Insulin signaling establishes a developmental trajectory of adipose regulatory T cells.

Systematic characterizations of adipose regulatory T (T) cell subsets and their phenotypes remain uncommon. Using single-cell ATAC-sequencing and paired single-cell RNA and T cell receptor (TCR) sequencing to map mouse adipose T cells, we identified CD73ST2 and CD73ST2 subsets with distinct clonal expansion patterns. Analysis of TCR-sharing data implied a state transition between CD73ST2 and CD73ST2 subsets.

Generation of a safe and efficacious llama single-domain antibody fragment (vHH) targeting the membrane-proximal region of 4-1BB for engineering therapeutic bispecific antibodies for cancer.

Background: The discovery of checkpoint inhibitors towards cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has been revolutionary for the treatment of cancers. These therapies have only offered an average of 20%-30% response rates across the tumor spectrum and the combination of agonists towards the tumor-necrosis superfamily members, such as 4-1BB and CD40, has shown potent efficacy in preclinical studies; however, these agonists have exhibited high degrees of toxicity with limited efficacy in human trials. In this study, we have generated a single-domain antibody towards a unique epitope of 4-1BB that limits its potential on-target toxicity while maintaining sufficient potency.

Correction: Histone demethylase LSD1 restricts influenza A virus infection by erasing IFITM3-K88 monomethylation.

[This corrects the article DOI: 10.1371/journal.ppat.

A novel biparatopic hybrid antibody-ACE2 fusion that blocks SARS-CoV-2 infection: implications for therapy.

In the absence of a proven effective vaccine preventing infection by SARS-CoV-2, or a proven drug to treat COVID-19, the positive results of passive immune therapy using convalescent serum provide a strong lead. We have developed a new class of tetravalent, biparatopic therapy, 89C8-ACE2. It combines the specificity of a monoclonal antibody (89C8) that recognizes the relatively conserved N-terminal domain of the viral Spike (S) glycoprotein, and the ectodomain of ACE2, which binds to the receptor-binding domain of S.

Single-cell RNA-seq unveils critical regulators of human FOXP3 regulatory T cell stability.

The heterogeneity and plasticity of T lymphocytes is critical for determining immune response outcomes. Functional regulatory T (Treg) cells are commonly characterized by stable FOXP3 expression and have reported to exhibit heterogeneous phenotypes under inflammatory conditions. However, the interplay between inflammation and Treg cell suppressive activity still remains elusive.

The deubiquitinase USP44 promotes Treg function during inflammation by preventing FOXP3 degradation.

The transcription factor forkhead box P3 (FOXP3) is essential for the development of regulatory T cells (Tregs) and their function in immune homeostasis. Previous studies have shown that in natural Tregs (nTregs), FOXP3 can be regulated by polyubiquitination and deubiquitination. However, the molecular players active in this pathway, especially those modulating FOXP3 by deubiquitination in the distinct induced Treg (iTreg) lineage, remain unclear.

Identification and functional analysis of heterogeneous FOXP3 Treg cell subpopulations in human pancreatic ductal adenocarcinoma.

CD4 CD25 regulatory T (Treg) cells express the transcription factor FOXP3 and play an essential role in preventing autoimmunity. Abundant Treg cell accumulation in tumors and tumor draining lymph nodes (TDLNs) has been reported to correlate with both poor and favorable prognosis in various cancers, which suggests that Tregs may have multiple effects on antitumor immunity. However, the heterogeneity of tumor- and TDLN-infiltrating Treg cells remains unclear.

Correction: Histone demethylase LSD1 restricts influenza A virus infection by erasing IFITM3-K88 monomethylation.

[This corrects the article DOI: 10.1371/journal.ppat.

Histone demethylase LSD1 restricts influenza A virus infection by erasing IFITM3-K88 monomethylation.

The histone demethylase LSD1 has been known as a key transcriptional coactivator for DNA viruses such as herpes virus. Inhibition of LSD1 was found to block viral genome transcription and lytic replication of DNA viruses. However, RNA virus genomes do not rely on chromatin structure and histone association, and the role of demethylase activity of LSD1 in RNA virus infections is not anticipated.

DNMT1 cooperates with MBD4 to inhibit the expression of Glucocorticoid-induced TNFR-related protein in human T cells.

Glucocorticoid-induced TNFR-related protein (GITR) is constitutively expressed in T regulatory (Treg) cells and regulates their suppressive function. We identified two methylated CpG islands in the Gitr locus. Using a ChIP assay, we demonstrate that both DNMT1 and methyl-CpG-binding domain Protein 4 (MBD4) bind to the Gitr promoter.

USP21 prevents the generation of T-helper-1-like Treg cells.

FOXP3 Regulatory T (Treg) cells play a key role in the maintenance of immune homeostasis and tolerance. Disruption of Foxp3 expression results in the generation of instable Treg cells and acquisition of effector T-cell-like function. Here we report that the E3 deubiquitinase USP21 prevents the depletion of FOXP3 at the protein level and restricts the generation of T-helper-1-like Treg cells.

Oncolytic Immunotherapy for Treatment of Cancer.

Immunotherapy entails the treatment of disease by modulation of the immune system. As detailed in the previous chapters, the different modes of achieving immune modulation are many, including the use of small/large molecules, cellular therapy, and radiation. Oncolytic viruses that can specifically attack, replicate within, and destroy tumors represent one of the most promising classes of agents for cancer immunotherapy (recently termed as oncolytic immunotherapy).

Reciprocal regulation of RORγt acetylation and function by p300 and HDAC1.

T helper 17 (Th17) cells not only play critical roles in protecting against bacterial and fungal infections but are also involved in the pathogenesis of autoimmune diseases. The retinoic acid-related orphan receptor (RORγt) is a key transcription factor involved in Th17 cell differentiation through direct transcriptional activation of interleukin 17(A) (IL-17). How RORγt itself is regulated remains unclear.

FOXP3(+) Treg Cells and Gender Bias in Autoimmune Diseases.

CD4(+)CD25(+) regulatory T (Treg) cells play a pivotal role in the maintenance of immune homeostasis, where the X-linked master transcription factor forkhead box P3 (FOXP3) determines Treg cell development and function. Genetic deficiency of foxp3 induces dysfunction of Treg cells and immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome in humans. Functionally deficient Treg cells or the development of exTreg cells positively correlate with autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and ankylosing spondylitis (AS).

MiR-125a-5p Decreases the Sensitivity of Treg cells Toward IL-6-Mediated Conversion by Inhibiting IL-6R and STAT3 Expression.

The transcription factor FOXP3 is essential for the differentiation and function of regulatory T cells (Treg). It is established that the transcription factor GATA-3 is induced in Treg cells under inflammatory conditions. GATA-3 stabilizes FOXP3 levels to avoid the differentiation of Treg cells into inflammatory-like T cells.

Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1.

Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells' signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex.

Kaempferol enhances the suppressive function of Treg cells by inhibiting FOXP3 phosphorylation.

Kaempferol is a natural flavonoid found in many vegetables and fruits. Epidemiologic studies have described that Kaempferol intake could reduce risk of cancer, especially lung, gastric, pancreatic and ovarian cancers. Recent studies have shown that Kaempferol could also be beneficial to the body to defend against inflammation, and infection by bacteria and viruses; however, the molecular mechanism of its immunoregulatory function remains largely unknown.

Cutting edge: Ubiquitin-specific protease 4 promotes Th17 cell function under inflammation by deubiquitinating and stabilizing RORγt.

RORγt is a key transcription factor that controls the development and function of inflammatory Th17. The mechanisms that regulate RORγt stability remain unclear. We report that Th17 cells highly express the deubiquitinase ubiquitin-specific protease (USP)4, which is essential for maintaining RORγt and Th17 cell function.

FOXP3+ regulatory T cells and their functional regulation.

FOXP3(+) regulatory T (Treg) cells are critical in maintaining immune tolerance and homeostasis of the immune system. The molecular mechanisms underlying the stability, plasticity and functional activity of Treg cells have been much studied in recent years. Here, we summarize these intriguing findings, and provide insight into their potential use or manipulation during Treg cell therapy for the treatment of autoimmune diseases, graft-versus-host disease (GVHD) and cancer.

Regulatory T-cell differentiation and their function in immune regulation.

Regulatory T-cells (Treg) represent a subset of CD4+ T-cells characterized by high suppressive capacity, which can be generated in the thymus or induced in the periphery. The deleterious phenotype of the Scurfy mouse, which develops an X-linked lymphoproliferative disease resulting from defective T-cell tolerance, clearly demonstrates the importance of Treg cells for the maintenance of immune homeostasis. Although significant progress has been achieved, much information regarding the development, characteristics and function of Treg cells remain lacking.

Treatment of postoperative infectious complications in patients with human immunodeficiency virus infection.

Background: Antibiotics are widely given for surgical patients to prevent infection. Because of the lack of study on the rational use of antibiotics in patients with human immunodeficiency virus (HIV) -infected during surgical procedures, we analyzed the risk factors affecting postoperative infectious complications in HlV-infected patients and explore the rational use of perioperative antibiotics.

Methods: This retrospective study consisted of 308 HlV-infected patients, 272 males and 36 females, who had undergone operation at the Shanghai Public Health Clinical Center from November 2008 to April 2012.

The E3 deubiquitinase USP17 is a positive regulator of retinoic acid-related orphan nuclear receptor γt (RORγt) in Th17 cells.

Stable retinoic acid-related orphan nuclear receptor γt (RORγt) expression is pivotal for the development and function of Th17 cells. Here we demonstrate that expression of the transcription factor RORγt can be regulated through deubiquitination, which prevents proteasome-mediated degradation. We establish that USP17 stabilizes RORγt protein expression by reducing RORγt polyubiquitination at its Lys-360 residue.

USP22 is a positive regulator of NFATc2 on promoting IL2 expression.

Nuclear factor of activated T cells (NFAT) is an important regulator of T cell activation. However, the molecular mechanism whereby NFATc2 regulates IL2 transcription is not fully understood. In this study, we showed that ubiquitin-specific protease 22 (USP22), known as a cancer stem cell marker, specifically interacted with and deubiquitinated NFATc2.

Negative regulation of interferon-induced transmembrane protein 3 by SET7-mediated lysine monomethylation.

Although lysine methylation is classically known to regulate histone function, its role in modulating antiviral restriction factor activity remains uncharacterized. Interferon-induced transmembrane protein 3 (IFITM3) was found monomethylated on its lysine 88 residue (IFITM3-K88me1) to reduce its antiviral activity, mediated by the lysine methyltransferase SET7. Vesicular stomatitis virus and influenza A virus infection increased IFITM3-K88me1 levels by promoting the interaction between IFITM3 and SET7, suggesting that this pathway could be hijacked to support infection; conversely, IFN-α reduced IFITM3-K88me1 levels.