TGF-ß Regulation of T Cells.

Transforming growth factor ß (TGF-ß) is a key cytokine regulating the development, activation, proliferation, differentiation, and death of T cells. In CD4+ T cells, TGF-ß maintains the quiescence and controls the activation of naive T cells. While inhibiting the differentiation and function of Th1 and Th2 cells, TGF-ß promotes the differentiation of Th17 and Th9 cells. TGF-ß is required for the induction of Foxp3 in naive T cells and the development of regulatory T cells. TGF-ß is crucial in the differentiation of tissue-resident memory CD8+ T cells and their retention in the tissue, whereas it suppresses effector T cell function. In addition, TGF-ß also regulates the generation or function of natural killer T cells, γδ T cells, innate lymphoid cells, and gut intraepithelial lymphocytes. Here I highlight the major findings and recent advances in our understanding of TGF-ß regulation of T cells and provide a personal perspective of the field.

Transcription factor Tox2 is required for metabolic adaptation and tissue residency of ILC3 in the gut.

Group 3 innate lymphoid cells (ILC3) are the major subset of gut-resident ILC with essential roles in infections and tissue repair, but how they adapt to the gut environment to maintain tissue residency is unclear. We report that Tox2 is critical for gut ILC3 maintenance and function. Gut ILC3 highly expressed Tox2, and depletion of Tox2 markedly decreased ILC3 in gut but not at central sites, resulting in defective control of Citrobacter rodentium infection. Single-cell transcriptional profiling revealed decreased expression of Hexokinase-2 in Tox2-deficient gut ILC3. Consistent with the requirement for hexokinases in glycolysis, Tox2-/- ILC3 displayed decreased ability to utilize glycolysis for protein translation. Ectopic expression of Hexokinase-2 rescued Tox2-/- gut ILC3 defects. Hypoxia and interleukin (IL)-17A each induced Tox2 expression in ILC3, suggesting a mechanism by which ILC3 adjusts to fluctuating environments by programming glycolytic metabolism. Our results reveal the requirement for Tox2 to support the metabolic adaptation of ILC3 within the gastrointestinal tract.

MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping.

MLL4 is an essential subunit of the histone H3 Lys4 (H3K4)-methylation complexes. We found that MLL4 deficiency compromised the development of regulatory T cells (Treg cells) and resulted in a substantial decrease in monomethylated H3K4 (H3K4me1) and chromatin interaction at putative gene enhancers, a considerable portion of which were not direct targets of MLL4 but were enhancers that interacted with MLL4-bound sites. The decrease in H3K4me1 and chromatin interaction at the enhancers not bound by MLL4 correlated with MLL4 binding at distant interacting regions. Deletion of an upstream MLL4-binding site diminished the abundance of H3K4me1 at the regulatory elements of the gene encoding the transcription factor Foxp3 that were looped to the MLL4-binding site and compromised both the thymic differentiation and the inducible differentiation of Treg cells. We found that MLL4 catalyzed methylation of H3K4 at distant unbound enhancers via chromatin looping, which identifies a previously unknown mechanism for regulating the T cell enhancer landscape and affecting Treg cell differentiation.

The Cytokine TGF-ß Induces Interleukin-31 Expression from Dermal Dendritic Cells to Activate Sensory Neurons and Stimulate Wound Itching.

Cutaneous wound healing is associated with the unpleasant sensation of itching. Here we investigated the mechanisms underlying this type of itch, focusing on the contribution of soluble factors released during healing. We found high amounts of interleukin 31 (IL-31) in skin wound tissue during the peak of itch responses. Il31-/- mice lacked wound-induced itch responses. IL-31 was released by dermal conventional type 2 dendritic cells (cDC2s) recruited to wounds and increased itch sensory neuron sensitivity. Transfer of cDC2s isolated from late-stage wounds into healthy skin was sufficient to induce itching in a manner dependent on IL-31 expression. Addition of the cytokine TGF-ß1, which promotes wound healing, to dermal DCs in vitro was sufficient to induce Il31 expression, and Tgfbr1f/f CD11c-Cre mice exhibited reduced scratching and decreased Il31 expression in wounds in vivo. Thus, cDC2s promote itching during skin would healing via a TGF-ß-IL-31 axis with implications for treatment of wound itching.

High Glucose Intake Exacerbates Autoimmunity through Reactive-Oxygen-Species-Mediated TGF-ß Cytokine Activation.

Diet has been suggested to be a potential environmental risk factor for the increasing incidence of autoimmune diseases, yet the underlying mechanisms remain elusive. Here, we show that high glucose intake exacerbated autoimmunity in mouse models of colitis and experimental autoimmune encephalomyelitis (EAE). We elucidated that high amounts of glucose specifically promoted T helper-17 (Th17) cell differentiation by activating transforming growth factor-ß (TGF-ß) from its latent form through upregulation of reactive oxygen species (ROS) in T cells. We further determined that mitochondrial ROS (mtROS) are key for high glucose-induced TGF-ß activation and Th17 cell generation. We have thus revealed a previously unrecognized mechanism underlying the adverse effects of high glucose intake in the pathogenesis of autoimmunity and inflammation.

The DNA-binding inhibitor Id3 regulates IL-9 production in CD4(+) T cells.

The molecular mechanisms by which signaling via transforming growth factor-ß (TGF-ß) and interleukin 4 (IL-4) control the differentiation of CD4(+) IL-9-producing helper T cells (TH9 cells) remain incompletely understood. We found here that the DNA-binding inhibitor Id3 regulated TH9 differentiation, as deletion of Id3 increased IL-9 production from CD4(+) T cells. Mechanistically, TGF-ß1 and IL-4 downregulated Id3 expression, and this process required the kinase TAK1. A reduction in Id3 expression enhanced binding of the transcription factors E2A and GATA-3 to the Il9 promoter region, which promoted Il9 transcription. Notably, Id3-mediated control of TH9 differentiation regulated anti-tumor immunity in an experimental melanoma-bearing model in vivo and also in human CD4(+) T cells in vitro. Thus, our study reveals a previously unrecognized TAK1-Id3-E2A-GATA-3 pathway that regulates TH9 differentiation.

T Cell Receptor-Regulated TGF-ß Type I Receptor Expression Determines T Cell Quiescence and Activation.

It is unclear how quiescence is enforced in naive T cells, but activation by foreign antigens and self-antigens is allowed, despite the presence of inhibitory signals. We showed that active transforming growth factor ß (TGF-ß) signaling was present in naive T cells, and T cell receptor (TCR) engagement reduced TGF-ß signaling during T cell activation by downregulating TGF-ß type 1 receptor (TßRI) through activation of caspase recruitment domain-containing protein 11 (CARD11) and nuclear factor κB (NF-κB). TGF-ß prevented TCR-mediated TßRI downregulation, but this was abrogated by interleukin-6 (IL-6). Mitigation of TCR-mediated TßRI downregulation through overexpression of TßRI in naive and activated T cells rendered T cells less responsive and suppressed autoimmunity. Naive T cells in autoimmune patients exhibited reduced TßRI expression and increased TCR-driven proliferation compared to healthy subjects. Thus, TCR-mediated regulation of TßRI-TGF-ß signaling acts as a crucial criterion to determine T cell quiescence and activation.

Transforming Growth Factor-ß Signaling in Regulatory T Cells Controls T Helper-17 Cells and Tissue-Specific Immune Responses.

Regulatory T cells (Treg cells) perform suppressive functions in disparate tissue environments and against many inflammatory insults, yet the tissue-enriched factor(s) that influence Treg cell phenotype and function remain largely unknown. We have shown a vital role for transforming growth factor-ß (TGF-ß) signals in safe-guarding specific Treg cell functions. TGF-ß signals were dispensable for steady-state Treg cell homeostasis and for Treg cell suppression of T cell proliferation and T helper-1 (Th1) cell differentiation. However, Treg cells require TGF-ß signals to appropriately dampen Th17 cells and regulate responses in the gastrointestinal tract. TGF-ß signaling maintains CD103 expression, promotes expression of the colon-specific trafficking molecule GPR15, and inhibits expression of GPR174, a receptor for lysophosphatidylserine, on Treg cells, collectively supporting the accumulation and retention of Treg cells in the colon and control of colitogenic responses. Thus, we reveal an unrecognized function for TGF-ß signaling as an upstream factor controlling Treg cell activity in specific tissue environments.

Dense sampling of bird diversity increases power of comparative genomics.

Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity1-4. Sparse taxon sampling has previously been proposed to confound phylogenetic inference5, and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families-including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species.

Evolutionary analysis of a complete chicken genome.

Microchromosomes are prevalent in nonmammalian vertebrates [P. D. Waters et al., Proc. Natl. Acad. Sci. U.S.A. 118 (2021)], but a few of them are missing in bird genome assemblies. Here, we present a new chicken reference genome containing all autosomes, a Z and a W chromosome, with all gaps closed except for the W. We identified ten small microchromosomes (termed dot chromosomes) with distinct sequence and epigenetic features, among which six were newly assembled. Those dot chromosomes exhibit extremely high GC content and a high level of DNA methylation and are enriched for housekeeping genes. The pericentromeric heterochromatin of dot chromosomes is disproportionately large and continues to expand with the proliferation of satellite DNA and testis-expressed genes. Our analyses revealed that the 41-bp CNM repeat frequently forms higher-order repeats (HORs) at the centromeres of acrocentric chromosomes. The centromere core regions where the kinetochore attaches often encompass telomeric sequence (TTAGGG)n, and in a one of the dot chromosomes, the centromere core recruits an endogenous retrovirus (ERV). We further demonstrate that the W chromosome shares some common features with dot chromosomes, having large arrays of hypermethylated tandem repeats. Finally, using the complete chicken chromosome models, we reconstructed a fine picture of chordate karyotype evolution, revealing frequent chromosomal fusions before and after vertebrate whole-genome duplications. Our sequence and epigenetic characterization of chicken chromosomes shed insights into the understanding of vertebrate genome evolution and chromosome biology.

Hydrogen Sulfide Promotes Tet1- and Tet2-Mediated Foxp3 Demethylation to Drive Regulatory T Cell Differentiation and Maintain Immune Homeostasis.

Regulatory T (Treg) cells are essential for maintenance of immune homeostasis. Here we found that hydrogen sulfide (H2S) was required for Foxp3(+) Treg cell differentiation and function and that H2S deficiency led to systemic autoimmune disease. H2S maintained expression of methylcytosine dioxygenases Tet1 and Tet2 by sulfhydrating nuclear transcription factor Y subunit beta (NFYB) to facilitate its binding to Tet1 and Tet2 promoters. Transforming growth factor-ß (TGF-ß)-activated Smad3 and interleukin-2 (IL-2)-activated Stat5 facilitated Tet1 and Tet2 binding to Foxp3. Tet1 and Tet2 catalyzed conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in Foxp3 to establish a Treg-cell-specific hypomethylation pattern and stable Foxp3 expression. Consequently, Tet1 and Tet2 deletion led to Foxp3 hypermethylation, impaired Treg cell differentiation and function, and autoimmune disease. Thus, H2S promotes Tet1 and Tet2 expression, which are recruited to Foxp3 by TGF-ß and IL-2 signaling to maintain Foxp3 demethylation and Treg-cell-associated immune homeostasis.

The relationship between serum resolvin D1, NLRP3, cytokine levels, and adolescents with first-episode medication-naïve major depressive disorder.

BACKGROUND: Inflammation has become a critical pathological mechanism of Major Depressive Disorder (MDD). NLRP3 is a critical inflammatory pathway to maintain the immune balance. Recently, preclinical evidence showed that Resolvin D1 might potentially offer a new option for antidepressant treatment due to its protective effects through the inhibition of neuroinflammation. However, whether they have clinical value in the diagnosis and treatment evaluation of adolescent depression was unclear. METHODS: Forty-eight untreated first-episode adolescent patients with moderate to severe major depressive disorder, as well as 30 healthy adolescents (HCs, age and gender-matched), were enrolled for this study. Their ages ranged from 13 to 18 (15.75 ± 1.36) years. The patients were treated with fluoxetine for 6-8 weeks. HDRS-17 was used to evaluate the severity of depressive symptoms. Venous blood samples were collected at baseline for the two groups and at the time-point of post-antidepressant treatment for the patients. Serum concentrations of RvD1, NLRP3, IL-1ß, IL-18, and IL-4 were measured by enzyme-linked immunosorbent assays (ELISA) pre- and post-fluoxetine treatment. RESULTS: Serum levels of RvD1 and anti-inflammatory cytokine IL-4 were significantly elevated in adolescents with MDD compared to healthy adolescents, but no significant difference in NLRP3, IL-1ß, and IL-18 between the two groups. Meanwhile, RvD1 (positively) and IL-4 (negatively) were correlated with the severity of symptoms (HDRS-17 scores) after adjusting age, gender, and BMI. Interestingly, fluoxetine treatment significantly reduced the serum levels of RvD1, NLRP3, IL-1ß, and IL-18 in MDD adolescents but increased the levels of IL-4 relative to baseline. Furthermore, we observed that serum levels of RvD1 might be an excellent distinguishing indicator for depression and healthy adolescents. CONCLUSIONS: Our study is the first to compare RvD1 and NLRP3 between adolescent MDD and HCs. Our findings of reactive increase of RvD1 in adolescent MDD comprised a novel and critical contribution. Our results showed the presence of inflammation resolution unbalanced in adolescents with MDD and indicated that RvD1 might be an ideal biomarker for diagnosing and treating adolescent MDD.

Factors associated with voluntary HIV counseling and testing among young students engaging in casual sexual activity: a cross-sectional study from Eastern China.

OBJECTIVES: To investigate the factors associated with voluntary HIV counseling and testing (VCT) among young students engaging in casual sexual activity and to establish a scientific rationale for developing targeted intervention strategies for preventing HIV/AIDS in this population. METHODS: Stratified cluster sampling was used to conduct a survey using questionnaires to collect demographic and behavioral information for statistical analysis. RESULTS: Data from 611 young students, who reported engaging in casual sexual activity, were included in the statistical analysis. Among these, 68 (11.13%) students underwent the VCT. Among young students who engaged in casual sexual activity, those who were non-Zhejiang residents (adjusted odds ratio [aOR]: 2.11; 95% Confidence Interval [CI]: 1.17-3.80), those who had received AIDS-themed lectures or health education courses from the school in the past year (aOR = 3.96, 95% CI = 1.49-10.50), those who had received HIV risk self-assessment conducted by the school in the past year (aOR = 2.31, 95% CI = 1.17-4.59), and those who had engaged in commercial sex activity in the past year (aOR = 1.98, 95% CI = 1.07-3.66) were more inclined to have undergone VCT. Male students (aOR = 0.37, 95% CI = 0.18-0.77) and those who used condoms consistently during casual sexual activity (aOR = 0.45, 95% CI = 0.21-0.97) were less likely to undergo VCT. CONCLUSION: Casual sexual activity was relatively prevalent among young students, posing a potential risk for HIV transmission. These findings will be instrumental in the development more effective HIV prevention and control strategies for young students. Additionally, it highlights the necessity of promoting and popularizing VCT among young students without Zhejiang province residency, who are involved in commercial sexual activity, and/or those who lacking HIV education. Moreover, additional research and implementation of refined HIV behavioral interventions specifically tailored to young students are necessary to enhance their awareness and knowledge of HIV prevention.

B cell residency but not T cell-independent IgA switching in the gut requires innate lymphoid cells.

Immunoglobulin A (IgA)-producing plasma cells derived from conventional B cells in the gut play an important role in maintaining the homeostasis of gut flora. Both T cell-dependent and T cell-independent IgA class switching occurs in the lymphoid structures in the gut, whose formation depends on lymphoid tissue inducers (LTis), a subset of innate lymphoid cells (ILCs). However, our knowledge on the functions of non-LTi helper-like ILCs, the innate counter parts of CD4 T helper cells, in promoting IgA production is still limited. By cell adoptive transfer and utilizing a unique mouse strain, we demonstrated that the generation of IgA-producing plasma cells from B cells in the gut occurred efficiently in the absence of both T cells and helper-like ILCs and without engaging TGF-ß signaling. Nevertheless, B cell recruitment and/or retention in the gut required functional NKp46-CCR6+ LTis. Therefore, while CCR6+ LTis contribute to the accumulation of B cells in the gut through inducing lymphoid structure formation, helper-like ILCs are not essential for the T cell-independent generation of IgA-producing plasma cells.

Criticality and Neuromorphic Sensing in a Single Memristor.

Resistive random access memory (RRAM) is an important technology for both data storage and neuromorphic computation, where the dynamics of nanoscale conductive filaments lies at the core of the technology. Here, we analyze the current noise of various silicon-based memristors that involves the creation of a percolation path at the intermediate phase of filament growth. Remarkably, we find that these atomic switching events follow scale-free avalanche dynamics with exponents satisfying the criteria for criticality. We further prove that the switching dynamics are universal and show little dependence on device sizes or material features. Utilizing criticality in memristors, we simulate the functionality of hair cells in auditory sensory systems by observing the frequency selectivity of input stimuli with tunable characteristic frequency. We further demonstrate a single-memristor-based sensing primitive for representation of input stimuli that exceeds the theoretical limits dictated by the Nyquist-Shannon theorem.

Control of the development of CD8αα+ intestinal intraepithelial lymphocytes by TGF-ß.

The molecular mechanisms that direct the development of TCRαß+CD8αα+ intestinal intraepithelial lymphocytes (IELs) are not thoroughly understood. Here we show that transforming growth factor-ß (TGF-ß) controls the development of TCRαß+CD8αα+ IELs. Mice with either a null mutation in the gene encoding TGF-ß1 or T cell-specific deletion of TGF-ß receptor I lacked TCRαß+CD8αα+ IELs, whereas mice with transgenic overexpression of TGF-ß1 had a larger population of TCRαß+CD8αα+ IELs. We observed defective development of the TCRαß+CD8αα+ IEL thymic precursors (CD4⁻CD8⁻TCRαß+CD5+) in the absence of TGF-ß. In addition, we found that TGF-ß signaling induced CD8α expression in TCRαß+CD8αα+ IEL thymic precursors and induced and maintained CD8α expression in peripheral populations of T cells. Our data demonstrate a previously unrecognized role for TGF-ß in the development of TCRαß+CD8αα+ IELs and the expression of CD8α in T cells.

Control of the differentiation of regulatory T cells and T(H)17 cells by the DNA-binding inhibitor Id3.

The molecular mechanisms that direct transcription of the gene encoding the transcription factor Foxp3 in CD4(+) T cells remain ill-defined. We show here that deletion of the DNA-binding inhibitor Id3 resulted in the defective generation of Foxp3(+) regulatory T cells (T(reg) cells). We identify two transforming growth factor-ß1 (TGF-ß1)-dependent mechanisms that were vital for activation of Foxp3 transcription and were defective in Id3(-/-) CD4(+) T cells. Enhanced binding of the transcription factor E2A to the Foxp3 promoter promoted Foxp3 transcription. Id3 was required for relief of inhibition by the transcription factor GATA-3 at the Foxp3 promoter. Furthermore, Id3(-/-) T cells showed greater differentiation into the T(H)17 subset of helper T cells in vitro and in a mouse asthma model. Therefore, a network of factors acts in a TGF-ß-dependent manner to control Foxp3 expression and inhibit the development of T(H)17 cells.

Factors associated with the choice of having multiple sexual partners among male college students with casual heterosexual sex in Zhejiang Province, Eastern China.

BACKGROUND: Young students infected with HIV have become a significant public health issue in China, this study aimed to understand the factors influencing the choice of having multiple sexual partners among male college students who had casual heterosexual sex in Zhejiang Province and to scientifically justify developing HIV/AIDS intervention strategies among them. METHODS: A stratified cluster sampling method was used for the survey of students from 13 colleges or universities in Zhejiang Province between October and November 2018. The questionnaire collected information on general demographic characteristics, knowledge of HIV/AIDS prevention and treatment, sexual attitudes and risk awareness, sexual behavioural characteristics, and acceptance of interventions. The univariable and multivariable analyses were conducted in this study. RESULTS: Study participants included 362 male college students who exhibited casual heterosexual sex and were aware of the number of sexual partners they had. Among them, 222 students engaged in casual heterosexual sex with multiple sexual partners (61.33%). The results of the multivariable analysis revealed several factors associated with male students' choice to have multiple sexual partners: monthly living expenses greater than or equal to 1501 CNY (adjusted OR = 2.24, 95% CI = 1.21-4.16), sexual behavior after consuming alcohol (adjusted OR = 2.19, 95% CI = 1.32-3.63), whose casual partner types were non-student (adjusted OR = 2.51, 95% CI = 1.45-4.22), and those who discussed using condoms during sexual intercourse (adjusted OR = 0.50, 95% CI = 0.28-0.89). CONCLUSION: The choice to engage in casual heterosexual sex with multiple partners was found to be associated with several factors among male college students, including economic status, engaging in sexual behavior after consuming alcohol, the type of the casual partner, and using condoms. These findings highlight the significance of implementing targeted interventions and comprehensive sexual health education programs within college settings in order to encourage safer sexual practices among students.

Disseminated Talaromyces Marneffei in a Patient with Newly Diagnosed HIV Co-Infection with Syphilis.

BACKGROUND: This article reports on a young male with respiratory symptoms as the first presentation. METHODS: We identified the suspected pathogen by microscopic examination of blood smears, which was subsequently confirmed by blood culture. RESULTS: The patient was confirmed to be infected with Talaromyces marneffei, and further testing revealed that he was a patient with HIV co-infected with syphilis. CONCLUSIONS: With heavy fungemia the organisms may be seen on the peripheral blood smear, which can facilitate prompt diagnosis and treatment.

A dual effect of ursolic acid to the treatment of multiple sclerosis through both immunomodulation and direct remyelination.

Current multiple sclerosis (MS) medications are mainly immunomodulatory, having little or no effect on neuroregeneration of damaged central nervous system (CNS) tissue; they are thus primarily effective at the acute stage of disease, but much less so at the chronic stage. An MS therapy that has both immunomodulatory and neuroregenerative effects would be highly beneficial. Using multiple in vivo and in vitro strategies, in the present study we demonstrate that ursolic acid (UA), an antiinflammatory natural triterpenoid, also directly promotes oligodendrocyte maturation and CNS myelin repair. Oral treatment with UA significantly decreased disease severity and CNS inflammation and demyelination in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Importantly, remyelination and neural repair in the CNS were observed even after UA treatment was started on day 60 post immunization when EAE mice had full-blown demyelination and axonal damage. UA treatment also enhanced remyelination in a cuprizone-induced demyelination model in vivo and brain organotypic slice cultures ex vivo and promoted oligodendrocyte maturation in vitro, indicating a direct myelinating capacity. Mechanistically, UA induced promyelinating neurotrophic factor CNTF in astrocytes by peroxisome proliferator-activated receptor γ(PPARγ)/CREB signaling, as well as by up-regulation of myelin-related gene expression during oligodendrocyte maturation via PPARγ activation. Together, our findings demonstrate that UA has significant potential as an oral antiinflammatory and neural repair agent for MS, especially at the chronic-progressive stage.