Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria

Yang, Rui; Mele, Federico; Worley, Lisa; Langlais, David; Rosain, Jérémie; Benhsaien, Ibithal; Elarabi, Houda; Croft, Carys A.; Doisne, Jean‐Marc; Zhang, Peng; Weißhaar, Marc; Jarrossay, David; Latorre, Daniela; Shen, Yichao; Han, Jian; Ogishi, Masato; Gruber, Conor; Markle, Janet; Ali, Fatima; Rahman, Mahbuba; Khan, Taushif; Seeleuthner, Yoann; Kerner, Gaspard; Husquin, Lucas T.; Maclsaac, Julia L.; Jeljeli, Mohamed; Errami, Abderrahmane; Ailal, Fatima; Kobor, Michael S.; Oleaga-Quintas, Carmen; Roynard, Manon; Bourgey, Mathieu; Baghdadi, Jamila El; Boisson–Dupuis, Stéphanie; Puel, Anne; Batteux, Frédéric; Rozenberg, Flore; Marr, Nico; Pan‐Hammarström, Qiang; Bogunovic, Dusan; Quintana-Murci, Lluı́s; Carroll, Thomas; Cindy, S.; Abel, Laurent; Bousfiha, Aziz; Santo, James P. Di; Glimcher, Laurie H.; Gros, Philippe; Tangye, Stuart G.; Sallusto, Federica; Bustamante, Jacinta; Casanova, Jean Laurent

doi:10.1016/j.cell.2020.10.046

Cited by 100 publications

(106 citation statements)

References 180 publications

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“…Discoveries over the past 12 months in the field of inborn errors of immunity have further identified non-redundant functions of key genes in human immune cell development, host defense, and immune regulation. In some cases, these functions go well beyond what may have been expected or anticipated based on animal models (e.g., TBX21 [ 25 ]). They have also already highlighted the heterogenous phenotypes that can result from variants in the same gene (e.g., CDC42 [ 33 – 39 , 52 ]), indicated that significant diseases can arise from mono-allelic or bi-allelic loss of function ( IL6ST [ 9 ], RIPK1 [ 42 , 43 ]) or bi-allelic loss- or gain-of-function ( CEBPE [ 24 ], STAT2 [ 40 , 41 ]) variants in the same gene, or from autoAb phenocopies of monogenic lesions (e.g., COVID19 and anti-IFN Abs) [ 48 ], and identified novel somatic mutations as pathogenic causes of immune disorders ( UBA1 ) [ 47 ].…”

Section: Discussionmentioning

confidence: 78%

“…They have also already highlighted the heterogenous phenotypes that can result from variants in the same gene (e.g., CDC42 [ 33 – 39 , 52 ]), indicated that significant diseases can arise from mono-allelic or bi-allelic loss of function ( IL6ST [ 9 ], RIPK1 [ 42 , 43 ]) or bi-allelic loss- or gain-of-function ( CEBPE [ 24 ], STAT2 [ 40 , 41 ]) variants in the same gene, or from autoAb phenocopies of monogenic lesions (e.g., COVID19 and anti-IFN Abs) [ 48 ], and identified novel somatic mutations as pathogenic causes of immune disorders ( UBA1 ) [ 47 ]. Importantly, they have also provided opportunities for therapeutic interventions, such as JAK inhibitors to treat STAT2 gain of function [ 40 , 41 ] or SOCS1 deficiency [ 22 ], IFNγ to treat mycobacterial disease [ 25 , 26 ], or early IFN-β or IFN-α2a treatment of SARS-CoV2 infection in COVID-19 patients with autoantibodies against IFN-α or IFN-ω [ 67 ] or impaired type 1 IFN responses [ 70 ]. This snapshot of genetic discoveries underpinning human immune disorders further highlights the critical contributions of inborn errors of immunity to our broader understanding of basic, translational, and clinical immunology.…”

Section: Discussionmentioning

confidence: 99%

“…Recently-reported gene defects have been found for most categories of inborn errors of immunity, including novel causes of: SCID ( PAX1 [ 5 , 6 ], SLP76 [ 7 ]); CID ( MCM10 [ 8 ], IL6ST [ 9 – 11 ]); Predominantly antibody deficiencies ( FNIP1 [ 14 , 15 ], PIK3CG [ 16 , 17 ], CTNNBL1 [ 18 ], TNFSF13 [ 19 ]); Autoinflammatory diseases ( SOCS1 [ 20 – 22 ], TET2 [ 23 ], CEBPE [ 24 ], CDC42 [ 33 – 39 ], LSM11 , RNU7–1 [ 32 ], STAT2 [ 40 , 41 ], RIPK1 [ 42 , 43 ], NCKAP1L [ 44 – 46 ]), UBA1 (somatic mutations) [ 47 ]; and Susceptibility to infection with specific pathogens ( MAPK8 [ 31 ]; TBX21 [ 25 ], IFNG [ 26 ], NOS2 [ 28 ], SNORA31 [ 29 ], ATG4A , MAP1LC3B2 [ 30 ]) (Table 1 ). …”

Section: Novel Causes Of Inborn Errors Of Immunitymentioning

confidence: 99%

“…Susceptibility to infection with specific pathogens ( MAPK8 [ 31 ]; TBX21 [ 25 ], IFNG [ 26 ], NOS2 [ 28 ], SNORA31 [ 29 ], ATG4A , MAP1LC3B2 [ 30 ]) (Table 1 ).…”

Section: Novel Causes Of Inborn Errors Of Immunitymentioning

confidence: 99%

“…Recent discoveries have further linked common clinical phenotypes with unique genotypes that converge in a shared pathway. Thus, the non-redundant role of IFNγ-mediated immunity in host defense against mycobacterial infection [ 58 ] has been definitively established by the identification of individuals with inactivating bi-allelic mutations in not only IFNG itself [ 26 ] but also TBX21 [ 25 ], the transcription factor that regulates expression and production of IFNγ.…”

Section: Joining the Dots With Discoveries Of Novel Inborn Errors Of mentioning

confidence: 99%

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The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

et al. 2021

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The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Novel Causes Of Inborn Errors Of Immunitymentioning

confidence: 99%

“…Susceptibility to infection with specific pathogens ( MAPK8 [ 31 ]; TBX21 [ 25 ], IFNG [ 26 ], NOS2 [ 28 ], SNORA31 [ 29 ], ATG4A , MAP1LC3B2 [ 30 ]) (Table 1 ).…”

Section: Novel Causes Of Inborn Errors Of Immunitymentioning

confidence: 99%

Section: Joining the Dots With Discoveries Of Novel Inborn Errors Of mentioning

confidence: 99%

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The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

et al. 2021

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Sexually Dimorphic Response to Hepatic Injury in Newborn Suffering from Intrauterine Growth Restriction

Wei,

Tang,

Mao

et al. 2024

Advanced Science

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Intrauterine growth restriction (IUGR), when a fetus does not grow as expected, is associated with a reduction in hepatic functionality and a higher risk for chronic liver disease in adulthood. Utilizing early developmental plasticity to reverse the outcome of poor fetal programming remains an unexplored area. Focusing on the biochemical profiles of neonates and previous transcriptome findings, piglets from the same fetus are selected as models for studying IUGR. The cellular landscape of the liver is created by scRNA‐seq to reveal sex‐dependent patterns in IUGR‐induced hepatic injury. One week after birth, IUGR piglets experience hypoxic stress. IUGR females exhibit fibroblast‐driven T cell conversion into an immune‐adapted phenotype, which effectively alleviates inflammation and fosters hepatic regeneration. In contrast, males experience even more severe hepatic injury. Prolonged inflammation due to disrupted lipid metabolism hinders intercellular communication among non‐immune cells, which ultimately impairs liver regeneration even into adulthood. Additionally, Apolipoprotein A4 (APOA4) is explored as a novel biomarker by reducing hepatic triglyceride deposition as a protective response against hypoxia in IUGR males. PPARα activation can mitigate hepatic damage and meanwhile restore over‐expressed APOA4 to normal in IUGR males. The pioneering study offers valuable insights into the sexually dimorphic responses to hepatic injury during IUGR.

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Eomes and T‐bet, a dynamic duo regulating NK cell differentiation

2022

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T-bet and Eomes are two related transcription factors (TFs) that regulate the differentiation of cytotoxic lymphocytes such as Natural Killer (NK) cells and CD8 T cells.Recent genome-wide analyses suggest they have complementary roles in instructing the transcriptional program of NK cells, although their DNA binding sites appear to be very similar. In this essay, we discuss the mechanisms that could specify their action, addressing their expression profile, the cofactors they interact with, as well as their roles in the epigenetic regulation of chromatin accessibility. Based on the recent literature on these TFs, we propose different models to describe how they regulate gene expression in NK cells at steady state, or in the context of activation or exhaustion.We also discuss recent findings in the field of CD8 T cell differentiation and residency, where Eomes and T-bet appear to be major regulators, and the parallels that can be drawn between mechanisms of NK and CD8 T cell differentiation and trafficking. K E Y W O R D S cytotoxicity, development, IFN-γ, natural Killer cells, T-box transcription factors NK CELL DIFFERENTIATION, PARALLELS WITH T CELLSNK cells develop mainly in the bone marrow (BM). At early developmental stages, they actively proliferate in this anatomical site before maturation. We previously reported that immature NK cells could be dissected into two different subsets expressing or not CD27. [10] However, mathematical modeling led us to refine this model and propose that most immature NK cells were in fact CD11b − CD27 + . [11]

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Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria

Cited by 100 publications

References 180 publications

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee

Sexually Dimorphic Response to Hepatic Injury in Newborn Suffering from Intrauterine Growth Restriction

Eomes and T‐bet, a dynamic duo regulating NK cell differentiation

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