Comparison Between Nr4a Transcription Factor Regulation and Function in Lymphoid and Tumor Treg Cells

Sekiya, Takashi

doi:10.3389/fimmu.2022.866339

Cited by 5 publications

(4 citation statements)

References 46 publications

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“…We found MYB upregulation following TNFR2 costimulation, in line with reported findings in WT versus TNFR2-deficient Tregs ( 21 ). Moreover, we observed that TNFR2-costimulated tTregs have increased levels of NR4A3 , which together with NR4A1 and NR4A2 maintains Treg stability by controlling FOXP3 expression ( 75 ). We also found that TNFR2 costimulation upregulates GATA3 in tTregs.…”

Section: Discussionmentioning

confidence: 99%

Treg cells from human blood differentiate into non-lymphoid tissue-resident effector cells upon TNFR2 costimulation

Mensink,

Verleng,

Schrama

et al. 2024

JCI Insight

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Tregs can facilitate transplant tolerance and attenuate autoimmune and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg expansion and function in vivo and to create therapeutic Treg products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naive, thymus-derived Tregs (tTregs) from human blood that promotes their differentiation into nonlymphoid tissue–resident (NLT-resident) effector Tregs, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue–resident (LT-resident) Treg phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4 + tTregs and conventional T cells (Tconvs), followed by bioinformatic comparison with published transcriptomic Treg signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminate that TNFR2 costimulation promoted tTreg capacity for survival, migration, immunosuppression, and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTregs. Flow cytometry validated the presence of the TNFR2-driven tTreg signature in effector/memory Tregs from the human placenta, as opposed to blood. Thus, TNFR2 can be exploited as a driver of NLT-resident tTreg differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease.

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Section: Discussionmentioning

confidence: 99%

Treg cells from human blood differentiate into non-lymphoid tissue-resident effector cells upon TNFR2 costimulation

Mensink,

Verleng,

Schrama

et al. 2024

JCI Insight

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“…These structural and functional similarities do not preclude a role for DIM-3,5 and DIM8-3,5 analogs acting as tissue/response-specific selective receptor modulators and this will be investigated in future studies. In addition, we will also investigate the applications of dual NR4A1/NR4A2 ligands on responses in which both receptors play similar roles, and this includes neuroinflammation and immune cell exhaustion [ 47 , 48 , 49 , 50 ], where it has recently been reported that DIM8-3-Cl-5-OCH 3 enhances CD8 + T-cell/CD4 + T-cell ratios in tumor-infiltrating lymphocytes [ 32 ]. Moreover, we have also reported that this compound also inhibited tumor growth in a syngeneic mouse model of colon cancer using MC-38 cells as xenografts and the analysis of T cells in tumor-infiltrating lymphocytes showed that the dual NR4A1/2 ligands reversed T-cell exhaustion [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Bis-Indole Derivatives as Dual Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands

Upadhyay,

Hailemariam,

Mariyam

et al. 2024

Biomolecules

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Bis-indole derived compounds such as 1,1-bis(3′-indolyl)-1-(3,5-disubstitutedphenyl) methane (DIM-3,5) and the corresponding 4-hydroxyl analogs (DIM8-3,5) are NR4A1 ligands that act as inverse NR4A1 agonists and are potent inhibitors of tumor growth. The high potency of several DIM-3,5 analogs (IC50 < 1 mg/kg/day), coupled with the >60% similarity of the ligand-binding domains (LBDs) of NR4A1 and NR4A2 and the pro-oncogenic activities of both receptors lead us to hypothesize that these compounds may act as dual NR4A1 and NR4A2 ligands. Using a fluorescence binding assay, it was shown that 22 synthetic DIM8-3,5 and DIM-3,5 analogs bound the LBD of NR4A1 and NR4A2 with most KD values in the low µM range. Moreover, the DIM-3,5 and DIM8-3,5 analogs also decreased NR4A1- and NR4A2-dependent transactivation in U87G glioblastoma cells transfected with GAL4-NR4A1 or GAL4-NR4A2 chimeras and a UAS-luciferase reporter gene construct. The DIM-3,5 and DIM8-3,5 analogs were cytotoxic to U87 glioblastoma and RKO colon cancer cells and the DIM-3,5 compounds were more cytotoxic than the DIM8-3,5 compounds. These studies show that both DIM-3,5 and DIM8-3,5 compounds previously identified as NR4A1 ligands bind both NR4A1 and NR4A2 and are dual NR4A1/2 ligands.

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“…NR4A2, also known as Nurr1, is an orphan nuclear receptor involved in immunology, neurodegenerative pathology, and cancer. [35][36][37][38] NR4A2 is significantly activated during the differentiation of human type II pneumocytes, the major targets of SARS-CoV-2. [13,39] The expression of NR4A2 positively correlates with aging in human lung tissue expression datasets, and older mice exhibit higher Nr4a2 expression than younger mice.…”

Section: Discussionmentioning

confidence: 99%

“…NR4A2 also acts as an upstream regulator of several inflammatory factors. [ 35 ] However, the feedback effects of inflammatory factors on the expression of NR4A2 have not been extensively studied. Notably, IFN‐λ members play crucial roles in the defense against SARS‐CoV‐2 infection.…”

Section: Discussionmentioning

confidence: 99%

Smoke and Spike: Benzo[a]pyrene Enhances SARS‐CoV‐2 Infection by Boosting NR4A2‐Induced ACE2 and TMPRSS2 Expression

et al. 2023

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Cigarette smoke aggravates severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. However, the underlying mechanisms remain unclear. Here, they show that benzo[a]pyrene in cigarette smoke extract facilitates SARS‐CoV‐2 infection via upregulating angiotensin‐converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Benzo[a]pyrene trans‐activates the promoters of ACE2 and TMPRSS2 by upregulating nuclear receptor subfamily 4 A number 2 (NR4A2) and promoting its binding of NR4A2 to their promoters, which is independent of functional genetic polymorphisms in ACE2 and TMPRSS2. Benzo[a]pyrene increases the susceptibility of lung epithelial cells to SARS‐CoV‐2 pseudoviruses and facilitates the infection of authentic Omicron BA.5 in primary human alveolar type II cells, lung organoids, and lung and testis of hamsters. Increased expression of Nr4a2, Ace2, and Tmprss2, as well as decreased methylation of CpG islands at the Nr4a2 promoter are observed in aged mice compared to their younger counterparts. NR4A2 knockdown or interferon‐λ2/λ3 stimulation downregulates the expression of NR4A2, ACE2, and TMPRSS2, thereby inhibiting the infection. In conclusion, benzo[a]pyrene enhances SARS‐CoV‐2 infection by boosting NR4A2‐induced ACE2 and TMPRSS2 expression. This study elucidates the mechanisms underlying the detrimental effects of cigarette smoking on SARS‐CoV‐2 infection and provides prophylactic options for coronavirus disease 2019, particularly for the elderly population.

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Comparison Between Nr4a Transcription Factor Regulation and Function in Lymphoid and Tumor Treg Cells

Cited by 5 publications

References 46 publications

Treg cells from human blood differentiate into non-lymphoid tissue-resident effector cells upon TNFR2 costimulation

Treg cells from human blood differentiate into non-lymphoid tissue-resident effector cells upon TNFR2 costimulation

Bis-Indole Derivatives as Dual Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands

Smoke and Spike: Benzo[a]pyrene Enhances SARS‐CoV‐2 Infection by Boosting NR4A2‐Induced ACE2 and TMPRSS2 Expression

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