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This study aimed to explore the molecular mechanism of neuronal cell adhesion molecule (NrCAM) by regulating Th17 cell differentiation in the pathogenesis of Graves' disease (GD). Naïve CD4+ T cells were isolated from peripheral blood mononuclear cells of GD patients and healthy control (HC) subjects. During the differentiation of CD4+ T cells into Th17 cells, NrCAM level in GD group was improved. Interference with NrCAM in CD4+ T cells of GD patients decreased the percentage of Th17 cells. NrCAM overexpression in CD4+ T cells of HC subjects increased the percentage of Th17 cells and upregulated p‐IκBα, p50, p65, c‐Rel protein expressions, and NF‐κB inhibitor BAY11‐7082 partially reversed NrCAM effect. NrCAM overexpression promoted the degradation of IκBα, and overexpression of small ubiquitin‐related modifier 1 (SUMO‐1) inhibited IκBα degradation. NrCAM overexpression reduced IκBα binding to SUMO‐1. During Th17 cell differentiation in HC group, NrCAM overexpression increased IL‐21 levels and secretion, and IL‐21 neutralizing antibody reversed this effect. IL‐21 level was decreased after p65 interference in CD4+ T cells of HC subjects. p65 interacts with IL‐21 promoter region. In conclusion, NrCAM binds to SUMO‐1 and increases phosphorylation of IκBα, leading to activation of NF‐κB pathway, which promotes Th17 cell differentiation. [ABSTRACT FROM AUTHOR]

Staphyloccocus aureus (S. aureus) is a major bacterial pathogen in orthopedic periprosthetic joint infection (PJI). S. aureus forms biofilms that promote persistent infection by shielding bacteria from immune cells and inducing an antibiotic‐tolerant metabolic state. We developed an in vitro system to study S. aureus biofilm interactions with primary human monocytes in the absence of planktonic bacteria. In line with previous in vivo data, S. aureus biofilm induced expression of inflammatory genes such as TNF and IL1B, and their anti‐inflammatory counter‐regulator IL10. S. aureus biofilm also activated expression of PD‐1 ligands, and IL‐1RA, molecules that have the potential to suppress T cell function or differentiation of protective Th17 cells. Gene induction did not require monocyte:biofilm contact and was mediated by a soluble factor(s) produced by biofilm‐encased bacteria that was heat resistant and >3 kD in size. Activation of suppressive genes by biofilm was sensitive to suppression by Jak kinase inhibition. These results support an evolving paradigm that biofilm plays an active role in modulating immune responses, and suggest this occurs via production of a soluble vita‐pathogen‐associated molecular pattern, a molecule that signals microbial viability. Induction of T cell suppressive genes by S. aureus biofilm provides insights into mechanisms that can suppress T cell immunity in PJI. [ABSTRACT FROM AUTHOR]

ABSTRACT Regulator of G‐protein signalling (RGS) 10 plays critical roles in several immune related diseases. However, whether RGS10 is involved in colonic inflammation of ulcerative colitis (UC) is still obscure. This study aimed to investigate the role of RGS10 in UC. In this study, RGS10 expression was examined by quantitative real‐time polymerase chain reaction (qRT‐PCR), western blotting, immunohistochemistry, and immunofluorescent analysis. Single‐cell RNA sequencing of intestinal mucosa was performed to identify key immune cells with differentially expressed RGS10. RGS10 knockout mice were generated and established dextran sulphate sodium (DSS)‐induced colitis. Expression of inflammatory cytokines on mRNA and protein levels was detected by qRT‐PCR, enzyme‐linked immunosorbent assay, and flow cytometry. We found that RGS10 expression was significantly elevated in UC patients, especially in CD4+ T cells, compared with healthy subjects. Intriguingly, RGS10 deficiency markedly alleviated DSS‐induced colitis and decreased the proportion of Th1 and Th17 cells in lamina propria mononuclear cells (LPMCs), peripheral blood (PB), spleens, and mesenteric lymph nodes (mLNs). Mechanistically, RGS10 deficiency blocked the differentiation of Th1 and Th17 cells by inhibiting the phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT3. The co‐immunoprecipitation analysis further showed that RGS10 could interact with protein tyrosine phosphatase non‐receptor type 2 (PTPN2), and further regulated Th1 and Th17 cells differentiation of CD4+ T cells. In conclusion, RGS10 deficiency alleviated intestinal mucosal inflammation through inhibition of Th1/Th17 cell‐mediated immune responses via interaction with PTPN2 in CD4+ T cells. Therefore, targeting RGS10 may represent a novel therapeutic approach for UC treatment. [ABSTRACT FROM AUTHOR]

In vitro T‐cell differentiation from pluripotent stem cells (PSCs) could potentially provide an unlimited source of T cells for cancer immunotherapy, which, however is still hindered by the inefficient obtaining functionally‐matured, terminally‐differentiated T cells. Here, we established a fluorescence reporter human induced pluripotent stem cell (iPSC) line termed TCF7mCherryRUNX1GFP, in which the endogenous expression of RUNX1 and TCF7 are illustrated by the GFP and mCherry fluorescence, respectively. Utilizing TCF7mCherryRUNX1GFP, we defined that the feeder cells incorporating CXCL12‐expressing OP9 cells with DL4‐expressing OP9 cells at a 1:3 ratio (OP9‐C1D3) significantly enhanced efficiency of CD8+ T cell differentiation from PSCs. Additionally, we engineered a chimeric antigen receptor (CAR) targeting EGFR into iPSCs. The CAR‐T cells differentiated from these iPSCs using OP9‐C1D3 feeders demonstrated effective cytotoxicity toward lung cancer cells. We anticipate this platform will help the in vitro HSPC and T cell differentiation optimization, serving the clinical demands of these cells. [ABSTRACT FROM AUTHOR]

The commitment to specific T lymphocytes (T cell) lineages is governed by distinct transcription factors, whose expression is modulated through epigenetic mechanisms. Unravelling these epigenetic mechanisms that regulate T cell differentiation and function holds significant importance for understanding T cells. Menin, a multifunctional scaffolding protein, is implicated in various cellular processes, such as cell proliferation, cell cycle control, DNA repair and transcriptional regulation, primarily through epigenetic mechanisms. Existing research indicates Menin's impact on T cell differentiation and function, while a comprehensive and systematic review is currently lacking to consolidate these findings. In the current review, we have highlighted recent studies on the role of Menin in T cell differentiation and function, focusing mainly on its impact on the memory Th2 maintenance, Th17 differentiation and maintenance, CD4+ T cell senescence, and effector CD8+ T cell survival. Considering Menin's crucial function in maintaining effector T cell function, the potential of inhibiting Menin activity in mitigating inflammatory diseases associated with excessive T cell activation has also been emphasised. [ABSTRACT FROM AUTHOR]

Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency disease caused by mutations in exon 45 of the DOCK8 gene. The clinical signs primarily consist of increased serum IgE levels, eczema, repeated skin infections, allergies, and upper respiratory tract infections. Using CRISPR/Cas9 technology, we generated a DOCK8 exon 45 mutation in mice, mirroring the mutation found in patients. The results indicated that DOCK8 mutation impairs peripheral T cell homeostasis, disrupts regulatory T cells (Tregs) development, increases ICOS expression in Tregs within peripheral lymph nodes (pLn), and promotes Th17 cell differentiation within the spleen and pLn. Upon virus infection, DOCK8 mutation CD4+ T cells have a Th2 effector fate. RNA‐bulk sequencing data revealed alternations in the mTOR pathway of DOCK8 mutant CD4+ T cells. We observed that DOCK8 mutation upregulates the glycolysis levels in CD4+ T cells, which is related to the Akt/mTOR/S6/HIF‐1α pathway. In summary, our research elucidates that DOCK8 regulates the differentiation of helper T cells by modulating the glycolytic pathway in CD4+ T cells, thereby advancing the comprehension and offering potential treatment of diseases in DOCK8‐deficient patients. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is a major global health concern, particularly affecting those with weakened immune systems, including the elderly. CD4+ T cell response is crucial for immunity against M.tb, but chronic infections and aging can lead to T cell exhaustion and senescence, worsening TB disease. Mitochondrial dysfunction, prevalent in aging and chronic diseases, disrupts cellular metabolism, increases oxidative stress, and impairs T‐cell functions. This study investigates the effect of mitochondrial transplantation (mito‐transfer) on CD4+ T cell differentiation and function in aged mouse models and human CD4+ T cells from elderly individuals. Mito‐transfer in naïve CD4+ T cells is found to promote protective effector and memory T cell generation during M.tb infection in mice. Additionally, it improves elderly human T cell function by increasing mitochondrial mass and altering cytokine production, thereby reducing markers of exhaustion and senescence. These findings suggest mito‐transfer as a novel approach to enhance aged CD4+ T cell functionality, potentially benefiting immune responses in the elderly and chronic TB patients. This has broader implications for diseases where mitochondrial dysfunction contributes to T‐cell exhaustion and senescence. [ABSTRACT FROM AUTHOR]

Cellular differentiation allows cells to transition between different functional states and adapt to various environmental cues. The diversity and plasticity of this process is beautifully exemplified by T cells responding to pathogens, which undergo highly specialized differentiation tailored to the ongoing infection. Such antigen‐induced T cell differentiation is regulated at the transcriptional level by DNA‐binding proteins and at the post‐transcriptional level by RNA‐binding proteins. Although traditionally defined as separate protein classes, a growing body of evidence indicates an overlap between these two groups of proteins, collectively coined DNA/RNA‐binding proteins (DRBPs). In this review, we describe how DRBPs might bind both DNA and RNA, discuss the putative functional relevance of this dual binding, and provide an exploratory analysis into characteristics that are associated with DRBPs. To exemplify the significance of DRBPs in T cell biology, we detail the activity of several established and putative DRBPs during the T cell response. Finally, we highlight several methodologies that allow untangling of the distinct functionalities of DRBPs at the DNA and RNA level, including key considerations to take into account when applying such methods. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Reasons for Th2 skewing in IgE‐mediated food allergies remains unclear. Clinical observations suggest impaired T cell activation may drive Th2 responses evidenced by increased atopic manifestations in liver transplant patients on tacrolimus (a calcineurin inhibitor). We aimed to assess differentiation potential, T cell activation and calcium influx of naïve CD4+ T cells in children with IgE‐mediated food allergies.Peripheral blood mononuclear cells from infants in the Starting Time for Egg Protein (STEP) Trial were analyzed by flow cytometry to assess Th1/Th2/Treg development. Naïve CD4+ T cells from children with and without food allergies were stimulated for 7 days to assess Th1/Th2/Treg transcriptional factors and cytokines. Store operated calcium entry (SOCE) was measured in children with and without food allergies. The effect of tacrolimus on CD4+ T cell differentiation was assessed by treating stimulated naïve CD4+ T cells from healthy volunteers with tacrolimus for 7 days.Egg allergic infants had impaired development of IFNγ+ Th1 cells and FoxP3+ transitional CD4+ T cells compared with non‐allergic infants. This parallels reduced T‐bet, IFNγ and FoxP3 expression in naïve CD4+ T cells from food allergic children after in vitro culture. SOCE of naïve CD4+ T cells was impaired in food allergic children. Naïve CD4+ T cells treated with tacrolimus had reduced IFNγ, T‐bet, and FoxP3, but preserved IL‐4 expression.In children with IgE‐mediated food allergies, dysregulation of T helper cell development is associated with impaired SOCE, which underlies an intrinsic impairment in Th1 and Treg differentiation. Along with tacrolimus‐induced Th2 skewing, this highlights an important role of SOCE/calcineurin pathway in T helper cell differentiation. [ABSTRACT FROM AUTHOR]

This article discusses the association between cytotoxic effector memory CD8+ T cells and sustained unresponsiveness (SU) after peanut oral immunotherapy (OIT). The study found that a higher frequency of effector memory CD8+ T cells was associated with a higher likelihood of achieving SU. The researchers also identified differentially expressed immune genes and observed that cytolytic molecules such as Granulysin (Gnly) and Granzyme B (GzB) may play a supportive role in the development of SU. However, the study acknowledges the need for further validation using larger cohorts. [Extracted from the article]

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron subvariants raises concerns regarding the effectiveness of immunity acquired from previous Omicron subvariants breakthrough infections (BTIs) or reinfections (RIs) against the current circulating Omicron subvariants. In this study, we prospectively investigate the dynamic changes of virus‐specific antibody and T cell responses among 77 adolescents following Omicron BA.2.3 BTI with or without subsequent Omicron BA.5 RI. Notably, the neutralizing antibodies (NAbs) titers against various detected SARS‐CoV‐2 variants, especially the emerging Omicron CH.1.1, XBB.1.5, XBB.1.16, EG.5.1, and JN.1 subvariants, exhibited a significant decrease along the time. A lower level of IgG and NAbs titers post‐BTI was found to be closely associated with subsequent RI. Elevated NAbs levels and shortened antigenic distances were observed following Omicron BA.5 RI. Robust T cell responses against both Omicron BA.2‐ and CH.1.1‐spike peptides were observed at each point visited. The exposure to Omicron BA.5 promoted phenotypic differentiation of virus‐specific memory T cells, even among the non‐seroconversion adolescents. Therefore, updated vaccines are needed to provide effective protection against newly emerging SARS‐CoV‐2 variants among adolescents. [ABSTRACT FROM AUTHOR]

Genetic variants of the OX40 ligand (OX40L) locus are associated with the risk of systemic lupus erythematosus (SLE), it is unclear how the OX40L blockade delays the lupus phenotype. Therefore, we examined the effects of an anti‐OX40L antibody in MRL/Lpr mice. Next, we investigated the effect of anti‐OX40L on immunosuppression in keyhole limpet hemocyanin‐immunized C57BL/6J mice. In vitro treatment of anti‐OX40L in CD4+ T and B220+ B cells was used to explore the role of OX40L in the pathogenesis of SLE. Anti‐OX40L alleviated murine lupus nephritis, accompanied by decreased production of anti‐dsDNA and proteinuria, as well as lower frequencies of splenic T helper (Th) 1 and T‐follicular helper cells (Tfh). In keyhole limpet hemocyanin‐immunized mice, decreased levels of immunoglobulins and plasmablasts were observed in the anti‐OX40L group. Anti‐OX40L reduced the number and area of germinal centers. Compared with the control IgG group, anti‐OX40L downregulated CD4+ T‐cell differentiation into Th1 and Tfh cells and upregulated CD4+ T‐cell differentiation into regulatory T cells in vitro. Furthermore, anti‐OX40L inhibited toll‐like receptor 7‐mediated differentiation of antibody‐secreting cells and antibody production through the regulation of the SPIB‐BLIMP1‐XBP1 axis in B cells. These results suggest that OX40L is a promising therapeutic target for SLE. [ABSTRACT FROM AUTHOR]

The utilization of anti‐CD3/CD28 magnetic beads for T cell expansion in vitro has been investigated for adoptive cell transfer therapy. However, the impact of the CD3/CD28 antibody ratio on T cell differentiation and function remains incompletely elucidated. This study seeks to address this knowledge gap. To begin with, CD3 antibodies with a relatively low avidity for Jurkat cells (Kd = 13.55 nM) and CD28 antibodies with a relatively high avidity (Kd = 5.79 nM) were prepared. Afterwards, anti‐CD3/CD28 antibodies with different mass ratios were attached to magnetic beads to examine the impacts of different antibody ratios on T cell capture, and proliferation. The research demonstrated that the most significant expansion of T cells was stimulated by the anti‐CD3/CD28 magnetic beads with a mass ratio of 2:1 for CD3 antibodies and CD28 antibodies. Moreover, CD25 and PD1 expression of expanded T cells increased and then decreased, with lower CD25 and PD1 expression in the later stages of expansion indicating that T cells were not depleted. These T cells, which are massively expanded in vitro and have excellent expansion potential, can be infused back into the patient to treat tumor patients. This study shows that altering the ratio of anti‐CD3/CD28 antibodies can control the strength of T cell stimulation, thereby leading to the improvement of T cell activation. This discovery can be utilized as a guide for the creation of other T cell stimulation approaches, which is beneficial for the further development of tumor immunotherapy technology. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion To explore T cell‐intrinsic mechanisms underpinning the mal‐differentiation of tissue‐resident memory T (Trm) cells in patients with rheumatoid arthritis (RA).Circulating T cells from patient with RA and healthy individuals were used for Trm cell differentiation. The role of Hobit in Trm differentiation was investigated through targeted silencing experiments. Psmb5 expression regulation was explored by identifying BRD2 as a key transcription factor, with the interaction validated through chromatin immunoprecipitation‐quantitative polymerase chain reaction. The impact of BRD2 succinylation on Trm differentiation was examined by manipulating succinyl‐CoA levels in T cells. Humanized NSG chimeras representing synovitis provided insights into Trm infiltration in RA synovitis and were used for translational experiments.In patients with RA, a notable predisposition of CD4+ T cells toward differentiation into Trm cells was observed, demonstrating a positive correlation with the disease activity score 28. Remarkably, Hobit was a pivotal facilitator in the formation of RA CD4+ Trm cells. Mechanistic studies unveiled the dysregulation of proteasomal Psmb5 in T cells of patients with RA as the key factor contributing to elevated Hobit protein levels. The deficiency of proteasomal Psmb5 was intricately linked to BRD2, with succinylation exerting a significant impact on Psmb5 transcription and Trm cell differentiation. This heightened BRD2 succinylation was attributed to elevated levels of mitochondrial succinyl‐CoA in RA T cells. Consequently, targeting succinyl‐CoA within CD4+ T cells controlled the inflammation of synovial tissues in humanized chimeras.Mitochondrial succinyl‐CoA fosters the succinylation of BRD2, resulting in compromised transcription of proteasomal Psmb5 and the differentiation of Trm cells in RA. [ABSTRACT FROM AUTHOR]

Although the roles of E proteins and inhibitors of DNA‐binding (Id) in T follicular helper (TFH) and T follicular regulatory (TFR) cells have been previously reported, direct models demonstrating the impact of multiple E protein members have been lacking. To suppress all E proteins including E2A, HEB and E2‐2, we overexpressed Id1 in CD4 cells using a CD4‐Id1 mouse model, to observe any changes in TFH and TFR cell differentiation. Our objective was to gain better understanding of the roles that E proteins and Id molecules play in the differentiation of TFH and TFR cells. The CD4‐Id1 transgenic (TG) mice that we constructed overexpressed Id1 in CD4 cells, inhibiting E protein function. Our results showed an increase in the proportion and absolute numbers of Treg, TFH and TFR cells in the spleen of TG mice. Additionally, the expression of surface characterisation molecules PD‐1 and ICOS was significantly upregulated in TFH and TFR cells. The study also revealed a downregulation of the marginal zone B cell precursor and an increase in the activation and secretion of IgG1 in spleen B cells. Furthermore, the peripheral TFH cells of TG mice enhanced the function of assisting B cells. RNA sequencing results indicated that a variety of TFH‐related functional molecules were upregulated in TFH cells of Id1 TG mice. In conclusion, E proteins play a crucial role in regulating TFH/TFR cell differentiation and function and suppressing E protein activity promotes germinal centre humoral immunity, which has important implications for immune regulation and treating related diseases. [ABSTRACT FROM AUTHOR]

Seminal plasma induces immune tolerance towards paternal allogenic antigens within the female reproductive tract and during foetal development. Recent evidence suggests a role for extracellular vesicles in seminal plasma (spEVs). We isolated spEVs from seminal plasma that was donated by vasectomized men, thereby excluding any contributions from the testis or epididymis. Previous analysis demonstrated that such isolated spEVs originate mainly from the prostate. Here we observed that when isolated fluorescently labelled spEVs were mixed with peripheral blood mononuclear cells, they were endocytosed predominantly by monocytes, and to a lesser extent also by T‐cells. In a mixed lymphocyte reaction, T‐cell proliferation was inhibited by spEVs. A direct effect of spEVs on T‐cells was demonstrated when isolated T cells were activated by anti‐CD3/CD28 coated beads. Again, spEVs interfered with T cell proliferation, as well as with the expression of CD25 and the release of IFN‐γ, TNF, and IL‐2. Moreover, spEVs stimulated the expression of Foxp3 and IL‐10 by CD4+CD25+CD127‐ T cells, indicating differentiation into regulatory T‐cells (Tregs). Prior treatment of spEVs with proteinase K revoked their effects on T‐cells, indicating a requirement for surface‐exposed spEV proteins. The adenosine A2A receptor‐specific antagonist CPI‐444 also reduced effects of spEVs on T‐cells, consistent with the notion that the development of Tregs and their immune suppressive functions are under the influence of adenosine‐A2A receptor signalling. We found that adenosine is highly enriched in spEVs and propose that spEVs are targeted to and endocytosed by T‐cells, after which they may release their adenosine content into the lumen of endosomes, thus allowing endosome‐localized A2A receptor signalling in spEVs targeted T‐cells. Collectively, these data support the idea that spEVs can prime T cells directly for differentiation into Tregs. [ABSTRACT FROM AUTHOR]

Cenicriviroc, a dual CCR2/CCR5 antagonist, initially developed as an anti‐HIV drug, has shown promising results in nonalcoholic steatohepatitis phase 2 clinical trials. It inhibits the infiltration and activation of CCR2+/CCR5+ monocytes and macrophages to the site of liver injury, preventing liver fibrosis. However, the role of Cenicriviroc in the modulation of helper T cell differentiation and functions remains to be explored. In inflamed colons of Crohn's disease patients, CCR2+ and CCR5+ CD4+ T cells are enriched. Considering the role of CCR2+ and CCR5+ T cells in IBD pathogenesis, we investigated the potential role of Cenicriviroc in colitis. Our in vitro studies revealed that Cenicriviroc inhibits Th1‐, Th2‐, and Th17‐cell differentiation while promoting the generation of type 1 regulatory T cells (Tr1), known for preventing inflammation through induction of IL‐10. This study is the first to report that Cenicriviroc promotes Tr1 cell generation by up‐regulating the signature of Tr1 cell transcription factors such as c‐Maf, Prdm1, Irf‐1, Batf, and EGR‐2. Cenicriviroc displayed a protective effect in experimental colitis models by preventing body weight loss and intestinal inflammation and preserving epithelial barrier integrity. We show that Cenicriviroc induced IL‐10 and inhibited the generation of pro‐inflammatory cytokines IFN‐γ, IL‐17, IL‐6, and IL‐1β during colitis. Based on our data, we propose Cenicriviroc as a potential therapeutic in controlling tissue inflammation by inhibiting the generation and functions of effector T cells and promoting the induction of anti‐inflammatory Tr1 cells. [ABSTRACT FROM AUTHOR]

Within the three‐dimensional (3D) nuclear space, the genome organizes into a series of orderly structures that impose important influences on gene regulation. T lymphocytes, crucial players in adaptive immune responses, undergo intricate transcriptional remodeling upon activation, leading to differentiation into specific effector and memory T cell subsets. Recent evidence suggests that T cell activation is accompanied by dynamic changes in genome architecture at multiple levels, providing a unique biological context to explore the functional relevance and molecular mechanisms of 3D genome organization. Here, we summarize recent advances that link the reorganization of genome architecture to the remodeling of transcriptional programs and conversion of cell fates during T cell activation and differentiation. We further discuss how various chromatin architecture regulators, including CCCTC‐binding factor and several transcription factors, collectively modulate the genome architecture during this process. [ABSTRACT FROM AUTHOR]

Weakened germinal center responses by the aged immune system result in diminished immunity against pathogens and reduced efficacy of vaccines. Prolonged contacts between activated B cells and CD4+ T cells are crucial to germinal center formation and T follicular helper cell (Tfh) differentiation, but it is unclear how aging impacts the quality of this interaction. Peptide immunization confirmed that aged mice have decreased expansion of antigen‐specific germinal center B cells and reduced antibody titers. Furthermore, aging was associated with accumulated Tfh cells, even in naïve mice. Despite increased numbers, aged Tfh had reduced expression of master transcription factor BCL6 and increased expression of the ectonucleotidase CD39. In vitro activation revealed that proliferative capacity was maintained in aged CD4+ T cells, but not the costimulatory molecule CD40L. When activated in vitro by aged antigen‐presenting cells, young CD4+ naïve T cells generated reduced numbers of activated cells with upregulated CD40L. To determine the contribution of cell‐extrinsic influences on antigen‐specific Tfh induction, young, antigen‐specific B and CD4+ T cells were adoptively transferred into aged hosts prior to peptide immunization. Transferred cells had reduced expansion and differentiation into germinal center B cell and Tfh and reduced antigen‐specific antibody titers when compared to young hosts. Young CD4+ T cells transferred aged hosts differentiated into Tfh cells with reduced PD‐1 and BCL6 expression, and increased CD39 expression, though they maintained their mitochondrial capacity. These results highlight the role of the lymphoid microenvironment in modulating CD4+ T cell differentiation, which contributes to impaired establishment and maintenance of germinal centers. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is characterized by nasal symptoms such as rubbing and sneezing, often triggered by allergen exposure. The purpose of this study is to dissect the roles of NLRP3‐mediated immune modulation and macrophage pyroptosis in modulating T cell differentiation within the context of ovalbumin (OVA)‐induced AR in mice. OVA‐induced AR was established in mice, evaluating nasal symptoms, macrophage infiltration, cytokine levels, and T cell differentiation. Manipulations using NLRP3−/−, ASC−/− mice, clodronate liposome treatment, and NLRP3 inhibitor MCC950 were performed to assess their impact on AR symptoms and immune responses. Following OVA stimulation, increased nasal symptoms were observed in the OVA group along with augmented GATA3 expression and elevated IL‐4 and IL‐1b levels, indicative of Th2 polarization and cellular pyroptosis involvement. NLRP3−/− and ASC−/− mice exhibited reduced CD3+ T cells post OVA induction, implicating cellular pyroptosis in AR. Macrophage depletion led to decreased IgE levels, highlighting their involvement in allergic responses. Further investigations revealed enhanced macrophage pyroptosis, influencing Th1/Th2 differentiation in AR models. IL‐18 released through NLRP3‐mediated pyroptosis induced Th2 differentiation, distinct from IL‐1b. Additionally, MCC950 effectively mitigated AR symptoms by modulating Th2 responses and reducing macrophage infiltration. This comprehensive study unravels the pivotal role of NLRP3‐mediated immune modulation and macrophage pyroptosis in Th1/Th2 balance regulation in OVA‐induced AR. Targeting NLRP3 pathways with MCC950 emerged as a promising strategy to alleviate AR symptoms, providing insights for potential therapeutic interventions in AR management. Significance statement: This study investigated the complex immune mechanisms underlying ovalbumin‐induced allergic rhinitis (AR) in mice, focusing on NLRP3‐mediated immune regulation and macrophage pyroptosis. This study reveals the critical role of NLRP3 in regulating Th1/Th2 balance and its impact on allergic responses. This study shows that inhibiting NLRP3 with MCC950 can effectively reduce AR symptoms, suggesting a promising therapeutic strategy. These findings contribute to the understanding of AR pathogenesis, emphasizing the involvement of pyroptosis, Th1/Th2 differentiation, and the NLRP3 pathway. This comprehensive exploration may pave the way for targeted therapies, providing potential interventions for the management of AR and improving the quality of life of affected individuals. [ABSTRACT FROM AUTHOR]

Introduction: Mucosa‐associated lymphoid tissue 1 (MALT1) modulates T helper cell differentiation, pro‐inflammatory cytokine production, and epidermal hyperplasia to participate in the pathology of psoriasis. This study aimed to explore the correlation of blood MALT1 with treatment outcomes in psoriasis patients. Methods: MALT1 was detected in peripheral blood mononuclear cells by reverse transcription‐quantitative polymerase chain reaction in 210 psoriasis patients before starting or converting to a new therapy, 50 disease controls, and 50 healthy controls. The psoriasis area severity index (PASI) score was evaluated at month (M)1, M3, and M6 in psoriasis patients. Results: MALT1 was increased in psoriasis patients versus disease controls and healthy controls (both p <.001); and positively related to body mass index (p =.019) and PASI score (p <.001) in psoriasis patients. PASI75 rate at M1, M3, and M6 was 22.9%, 46.2%, and 71.0%, respectively; while PASI90 rate at M1, M3, and M6 was 3.8%, 29.0%, and 50.5%, respectively, in psoriasis patients. PASI75/90 rates at M1, M3, and M6 were increased in psoriasis patients receiving biologics versus those without (all p <.05). Pretreatment MALT1 was higher in psoriasis patients who achieved PASI75 (p =.001) and PASI90 (p <.001) at M6 compared to those who did not achieve that. Subgroup analyses discovered that pretreatment MALT1 had a stronger ability to predict PASI75 and 90 realizations in psoriasis patients receiving biologics (area under the curve [AUC]: 0.723 and 0.808) versus those without (AUC: 0.594 and 0.675). Conclusion: Blood MALT1 measurement may assist in predicting outcomes in psoriasis patients, especially in those receiving biologics. [ABSTRACT FROM AUTHOR]

Serum amyloid A (SAA) is a clinically useful inflammatory marker involved in the pathogenesis of autoimmune diseases. This study aimed to explore the SAA levels in a cohort of patients with myasthenia gravis (MG) in relation to disease‐related clinical parameters and myasthenic crisis (MC) and elucidate the effects of SAA on immune response. A total of 82 MG patients including 50 new‐onset MG patients and 32 MC patients were enrolled in this study. Baseline data and laboratory parameters of all enrolled MG patients were routinely recorded through electronic medical systems. SAA levels were measured by enzyme‐linked immunosorbent assay (ELISA) kit. CD4+ T and CD19+ B cell subsets were analyzed by flow cytometry. In vitro, human recombinant SAA (Apo‐SAA) was applied to stimulate peripheral blood mononuclear cells (PBMCs) from MG patients to observe the effect on T and B cell differentiation. Our results indicated that SAA levels in new‐onset MG patients were higher than those in controls and were positively correlated with QMG score, MGFA classification, plasmablast cells, IL‐6, and IL‐17 levels. Subgroup analysis revealed that SAA levels were increased in generalized MG (GMG) patients than in ocular MG (OMG), as well as elevated in late‐onset MG (LOMG) than in early‐onset MG (EOMG) and higher in MGFA III/IV compared with MGFA I/II. The ROC curve demonstrated that SAA showed good diagnostic value for MC, especially when combined with NLR. In vitro, Apo‐SAA promoted the Th1 cells, Th17 cells, plasmablast cells, and plasma cells differentiation in MG PBMCs. The present findings suggested that SAA was increased in MG patients and promoted expansion of CD4+ T cell and CD19+ B cell subsets, which implicated in the severity of MG patients. [ABSTRACT FROM AUTHOR]

Background: Inflammation can worsen spinal cord injury (SCI), with dendritic cells (DCs) playing a crucial role in the inflammatory response. They mediate T lymphocyte differentiation, activate microglia, and release cytokines like NT‐3. Moreover, DCs can promote neural stem cell survival and guide them toward neuron differentiation, positively impacting SCI outcomes. Objective: This review aims to summarize the role of DCs in SCI‐related inflammation and identify potential therapeutic targets for treating SCI. Methods: Literature in PubMed and Web of Science was reviewed using critical terms related to DCs and SCI. Results: The study indicates that DCs can activate microglia and astrocytes, promote T‐cell differentiation, increase neurotrophin release at the injury site, and subsequently reduce secondary brain injury and enhance functional recovery in the spinal cord. Conclusions: This review highlights the repair mechanisms of DCs and their potential therapeutic potential for SCI. [ABSTRACT FROM AUTHOR]

Tapasin, a crucial molecular chaperone involved viral antigen processing and presentation, plays an important role in antivirus immunity. However, its impact on T cell differentiation in the context of virus clearance remains unclear. In this study, we employed induced pluripotent stem cells to differentiate into hepatocyte‐like cell, which were subsequently inserted to the inverted colloidal crystal scaffolds, thus establishing a hepatocyte organoid (HO). By inoculating hepatitis B virus (HBV) particles in the system, we successfully engineered a robust in vitro HBV infection model for at least 3 weeks. Furthermore, we aimed to explore the effects of lentivirus‐mediated short hairpin RNA (shRNA) targeting human Tapasin on the differentiation and antiviral function of CD8+ T cells. Specifically, we transfected dendritic cells (DCs) with Tapasin‐shRNA and cocultured with T cells. The results demonstrated that Tapasin‐shRNA transfected DCs effectively suppressed T cell proliferation and impeded HBV‐specific cytotoxic T lymphocyte responses. Our investigation also revealed the role of mTOR pathway activation in reducing autophagy activity within CD8+ T cells. Expressions of autophagy‐related proteins, beclin‐1, LC3II/LC3I were decreased and PI3K/AKT/mTOR activity was increased in Tapasin‐shRNA group. Collectively, our findings elucidate that shRNA targeting the Tapasin gene within DCs inhibits T cell differentiation by reducing autophagy activity to hamper viral clearance in the HBV‐infected HO. [ABSTRACT FROM AUTHOR]

This article provides a summary of recent research on unconventional T cells, specifically focusing on gamma delta (γδ) T cells and mucosal-associated invariant T (MAIT) cells. The research highlights the development, trafficking, and target cell recognition of these T cell subsets. The article discusses the differentiation stages of Vγ9Vδ2 T cells in the thymus and their functional maturity. It also explores the AMPK-dependent mechanism that allows Vγ9Vδ2 T cells to recognize stress-transformed cancer cells. Additionally, the article examines the role of γδ T cells, including Vδ1 and Vδ3 subsets, in HLA-class-I-negative colon cancers and their contribution to immune checkpoint blockade responsiveness. The research also investigates the involvement of unconventional T cells, such as γδ T cells and MAIT cells, in tissue repair, particularly in burn injuries and skin wound healing. Overall, these studies contribute to a better understanding of the functionality and therapeutic potential of unconventional T cell subsets. [Extracted from the article]

Atherosclerosis can cause severe cardiovascular disease, which is usually diagnosed in late stages with life‐threatening complications. The lack of obvious symptoms limits its early diagnosis and timely treatment. In this work, a theranostic nanoplatform PGA@PMP is constructed for targeting photoacoustic diagnosis and a "hand‐in‐hand" immunoregulation of early‐stage atherosclerosis. Coated with biomimetic platelet membrane, PGA@PMP can actively target to the pathological endothelium and respond to the reactive oxygen species (ROS) in lesions for further disassembly and releasing photoacoustic probe along with immune‐regulate complex GWAS. The photoacoustic probe performs a noninvasive imaging with distinct recognition of plaques. In company, triggered by local cathepsin B, GWAS can be degraded for respective regulation on inducing M2 macrophages and stimulating regulatory T (Treg) cells. The transforming growth factor beta (TGF‐β) expressed by up‐regulated M2 macrophages also intensifies the Treg cell differentiation, which synergistically inhibits the foam cell formation and rebuilds a well‐balanced immune microenvironment. The in vivo evaluations suggest that the "hand‐in‐hand" strategy on regulating macrophages polarization and T cell differentiation indicates the restraint on atherosclerotic progression and the reversal of formed lesions even under high‐fat diet. Together, PGA@PMP provides an integrated solution for targeting theranostics of early‐stage atherosclerosis and delivers an exciting outcome of reversing the formed lesions. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effect of IWP‐2, Wnt inhibitor, on human dental pulp stem cells (hDPSCs) responses. Methodology: hDPSCs were isolated from human dental pulp tissues. Cells were treated with 25 μM IWP‐2 for 24 h, and subsequently, the gene expression profile was examined using high‐throughput RNA sequencing. The mRNA expression was analysed using qPCR. The effect of IWP‐2 was investigated in both normal and LPS‐induced hDPSCs (inflamed hDPSCs). CD4+ T cells and CD14+ monocyte‐derived macrophages were cultured with conditioned media of IWP‐2 treated hDPSCs to observe the immunosuppressive property. Results: RNA sequencing indicated that IWP‐2 significantly downregulated several KEGG pathways, including cytokine‐cytokine receptor interaction, IL‐17 signalling pathway, and TNF signalling pathway. In both normal and inflamed conditions, IWP‐2 markedly upregulated TGFB1 mRNA expression while the mRNA expression of pro‐inflammatory cytokines, TNFA, IL1B, IFNG, and IL6, was inhibited. In the inhibition experiment, the pretreatment with p38, MAPK, or PI3K inhibitors abolished the effects of IWP‐2 in LPS‐induced inflammation. In terms of immune cells, IWP‐2‐treated‐inflamed hDPSCs conditioned media attenuated T cell proliferation and regulated regulatory T cell differentiation. In addition, the migratory property of macrophage was decreased after being exposed to IWP‐2‐treated inflamed hDPSCs conditioned media. Conclusion: IWP‐2 suppressed inflammatory cytokine expression in both normal and inflamed hDPSCs. Moreover, hDPSCs exerted the immunosuppressive property after IWP‐2 treatment. These results suggest the role of Wnt in inflammatory responses and immunomodulation in dental pulp tissues. [ABSTRACT FROM AUTHOR]

Fucosylation plays a critical role in cell‐to‐cell interactions and disease progression. However, the effects of fucosylation on splenocytes and their interactions with T cells remain unclear. In this study, we aimed to explore the transcriptome profiles of splenocytes deficient in fucosyltransferase (FUT) 1, an enzyme that mediates fucosylation, and investigate their impact on the proliferation and differentiation of T cells. We analysed and compared the transcriptomes of splenocytes isolated from Fut1 knockout (KO) mice and those from wild‐type (WT) mice using RNA‐seq. Additionally, we examined the effects of Fut1 KO splenocytes on CD4 T cell proliferation and differentiation, in comparison to WT splenocytes, and elucidated the mechanisms involved. The comparative analysis of transcriptomes between Fut1 KO and WT splenocytes revealed that thrombospondin‐1, among the genes related to immune response and inflammation, was the most highly downregulated gene in Fut1 KO splenocytes. The reduced expression of thrombospondin‐1 was further confirmed using qRT‐PCR and flow cytometry. In coculture experiments, Fut1 KO splenocytes promoted the proliferation of CD4 T cells and drove their differentiation toward Th1 and Th17 cells, compared with WT splenocytes. Moreover, the levels of IL‐2, IFN‐γ and IL‐17 were increased, while IL‐10 was decreased, in T cells cocultured with Fut1 KO splenocytes compared with those with WT splenocytes. These effects of Fut1 KO splenocytes on T cells were reversed when thrombospondin‐1 was replenished. Taken together, our results demonstrate that splenocytes with Fut1 deficiency promote CD4 T cell proliferation and Th1/Th17 differentiation at least in part through thrombospondin‐1 downregulation. [ABSTRACT FROM AUTHOR]

Gut microbiome is integral to the pathogenesis of ulcerative colitis. A novel probiotic Lactobacillus intestinalis (L. intestinalis) exerts a protective effect against dextran sodium sulfate‐induced colitis in mice. Based on flow cytometry, colitis‐associated Th17 cells are the target of L. intestinalis, which is supported by the lack of protective effects of L. intestinalis in T cell‐null Rag1−/− mice or upon anti‐IL‐17‐A antibody‐treated mice. Although L. intestinalis exerts no direct effect on T cell differentiation, it decreases C/EBPA‐driven gut epithelial SAA1 and SAA2 production, which in turn impairs Th17 cell differentiation. Cometabolism of L. intestinalis ALDH and host ALDH1A2 contributed to elevated biosynthesis of retinoic acid (RA), which accounts for the anti‐colitis effect in RAR‐α ‐mediated way. In a cohort of ulcerative colitis patients, it is observed that fecal abundance of L. intestinalis is negatively associated with the C/EBPA‐SAA1/2‐Th17 axis. Finally, L. intestinalis has a synergistic effect with mesalazine in alleviating murine colitis. In conclusion, L. intestinalis and associated metabolites, RA, have potential therapeutic effects for suppressing colonic inflammation by modulating the crosstalk between intestinal epithelia and immunity. [ABSTRACT FROM AUTHOR]

Mononuclear phagocytes (MPs) are vital components of host immune defenses against cancer. However, tumor‐infiltrating MPs often present tolerogenic and pro‐tumorigenic phenotypes via metabolic switching triggered by excessive lipid accumulation in solid tumors. Inspired by viral infection‐mediated MP modulation, here enveloped immunometabolic nanoparticles (immeNPs) are designed to co‐deliver a viral RNA analog and a fatty acid oxidation regulator for synergistic reshaping of intratumoral MPs. These immeNPs are camouflaged with cancer cell membranes for tumor homing and opsonized with anti‐CD163 antibodies for specific MP recognition and uptake. It is found that internalized immeNPs coordinate lipid metabolic reprogramming with innate immune stimulation, inducing M2‐to‐M1 macrophage repolarization and tolerogenic‐to‐immunogenic dendritic cell differentiation for cytotoxic T cell infiltration. The authors further demonstrate that the use of immeNPs confers susceptibility to anti‐PD‐1 therapy in immune checkpoint blockade‐resistant breast and ovarian tumors, and thereby provide a promising strategy to expand the potential of conventional immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Autoimmune diseases (AD) are severe pathophysiological ailments that are stimulated by an exaggerated immunogenic response towards self‐antigens, which can cause systemic or site‐specific organ damage. An array of complex genetic and epigenetic facets majorly contributes to the progression of AD, thus providing significant insight into the regulatory mechanism of microRNA (miRNA). miRNAs are short, non‐coding RNAs that have been identified as essential contributors to the post‐transcriptional regulation of host genome expression and as crucial regulators of a myriad of biological processes such as immune homeostasis, T helper cell differentiation, central and peripheral tolerance, and immune cell development. Aims: This article tends to deliberate and conceptualize the brief pathogenesis and pertinent epigenetic regulatory mechanism as well as miRNA networks majorly affecting five different ADs namely rheumatoid arthritis (RA), type 1 diabetes, multiple sclerosis (MS), systemic lupus erythematosus (SLE) and inflammatory bowel disorder (IBD) thereby providing novel miRNA‐based theranostic interventions. Results & Discussion: Pertaining to the differential expression of miRNA attributed in target tissues and cellular bodies of innate and adaptive immunity, a paradigm of scientific expeditions suggests an optimistic correlation between immunogenic dysfunction and miRNA alterations. Conclusion: Therefore, it is not astonishing that dysregulations in miRNA expression patterns are now recognized in a wide spectrum of disorders, establishing themselves as potential biomarkers and therapeutic targets. Owing to its theranostic potencies, miRNA targets have been widely utilized in the development of biosensors and other therapeutic molecules originating from the same. [ABSTRACT FROM AUTHOR]

Metabolism and metabolic processes have long been considered to shape the tumour immunosuppressive microenvironment. Recent research has demonstrated that T regulatory cells (Tregs) display high rates of fatty acid oxidation (FAO) and a relatively low rate of glycolysis. Sphingosine 1‐phosphate (S1P), which is a G protein signalling activator involved in immune regulation and FAO modulation, has been implicated in Treg differentiation. However, the precise relation between Treg differentiation and S1P remains unclear. In this study, we isolated naïve CD4+ T cells from the spleens of 6–8‐week‐old BALB/c mice using magnetic bead sorting, which was used in our study for Treg differentiation. S1P stimulation was performed during Treg differentiation. We examined the oxygen consumption and palmitic acid metabolism of the differentiated Tregs and evaluated the expression levels of various proteins, including Nrf2, CPT1A, Glut1, ACC1 and PPARα, through Western blotting. Our results demonstrate that S1P promotes Treg differentiation and enhances FAO, and that the expression of nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) and peroxisome proliferator‐activated receptor α (PPARα) is upregulated. Furthermore, Nrf2 or PPARα knockdown dampened the Treg differentiation and FAO that were promoted by S1P, confirming that S1P can bind with S1PR4 to promote Treg differentiation through the Nrf2/PPARα signalling pathway, which may be related to FAO facilitation. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 4 (STAT4) is a critical transcription factor for T helper cell differentiation and tumor cells. Although its prognostic role and gene function have been reported in several carcinomas, the role of STAT4 in vitro and in vivo in breast cancer remains poorly understood. The effect of STAT4 in immunotherapy is also unclear. Therefore, we integrated bulk transcriptomics, experiments, and single‐cell transcriptomics to systematically analyze its function in prognosis and signaling pathway. Several clinical breast cancer cohorts confirmed STAT4 as a T‐cell relevant prognostic biomarker. Overexpressed STAT4 increased programmed cell death ligand 1 (PD‐L1) and major histocompatibility complex class II levels in breast cancer cells. In molecular mechanism, transcriptional synergy between STAT4 and STAT3 transactivated interleukin (IL)‐12R and involved a positive feedback loop: STAT4/IL‐12R/JAK2–STAT3–STAT4, which contributed to the upregulation of PD‐L1 expression. The above signaling axis was defined as the STAT4‐related pathway and its score was used to predict T‐cell expansion and anti‐PD1 treatment response. These findings highlight a novel molecular mechanism indirectly regulating PD‐L1 through the STAT4‐related pathway: IL‐12R/JAK2–STAT3–STAT4/PD‐L1, and it has potential application in predicting anti‐PD‐1 immunotherapy response, which may pave the way for stratified immunotherapy in breast cancer. [ABSTRACT FROM AUTHOR]

Immunotherapeutic modulation of antigen‐specific T‐cell responses instead of the whole repertoire helps avoid immune‐related adverse events. We have developed an artificial antigen‐presenting system (aAPS) where multiple copies of a multimeric peptide‐MHC class I complex presenting a murine class I MHC restricted ovalbumin‐derived peptide (signal 1), along with a costimulatory ligand (signal 2) are chemically conjugated to a dextran backbone. Cognate naive CD8+ T cells, when treated with this aAPS underwent significant expansion and showed an activated phenotype. Furthermore, elevated expression of effector cytokines led to the differentiation of these cells to cytotoxic T lymphocytes which resulted in target cell lysis, indicative of the functional efficacy of the aAPS. CD8+ T cells with decreased proliferative potential due to repeated antigenic stimulation could also be re‐expanded by the developed aAPS. Thus, the developed aAPS warrants further engineering for future application as a rapidly customizable personalized immunotherapeutic agent, incorporating patient‐specific MHC‐restricted tumor antigens and different costimulatory signals to modulate both naive and antigen‐experienced but exhausted tumor‐specific T cells in cancer. [ABSTRACT FROM AUTHOR]

Hypoxia‐inducible factor 1 alpha (HIF1α), under hypoxic conditions, is known to play an oxygen sensor stabilizing role by exerting context‐ and cell‐dependent stimulatory and inhibitory functions in immune cells. Nevertheless, how HIF1α regulates T cell differentiation and functions in tumor settings has not been elucidated. Herein, we demonstrated that T‐cell‐specific deletion of HIF1α improves the inflammatory potential and memory phenotype of CD8+ T cells. We validated that T cell‐specific HIF1α ablation reduced the B16 melanomas development with the indication of ameliorated antitumor immune response with enhanced IFN‐γ+ CD8+ T cells despite the increase in the Foxp3+ regulatory T‐cell population. This was further verified by treating tumor‐bearing mice with a HIF1α inhibitor. Results indicated that HIF1α inhibitor also recapitulates HIF1α ablation effects by declining tumor growth and enhancing the memory and inflammatory potential of CD8+ T cells. Furthermore, a combination of Treg inhibitor with HIF1α inhibitor can substantially reduce tumor size. Collectively, these findings highlight the notable roles of HIF1α in distinct CD8+ T‐cell subsets. This study suggests the significant implications for enhancing the potential of T cell‐based antitumor immunity by combining HIF1α and Tregs inhibitors. [ABSTRACT FROM AUTHOR]

This article discusses the safety and efficacy of using dual biological therapy, specifically the combination of dupilumab and fremanezumab, for the treatment of inflammatory cutaneous diseases and migraines. Dupilumab is an interleukin-4/13 receptor alpha antagonist used for conditions such as atopic dermatitis, asthma, and chronic rhinosinusitis. Fremanezumab is a monoclonal antibody used for chronic migraines. The article presents a case study of a patient who successfully received both therapies without adverse events. While there is limited literature on the use of dual biological therapies, this case adds to the evidence suggesting that combining these treatments may be safe and effective. [Extracted from the article]

KeChuanLiuWei‐Mixture (KCLW) is widely used as a Chinese medicine prescription to treat severe asthma. However, the underlying therapeutic mechanism of KCLW remains unclear. In this study, a network pharmacology method was used to identify the chemical constituents of KCLW by the TCMSP database and ultra‐performance liquid chromatography coupled with time‐of‐flight mass spectrometry. Differential expression identification, protein–protein interaction (PPI) network and functional enrichment analysis were used to screen key targets of KCLW for severe asthma. Our results confirmed that quercetin, luteolin, kaempferol, and wogonin are the most critical active ingredients in KCLW. Moreover, the 16 relevant severe asthma‐related targets of KCLW were obtained by overlapping the PPI networks of the KCLW putative targets and severe asthma‐related genes, among which the most important targets were IL‐6, NOS2, VEGFA, CXCL2, and PLAT. Functionally, the 16‐targets and their interacting differentially expressed genes were primarily related to biological functions and pathways related to immunity and inflammation, such as inflammatory response, T cell differentiation, Nrf2/HO‐1 signaling pathway, TGF‐β/Smad signaling pathway, and NF‐κB signaling pathway. KCLW inhibited inflammation in PDGF‐BB‐induced airway smooth muscle cells. In summary, this study demonstrates the active substance and potential therapeutic mechanism of KCLW in severe asthma, and offers a clinical direction for KCLW against severe asthma. [ABSTRACT FROM AUTHOR]

Targeting programmed death 1(PD‐1) has been approved for relapsed cervical cancer with unsatisfactory clinical efficacy. This study aims to analyse the impact of PI3K pathway activation on tumour immune microenvironment and evaluates the immune sensitization effect by PI3K inhibition in cervical cancer. The effect of PIK3CA mutation on PD‐L1 expression and CD8+ T cells differentiation was determined in cervical cancer tissues. Luciferase and ChIP‐qPCR/PCR assays were used to determine the transcriptional regulation of PD‐L1 by PIK3CA‐E545K. The effects of PI3K inhibitor treatment on immune environment in vitro and in vivo were evaluated by RNA sequencing (RNA‐seq) and flow cytometry. The efficacy of PI3K inhibitor and anti‐PD‐1 therapy was assessed in cell‐derived xenografts (CDX) and patients‐derived xenografts (PDX). PD‐L1 overexpression is more frequently observed in elder women with squamous cervical carcinoma. It predicts longer progress‐free survival and overall survival. PIK3CA mutation results in increased mRNA and protein levels of PD‐L1, the repression of CD8+ T cell differentiation in cervical cancer. Here, we report a case that continuous pembrolizumab monotherapy treatment induced complete remission of a recurrent cervical cancer patient with systemic metastasis and PIK3CA‐E545K mutation, implying that PIK3CA mutation is potentially a biomarker for pembrolizumab treatment in cervical cancer. Specifically, this mutation promotes the expression of PD‐L1 by upregulating the transcription factor IRF1. PI3Kα‐specific inhibitor markedly activates immune microenvironment by regulating the PD‐1/L1‐related pathways and promoting CD8+ T cell differentiation and proliferation in Caski‐CDXs with PIK3CA‐E545K mutation. PI3Kα inhibitor significantly enhances the anti‐tumour efficacy of PD‐1 blockade in CDXs and PDXs. PIK3CA mutations may predict the response of cervical cancer to PD‐1 blockade. The efficacy of PI3Kα inhibitors combined with PD‐1 antibodies is promising in cervical cancer and warrants additional clinical and mechanistic investigations. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disease, which is an important cause of female infertility worldwide. PCOS patients are in a state of chronic low‐grade inflammation, and immune imbalance is considered as a potential cause of its pathogenesis. Methods: The expression of AOC4P in PCOS and normal ovarian granulosa cells (GCs) was detected by real‐time quantitative PCR. KGN cells were induced by dihydrotestosterone at 500 ng/mL to construct the PCOS model. After lentivirus‐infected, KGN cells were constructed with AOC4P overexpression cell lines, the proliferation and apoptosis levels of KGN cells in AOC4P and NC groups were detected. Human monocyte cell line (THP‐1)‐derived macrophages and peripheral blood mononuclear cells (PBMC) were co‐cultured with KGN cells for 48 h, respectively, and the differentiation of macrophages and CD4+ T cells were detected by flow cytometry. Results: Decreased AOC4P expression was found in PCOS patients. After constructing the PCOS cell model, we observed that overexpression of AOC4P promoted KGN cell proliferation and inhibited apoptosis. After co‐culture with AOC4P overexpressed KGN cells, M1 macrophages decreased, M2 macrophages increased, T helper cells type 1 (Th1)/Th2 ratio increased, and regulatory T cell (Treg) cells increased. Finally, we found that AOC4P inhibited the activation of the nuclear factor κ B (NF‐κB) pathway in KGN cells. Conclusions: In this study, we found that AOC4P regulated the NF‐κB signaling pathway by inhibiting the phosphorylation of P65, thereby affecting the proliferation and apoptosis of GCs, altering the differentiation of macrophages and T cells, thus contributing to the pathogenesis of PCOS. [ABSTRACT FROM AUTHOR]

Introduction: With the advancements in early diagnosis, more and more patients with multiple primary lung cancer (MPLC) have been identified. However, the progression of MPLC involves complex changes in cell composition and metabolic function, which remains largely controversial. Objective: Our study aims to comprehensively reveal the cellular characteristics and inter‐cellular connections of MPLC. Methods: We performed scRNA‐seq from 23 samples of six MPLC patients, combined with bulk whole‐exome sequencing. We performed trajectory analysis to investigate the transition of different cell types during the development of MPLC. Results: A total of 1 67 397 cells were sequenced derived from tumour and adjacent tissues of MPLC patients, and tumour, normal, immune and stromal cells were identified. Two states of epithelial cells were identified, which were associated with immune response and cell death, respectively. Furthermore, both CD8+ naïve and memory T cells participated in the differentiation of CD8+ T cells. The terminal states of CD8+ T cells were exhausted T cells and cytotoxic T cells, which positively regulated cell death and were implicated in the regulation of cytokine production, respectively. Two main subpopulations of B cells with distinct functions were identified, which participate in the regulation of the immune response and antigen presentation, respectively. In addition, we found a specific type of endothelial cells that were abundant in tumour samples, with an increasing trend from normal to tumour samples. Conclusions: Our study showed the comprehensive landscape of different cells of MPLC, which might reveal the key cellular mechanisms and, therefore, may provide new insights into the early diagnosis and treatment of MPLC. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that often involves abnormal activation of regulatory IFN genes and regulation of B cells by CD4+ T cells. Radical S‐adenosyl methionine domain containing 2 (RSAD2) is a viral suppressor protein regulated by type I IFN, and it has been proven to play an important regulatory role in SLE. However, the mechanism by which RSAD2 participates in the pathogenesis of SLE is unclear. In this study, we observed higher expression levels of RSAD2 in CD4+ T‐cell subsets from the peripheral blood of SLE patients than in those from healthy controls by bioinformatics analysis and validation experiments. We analyzed the expression of RSAD2 in CD4+ T cells of patients with SLE and other autoimmune diseases. In addition, we found that the expression of RSAD2 in CD4+ T cells might be regulated by IFN‐α, and RSAD2 significantly affected the differentiation of Th17 cells and T follicular helper (Tfh) cells. Our findings underlined that RSAD2 may promote B‐cell activation by promoting the differentiation of Th17 and Tfh cells in SLE patients, a process that is regulated by IFN‐α. [ABSTRACT FROM AUTHOR]

Follicular T helper (Tfh) cells are a subset of CD4+ T cells that play an important role in the formation of germinal centers and the maturation and differentiation of affinity‐matured B cells. Recent studies have demonstrated important functions of Tfh cells in tertiary lymphoid structures of tumors, revealing great potential of Tfh cells in tumor immunity. However, Tfh development is incompletely understood. The differentiation of Tfh cells is a complex, multistage process regulated at the DNA, RNA and protein levels. This review just summarizes current research on the molecular mechanisms of Tfh cell differentiation to better understand the role of Tfh cells in antitumor immunity. [ABSTRACT FROM AUTHOR]

Summary: Upon resolution of an acute viral infection, during latent‐reactivating infection and during chronic active infections virus‐specific T‐cells differentiate into distinct subsets that differ in phenotype, longevity, transcriptional, metabolic, and epigenetic profiles, and effector functions. With recent advances in single‐cell profiling, this substantial heterogeneity has become apparent and new subsets of virus‐specific T cells, either of stable or transitory nature, are being identified. A unifying principle of T cells emerging in these different conditions is their precursor–progeny relationship. For acute and resolved viral infections, this relationship becomes apparent during re‐challenge, whereas a constant differentiation of progenitor T cells into more differentiated cells occurs during latent‐reactivating and active chronic viral infections. In this review, we summarize and discuss current knowledge about T‐cell heterogeneity and progenitor–progeny relationships in the setting of persistent viral infections. [ABSTRACT FROM AUTHOR]

Follicular regulatory T (Tfr) cells are a novel and unique subset of effector regulatory T (Treg) cells that are located in germinal centers (GCs). Tfr cells express transcription profiles that are characteristic of both follicular helper T (Tfh) cells and Treg cells and negatively regulate GC reactions, including Tfh cell activation and cytokine production, class switch recombination and B cell activation. Evidence also shows that Tfr cells have specific characteristics in different local immune microenvironments. This review focuses on the regulation of Tfr cell differentiation and function in unique local immune microenvironments, including the intestine and tumor. [ABSTRACT FROM AUTHOR]

Background: Pulmonary eosinophils comprise at least two distinct populations of resident eosinophils (rEOS) and inflammatory eosinophils (iEOS), the latter recruited in response to pulmonary inflammation. Here, we determined the impact of complement activation on rEOS and iEOS trafficking and function in two models of pulmonary inflammation. Methods: BALB/c wild‐type and C5ar1−/− mice were exposed to different allergens or IL‐33. Eosinophil populations in the airways, lung, or mediastinal lymph nodes (mLN) were characterized by FACS or immunohistochemistry. rEOS and iEOS functions were determined in vivo and in vitro. Results: HDM and IL‐33 exposure induced a strong accumulation of iEOS but not rEOS in the airways, lungs, and mLNs. rEOS and iEOS expressed C3/C5 and C5aR1, which were significantly higher in iEOS. Initial pulmonary trafficking of iEOS was markedly reduced in C5ar1−/− mice and associated with less IL‐5 production from ILC2 cells. Functionally, adoptively transferred pulmonary iEOS from WT but not from C5ar1−/− mice‐induced airway hyperresponsiveness (AHR), which was associated with significantly reduced C5ar1−/− iEOS degranulation. Pulmonary iEOS but not rEOS were frequently associated with T cells in lung tissue. After HDM or IL‐33 exposure, iEOS but not rEOS were found in mLNs, which were significantly reduced in C5ar1−/− mice. C5ar1−/− iEOS expressed less costimulatory molecules, associated with a decreased potency to drive antigen‐specific T cell proliferation and differentiation into memory T cells. Conclusions: We uncovered novel roles for C5aR1 in iEOS trafficking and activation, which affects key aspects of allergic inflammation such as AHR, ILC2, and T cell activation. [ABSTRACT FROM AUTHOR]

Our previous study found that double negative T cells (DNTs) could promote the NLRP3 activation through high expression of TNF‐α, thereby leading to hepatic fibrosis progression. We focused on investigating the role and mechanism of DNTs in regulating the Th9 cells differentiation in liver fibrosis. In our results, among patients with liver fibrosis, the proportions of peripheral blood DNTs and Th9 cells were up‐regulated and positively correlated. While promoting the progression of liver fibrosis in mice, DNTs could elevate the proportion of Th9 cells and activate the TNFR2‐STAT5‐NF‐κB pathway. The use of IL‐9 and TNF‐α monoclonal antibodies (mAbs) inhibited the effect of DNTs and lowered the proportion of Th9 cells in tissues. In vitro experiments showed that DNTs could promote the Th9 cells differentiation of Naive T cells, while TNF‐α mAbs could inhibit such effect of DNTs to lower the proportion of Th9 cells. We found that DNTs can activate TNFR2‐STAT5‐NF‐κB pathway by secreting TNF‐α, thereby promoting the Th9 Cells differentiation to facilitate the progression of liver fibrosis. There is interaction between DNTs and Th9 cells. [ABSTRACT FROM AUTHOR]

Background: Although abnormal metabolism plays a critical role in the pathogenesis of psoriasis, the details are unclear. Objectives: Here, we identified to explore the role and mechanism of lysophosphatidylcholine (LPC) on the pathogenesis of psoriasis. Methods: The level of LPC in plasma and skin lesions and the expression of G2A on skin lesions of psoriasis patients were detected by enzyme‐linked immunosorbent assay, liquid chromatography–tandem mass spectrometry, or immunohistochemistry, respectively. The glycolysis in the skin lesions of imiquimod (IMQ)‐induced psoriasis‐like mouse model was detected by extracellular acidification rate. LPC was subcutaneously injected into IMQ‐treated mouse ears, and the phenotype as well as the glycolysis were evaluated. Exploring the effects and mechanism of LPC on keratinocytes and CD4+ T cells by culturing primary keratinocytes and CD4+ T in vitro. Results: We found that LPC was significantly increased both in the plasma and skin lesions of psoriatic patients, while G2A, exerting an essential role in LPC‐inducing biological functions, was increased in psoriatic lesions. The abundance of LPC was positively correlated with glycolytic activity in the psoriasis‐like mouse model. LPC treatment facilitated psoriasis‐like inflammation and glycolytic activity in skin lesions. Mechanistically, the LPC/G2A axis significantly triggered glycolytic activity and produced inflammatory factors in keratinocytes, and blockade of glycolysis abrogated LPC‐induced expression of inflammatory mediators in keratinocytes. LPC activated STAT1, resulting in recognition and binding to the promoters of GCK and PKLR, which are glycolytic rate‐limiting enzymes. Furthermore, the LPC/G2A axis directly benefited Th1 differentiation, which was dependent on LPC‐induced glycolytic activity. Notably, LPC indirectly facilitated Th17 differentiation by inducing the secretion of IL‐1β in keratinocytes‐T cells coculture system. Conclusions: Taken together, our findings revealed the role of the LPC/G2A axis in the pathogenesis of psoriasis; targeting LPC/G2A is a potential strategy for psoriasis therapy. [ABSTRACT FROM AUTHOR]

The costimulation molecule CD226 is widely involved in T cell differentiation, activation and immune functional regulation in peripheral immune tissues. CD226‐deficient mice have impaired immune response capacity. The function of CD226 in regulating T cell development in the thymus, a central immune organ, is not yet fully understood. We investigated the development of thymocytes using CD226 knockout mice and single‐cell sequencing techniques. CD226 began to be expressed in the second half of thymocyte development, with a gradual increase from the double‐positive (DP) to single‐positive (SP) phase and higher levels of CD226 on CD8+ T cells than on CD4+ T cells from the SP phase to mature T cells. In the thymus of CD226KO mice, the proportion of DPT at the quiescent phase (DPT‐Q) increased, of which the Gzma+ cluster that tends to be CD8+ T cells and CD5+ cluster that is undergoing positive selection decreased dramatically. Afterward, the proportion of mature CD8+ T cells reduced dramatically. Depletion of CD226 impaired TCR activation signalling and diminished AKT/ERK/NF‐κB/p38 phosphorylation levels. The diminished TCR responsiveness of DPT cells impeded their positive selection process and influenced the maturation of CD8+ T cells. In mechanism, CD226 knockout enhanced DPT cell apoptosis via impairing AKT phosphorylation. These results suggest that CD226 plays a significant role in T cell thymic development via modulation of TCR signalling, affecting CD8+ T cell maturation. [ABSTRACT FROM AUTHOR]

Aplastic anaemia (AA) is an autoimmune disease characterized by haematopoietic failure in the bone marrow. Abnormal activation and hyperfunction of T lymphocytes are believed to cause bone marrow damage, which plays a major role in AA pathogenesis. Dendritic cells (DCs) play a vital role in the immune system by processing antigens for presentation to T cells and regulating their differentiation and function. DC dysfunction may cause abnormal T‐cell activation. Recent studies have associated the occurrence and development of AA with DC function. In this review, we have discussed the role of DCs in AA pathogenesis and their potential as putative therapeutic targets for AA. [ABSTRACT FROM AUTHOR]