immune homeostasis. Yet whether immunomodulatory bacteria from the gut microbiota operate through IFN signaling to promote immune tolerance remains largely unanswered. Here we show that commensal microbes are necessary to maintain type I IFN responses in intestinal tissues. Specifically, Bacteroides fragilis induced type I IFN response in dendritic cells (DCs) and this pathway is necessary for the induction of IL-10-producing Foxp3+ regulatory T cells (Tregs). In addition, we show upregulation of type I IFN related genes in Tregs from mesenteric lymph nodes and colonic lamina propria of mice colonized with B. fragilis. Our findings demonstrate type I interferon signaling plays an important role in microbiota-mediated immune tolerance in the gut.

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Section: Discussionsupporting

confidence: 88%

Commensal bacteria promote type I interferon signaling to maintain immune tolerance

Ayala

Matsuo

Hsü

et al. 2021

Preprint

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“…Such chronic immune activation has been observed in chronic viral infections, such as HIV, and can result in an overall state of immune dysfunction. The constitutive upregulation of IFNRs and the consequent increase in their downstream signalling can result in an interferonopathy, which may impair immune responses to infections, possibly owing to the upregulation of several co-inhibitory receptors, such as PD1, TIM3 and LAG3, on T cells 3 . These receptors dampen adaptive immune responses and lead to immune senescence and exhaustion.…”

Section: Factors Influencing Covid-19 Severitymentioning

confidence: 99%

COVID-19 and Down syndrome: the spark in the fuel

Majithia

Ribeiro

2022

Nat Rev Immunol

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“…107 Co-inhibitory module upregulation most commonly follows continuous TCR engagement and T cell activation to facilitate homeostatic contraction, 194,195 and therefore their upregulation on TFH cells in autoimmune disease likely signals antigen experience in the GC. Alternatively, type I interferon signaling can also increase co-inhibitory module expression, 196 and both 564Igi and B6.Sle1yaa have elevated interferon signaling. [197][198][199] As in CD8 T cells, 200 PD-1 signaling can attenuate TFH expansion and activation.…”

Section: Co-inhibitory Module Inductionmentioning

confidence: 99%

T cell help in the autoreactive germinal center

Akama-Garren

Carroll

2022

Scand J Immunol

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The germinal center serves as a site of B cell selection and affinity maturation, critical processes for productive adaptive immunity. In autoimmune disease tolerance is broken in the germinal center reaction, leading to production of autoreactive B cells that may propagate disease. Follicular T cells are crucial regulators of this process, providing signals necessary for B cell survival in the germinal center. Here, we review the emerging roles of follicular T cells in the autoreactive germinal center. Recent advances in immunological techniques have allowed study of the gene expression profiles and repertoire of follicular T cells at unprecedented resolution. These studies provide insight into the potential role follicular T cells play in preventing or facilitating germinal center loss of tolerance. Improved understanding of the mechanisms of T cell help in autoreactive germinal centers provides novel therapeutic targets for diseases of germinal center dysfunction.

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Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells

Cited by 71 publications

References 69 publications

Commensal bacteria promote type I interferon signaling to maintain immune tolerance

Commensal bacteria promote type I interferon signaling to maintain immune tolerance

COVID-19 and Down syndrome: the spark in the fuel

T cell help in the autoreactive germinal center

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