Interleukin-17 receptor A (IL17RA) and IL17RC form a receptor complex critical for initiating IL-17A-mediated immune responses, a hallmark of T helper 17 (Th17) cells. In this study, il17ra and il17rc were identified in miiuy croaker (Miichthys miiuy) and bioinformatics analysis revealed their evolutionary and structural conservation, underscoring their roles in immunity. However, there has been little research on the IL-17 receptor family from the perspective of N6-methyladenosine (m6A) modifications. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we identified strong m6A modifications on the last exons of il17ra and il17rc, validated by MeRIP-PCR. Poly(I:C) stimulation significantly upregulated il17ra and il17rc expression, while reducing their m6A modification levels, implicating these changes in antiviral immunity. Interestingly, cycloleucine (CL), a well-known methylation inhibitor, did not alter the expression of il17ra and il17rc but promoted the nuclear-to-cytoplasmic transport of il17ra mRNA, potentially influencing its translation process. These findings provide valuable insights into the regulatory roles of m6A modifications in il17ra and il17rc function and highlight their importance in the antiviral immune response.

Autoimmune uveitis is a sight-threatening inflammatory disease of the retina. MicroRNA-142 (miR-142) has been implicated in its pathogenesis. This study aimed to elucidate the role of miR-142 in uveitis and its underlying mechanisms.

The expression of miR-142-3p was analyzed in peripheral blood mononuclear cells from uveitis patients and in experimental autoimmune uveitis (EAU) models. With EAU induction for 14 days, clinical and histopathological scores were graded to evaluate the retinal inflammation. To investigate the effects of miR-142 deficiency on uveitis development, the miR-142 knockout (miR-142-/-) mouse model was used. The miR-142-/- T cell phenotype and function were characterized using flow cytometry and single-cell sequencing for both in vivo and in vitro experiments. The Seahorse Analyzer, mitochondrial staining and electron microscope analysis were conducted to reveal the mitochondrial function and morphology. And then Luciferase Assays and Western-Blot analysis were used to explore the target of miR-142.

We found that miR-142-3p was significantly up-regulated in uveitis and that its deletion in mice prevented EAU development. The T cell isolated from miR-142-/- mice lose its uveitogenic nature. T cell lacking miR-142 exhibited reduced numbers and attenuated pathogenicity in uveitis, characterized by decreased proliferation, increased apoptosis, and abnormal differentiation. Single-cell sequencing, energy metabolism analysis and flow cytometry analysis unveiled metabolic reprogramming in miR-142-/- T cells, with a distinct shift toward glycolysis and restrained oxidative phosphorylation. Further investigation revealed mitochondrial fission regulator 1 (MTFR1) as a direct target of miR-142. The over-expressed protein of MTFR1 in CD4+ T cells was found in miR-142-/- mice.

Our findings highlight the indispensable role of miR-142 in maintaining T cell mitochondrial function. By modulating MTFR1, miR-142 orchestrates mitochondrial homeostasis, metabolic alterations, apoptosis susceptibility, and proliferation capacity in T cells, thereby influencing susceptibility to autoimmune uveitis.

Anti-IL-17A antibodies are used in rheumatological conditions. While not approved for multiple sclerosis (MS), anti-IL-17As reduce new gadolinium-enhancing lesions. Optimal treatment for those with MS and comorbid rheumatological conditions remains unclear. We report safety and efficacy outcomes for anti-IL-17A treatment with and without concurrent MS disease modifying therapy (DMT). Patients with MS and anti-IL-17A use were identified using electronic medical records. Primary outcomes were severe infections and markers of immunosuppression. Secondary outcomes were MS relapses and new MRI lesions. Six patients (median age: 50.1) without recent MS disease activity had anti-IL-17A monotherapy exposures (17.4 total patient-years); seven (median age: 48.2) had concurrent MS DMT use (8.8 patient-years), including anti-CD20 treatment in three patients. One patient on anti-IL-17A monotherapy had a serious infection. No patients had new or worsening lymphopenia. Four of six patients on anti-IL-17A monotherapy had new MS disease activity. No relapses or new MRI lesions occurred during concurrent MS DMT use. No significant safety concerns were identified with anti-IL-17A and MS DMT combination therapy, although exposure duration was limited. More MS disease activity was seen with anti-IL-17A monotherapy. Dual therapy with an MS DMT may be reasonable for MS patients who require anti-IL-17A treatment.

The role of neutrophils in defending against infections and regulating immune responses is well-known. In cancer, tumor-associated neutrophils also play a significant role in the progression of tumors. However, the specific mechanisms of their interaction with human colorectal tumors have not been fully elucidated. Our study found that tumor-educated neutrophils can activate the STAT3 signaling pathway in colorectal cancer cells by secreting IL-17a. This leads to increased migration and invasion of colorectal cancer cells, promoting tumor growth by triggering epithelial-to-mesenchymal transition (EMT). These findings suggest that IL-17a secreted by tumor-educated neutrophils contributes to the development of colorectal cancer through the IL-17a/STAT3 signaling pathway. This provides new insights for potential treatments for colorectal cancer.

Fish are exposed to numerous stressors which negatively affect their immune response and increase infection susceptibility. The risk of bacterial infections results in the excessive and preventive use of antibiotics. Therefore, we aimed to study how antibiotic treatment and restraint stress will affect the stress response, microbiota composition, gut morphology, and inflammatory reaction in common carp. Both restraint stress and antibiotic treatment increased cortisol level. Moreover, antibiotics induced dysbiosis in fish gut, manifested by a decrease in the total abundance of bacteria, and a shift in bacteria diversity, including a reduced number of Aeromonas, Bacteroides, Barnesiellaceae, Cetobacterium and Shewanella and an increased abundance of Flavobacterium. To a lesser extent, stress modified gut microbiota, as it decreased bacteria number and slightly changed the microbiota composition by decreasing Cetobacterium abundance and increasing Vibrio abundance. Microbiota of the antibiotic-treated and stressed fish shifted from the beneficial bacterial genera - Cetobacterium and Bacteroides, to the increased presence of unfavorable bacteria such as Brevinema, Flavobacterium and Desulfovibrionaceae. Stress and antibiotic-induced changes in the gut microbiota were related to the changes in the gut morphology when the higher abundance of goblet and rodlet cells and increased secretion activity of goblet cells were observed. Moreover, up-regulation of the expression of genes encoding pro-inflammatory mediators and cytokines involved in the Th17 immune response was present in the gut of the antibiotic-treated and stressed fish. We conclude that in carp antibiotics and stress alter the abundance and composition of the microbiota and induce Th17-dependent inflammatory reaction in the gut. Moreover, our results strongly suggest the interplay of the stress axis and the brain-gut-microbiota axis.

Th17 lymphocytes are a distinct subpopulation of T cells that are characterized by the production of interleukins IL-17, IL-21, IL-22, and IL-26, and high expression of RORγt. These cells play an important role in inflammation and autoimmune diseases. Recent studies using rodent and human models have also highlighted their promising properties as agents in cellular immunotherapy for cancer. However, much less is known about the properties of canine Th17 lymphocytes, despite the domestic dog being an important model used in comparative medicine. In this study, we developed methods of activation and differentiation of canine CD4+ T lymphocytes towards the Th17 phenotype. Additionally, we targeted the Wnt/β-catenin signaling pathway to modulate the efficiency of Th17 cells differentiation. CD4+ T cells were successfully activated with magnetic EpoxyBeads, and in combination with the appropriate programming medium, they acquired the Th17 phenotype. Furthermore, indomethacin, an inhibitor of the Wnt/β-catenin pathway, significantly increased the efficiency of differentiation, causing elevated production of IL-17 and changed T cell metabolism by promoting oxidative phosphorylation. The protocol elaborated in our study provides an efficient method of canine Th17 lymphocyte differentiation. Our findings also suggested that the modification of the Wnt/β-catenin signaling pathway could be a valuable strategy for optimizing canine Th17 cell differentiation and advancing cell-based immunotherapy.

T cells play a central role in anti-tumor immunity, yet their function is often compromised within the immunosuppressive tumor microenvironment, leading to cancer progression and resistance to immunotherapies. T-cell activation and differentiation require dynamic metabolic shifts, with mitochondrial metabolism playing a crucial role in sustaining their function. Research in cancer immunometabolism has revealed key mitochondrial abnormalities in tumor-infiltrating lymphocytes, including reduced mitochondrial capacity, depolarization, structural defects, and elevated reactive oxygen species. While these mitochondrial disruptions are well-characterized in solid tumors and linked to T-cell exhaustion, their impact on T-cell immunity in lymphoproliferative disorders remains underexplored. Chronic lymphocytic leukemia (CLL), the most prevalent chronic adult leukemia, is marked by profound T-cell dysfunction that limits the success of adoptive cell therapies. Emerging studies are shedding light on the role of mitochondrial disturbances in CLL-related T-cell dysfunction, but significant knowledge gaps remain. This review explores mitochondrial metabolism in T-cell exhaustion, emphasizing recent findings in CLL. We also discuss therapeutic strategies to restore T-cell mitochondrial function and identify key research gaps.

Hidradenitis suppurativa (HS) is a chronic skin condition with a significant impact on patient quality of life, highlighting the need for innovative therapeutic approaches. HS is characterized by its chronicity; it presents in the form of painful nodules, abscesses, and sinus tracts or fistulas, typically localized in intertriginous areas, emerging in early adulthood and in predominantly the female population.

In this review, the authors discuss the preclinical discovery and development of secukinumab for HS, highlighting target identification, validation, and compound selection. Methodologies such as high-content screening, chemoinformatics, and animal models that validate the IL-17 pathway's role in HS are explored. The transition from preclinical to clinical development, including pharmacokinetics (PK), pharmacodynamics (PD), and ADME-Tox studies, is elaborated. The literature search was conducted using PubMed, Web of Science, Scopus, UpToDate, Cochrane Library, Embase, and Google Scholar, covering relevant studies published up to December 2024.

The integration of secukinumab into HS treatment highlights the critical role of targeting the IL-17A pathway. Although efficacious and safe in trials, understanding secukinumab's long-term effects and optimal treatment placement remains challenging. Future research should prioritize the development of tailored therapeutic strategies that align with individual disease phenotypes and immune profiles to enhance treatment outcomes in HS management.

Effective bidirectional communication between the innate and adaptive immune systems is crucial for tissue homeostasis and protective immunity against infections. The innate immune system is responsible for the early sensing of and initial response to threats, including microbial ligands, toxins, and tissue damage. Pathogen-related information, detected primarily by the innate immune system via dendritic cells, is relayed to adaptive immune cells, leading to the priming and differentiation of naive T cells into effector and memory lineages. Memory T cells that persist long after pathogen clearance are integral for durable protective immunity. In addition to rapidly responding to reinfections, memory T cells also directly instruct the interacting myeloid cells to induce innate inflammation, which resembles microbial inflammation. As such, memory T cells act as newly emerging activators of the innate immune system and function independently of direct microbial recognition. While T cell-mediated activation of the innate immune system likely evolved as a protective mechanism to combat reinfections by virulent pathogens, the detrimental outcomes of this mechanism manifest in the forms of autoimmunity and other T cell-driven pathologies. Here, we review the complexities and layers of regulation at the interface between the innate and adaptive immune systems to highlight the implications of adaptive instruction of innate immunity in health and disease.

Interleukin (IL)-17, a pro-inflammatory cytokine, plays a pivotal role in immune regulation by bridging innate and adaptive responses. Beyond its canonical involvement in T helper-17 cells-mediated immunity, IL-17 contributes significantly to the pathogenesis of systemic autoinflammatory diseases (SAIDs) including Familial Mediterranean Fever (FMF), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-associated autoinflammatory diseases, and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. Dysregulated IL-17 signaling drives inflammasome activation, neutrophil recruitment, and chronic tissue inflammation. IL-17 inhibitors have demonstrated efficacy in refractory SAIDs, though challenges such as increased infection risks, paradoxical inflammatory reactions, and uncertainties regarding long-term safety persist. Currently, there is insufficient data to support the use of IL-17 inhibitors as first-line treatments, and their role in managing SAIDs is yet to be fully defined. This review highlights the mechanistic role of IL-17 in SAIDs and emerging therapeutic strategies, including IL-17-targeted monotherapies and combination approaches with IL-1 or tumor necrosis factor (TNF) inhibitors. Future research should focus on biomarker development, combination therapies, and long-term studies to optimize the safety and efficacy of IL-17-targeted therapies in SAIDs.

Natural products, especially specific metabolites found in many medicinal plants, exhibit extensive therapeutic potential due to their diverse biological characteristics. Among these compounds, diterpenes stand out for their active principles described in phytochemical studies. Diterpenes exhibit immunomodulatory effects by influencing the production of cytokines and other signaling molecules involved in the immune response. These actions contribute to achieving a more balanced immune profile. The ability to selectively and harmoniously modulate the immune response positions compounds derived from natural products is a promising research field in the development of immunomodulatory therapies. Due to the broad biological activities of diterpenes, the use of molecular docking emerges as a relevant tool for the quantitative screening of a large number of these substances. This review comprehensively examines the pharmacological potential of diterpenes in modulating the immune system. It highlights the existing experimental evidence supporting the efficacy and safety of these compounds as potential treatment for immune dysfunctions. Ultimately, this review aims to contribute to the development of new therapeutic strategies in this field.

The relationship between the gut microbiome and ocular health has garnered increasing attention within the scientific community. Recent research has focused on the gut-eye axis, examining whether imbalances within the gut microbiome can influence the development, progression and severity of ocular diseases, including dry eye disease, uveitis, and glaucoma. Dysbiosis within the gut microbiome is linked to immune dysregulation, chronic inflammation, and epithelial barrier dysfunction, all of which contribute to ocular pathology. This review synthesises current evidence on these associations, exploring how gut microbiome alterations drive disease mechanisms. Furthermore, it examines the therapeutic potential of microbiome-targeted interventions, including antibiotics, prebiotics, probiotics, and faecal microbiota transplantation, all of which aim to restore microbial balance and modulate immune responses. As the prevalence of these conditions continues to rise, a deeper understanding of the gut-eye axis may facilitate the development of novel, targeted therapies to address unmet needs in the management of ocular diseases.

This study investigates the immunomodulatory effects of various aqueous plant extracts on immune cells and cytokine production. In vitro, several extracts, including holy basil (Ocimum sanctum), patawali (Tinospora crispa), and Indian borage (Plectranthus amboinicus L.), significantly increased CD3+ T-cell populations, while soap pod (Acacia concinna), garlic (Allium sativum L.), and neem (Azadirachta indica) also boosted CD45RA+ B-cells. In vivo, the extracts had subtle effects on spleen morphology and Peyer's Patches, with milk bush (Euphorbia tirucalli L.) and Indian borage enhancing T-cell responses, while soap pod stimulated B-cells. Additionally, we observed that Neem and milk bush significantly suppressed B-cell populations. Furthermore, cytokine analysis showed that garlic and patawali reduced IL-2, while soap pod, holy basil, and patawali increased TNF-alpha levels. Soap pod also elevated IL-10 and IL-17A, indicating both anti-inflammatory and pro-inflammatory signaling, while patawali induced an increase in IL-4. In conclusion, Thai medicinal plants show strong potential as both immunostimulants and immunosuppressants. They can enhance lymphocyte proliferation, particularly in T-cells, and modulate B-cell populations. Their aqueous extracts play a key role in regulating Th1, Th2, and Th17 cytokine production. Thus, these plants could serve as natural agents and alternative medicines for boosting or modulating immune function.

This review discusses findings related to neurological disorders, gut microbiota, and bariatric surgery, focusing on neurotransmitters, neuroendocrine, the pathophysiology of bacteria contributing to disorders, and possible therapeutic interventions. Research on neurotransmitters suggests that their levels are heavily influenced by gut microbiota, which may link them to neurological disorders such as Alzheimer's disease, Parkinson's disease, Multiple sclerosis, Depression, and Autism spectrum disorder. The pathophysiology of bacteria that reach and influence the central nervous system has been documented. Trends in microbiota are often observed in specific neurological disorders, with a prominence of pro-inflammatory bacteria and a reduction in anti-inflammatory types. Furthermore, bariatric surgery has been shown to alter microbiota profiles similar to those observed in neurological disorders. Therapeutic interventions, including fecal microbiota transplants and probiotics, have shown potential to alleviate neurological symptoms. We suggest a framework for future studies that integrates knowledge from diverse research areas, employs rigorous methodologies, and includes long-trial clinical control groups.

Allergic and autoimmune disorders are characterised by dysregulation of the immune responses to otherwise inert environmental substances and autoantigens, leading to inflammation and tissue damage. Their incidence has constantly increased in the last decades, and their co-occurrence defies current standards in patient care. For years, allergy and autoimmunity have been considered opposite conditions, with IgE and Th2 lymphocytes cascade driving canonical allergic manifestations and Th1/Th17-related pathways accounting for autoimmunity. Conversely, growing evidence suggests that these conditions not only share some common inciting triggers but also are subtended by overlapping pathogenic pathways. Permissive genetic backgrounds, along with epithelial barrier damage and changes in the microbiome, are now appreciated as common risk factors for both allergy and autoimmunity. Eosinophils and mast cells, along with autoreactive IgE, are emerging players in triggering and sustaining autoimmunity, while pharmacological modulation of B cells and Th17 responses has provided novel clues to the pathophysiology of allergy. By combining clinical and therapeutic evidence with data from mechanistic studies, this review provides a state-of-the-art update on the complex interplay between allergy and autoimmunity, deconstructing old dichotomic paradigms and offering potential clues for future research.

Occupational exposure to crystalline silica (CS) is known to induce silicosis, a chronic lung disease characterized by the formation of granulomas and severe lung fibrosis. Specifically, individuals exposed to low doses of CS may develop silicosis after a decade or more of exposure. Similarly, in rat silicosis models exposed to occupationally relevant doses of α-quartz, there is an initial phase characterized by minimal and well-controlled pulmonary inflammation, followed by the development of robust and persistent inflammation. During the initial phase, the inflammation provoked by α-quartz is subdued by two mechanisms. Firstly, α-quartz particles are engulfed by alveolar macrophages (AMs) of the alternatively activated (M2) subtype and interstitial macrophages (IMs), limiting their interaction with other lung cells. Secondly, the anti-inflammatory cytokine, interleukin (IL)-10, is constitutively expressed by these macrophages, further dampening the inflammatory response. In the later inflammatory phase, IL-10-dependent anti-inflammatory state is disrupted by Type I interferons (IFNs), leading to the production of pro-inflammatory cytokines in response to α-quartz, aided by lipopolysaccharides (LPS). This review delves into the complex pathways involving IL-10, LPS, and Type I IFNs in α-quartz-induced pulmonary inflammation, offering a detailed analysis of the underlying mechanisms and identifying areas for future research.

Airway inflammation, a hallmark feature of asthma, drives many canonical features of the disease, including airflow limitation, mucus plugging, airway remodeling, and hyperresponsiveness. The T2 inflammatory paradigm is firmly established as the dominant mechanism of asthma pathogenesis, largely due to the success of inhaled corticosteroids and biologic therapies targeting components of the T2 pathway, including IL-4, IL-5, IL-13, and thymic stromal lymphopoietin (TSLP). However, up to 30% of patients may lack signatures of meaningful T2 inflammation (ie, T2 low). In T2-low asthma patients, T2 inflammation may be masked due to anti-inflammatory treatments or may be highly variable depending on exposure to common asthma triggers such as allergens, respiratory infections, and smoke or pollution. The epithelium and epithelial cytokines (TSLP, IL-33) are increasingly recognized as upstream drivers of canonical T2 pathways and as modulators of various effector cells, including mast cells, eosinophils, and neutrophils, which impact the pathological manifestations of airway smooth muscle hypertrophy, hypercontractility, and airway hyperresponsiveness. Approved biologics for severe asthma target several distinct mechanisms of action, leading to differential effects on the spectrum of T2 inflammation, inflammatory biomarkers, and treatment efficacy (reducing asthma exacerbations, improving lung function, and diminishing symptoms). The approved anti-asthma biologics primarily target T2 immune pathways, with little evidence suggesting a benefit of targeting non-T2 asthma-associated mediators. Indeed, many negative results challenge current assumptions about the etiology of non-T2 asthma and raise doubts about the viability of targeting popular alternative inflammatory pathways, such as T17. Novel data have emerged from the use of biologics to treat various inflammatory mediators and have furthered our understanding of pathogenic mechanisms that drive asthma. This review discusses inflammatory pathways that contribute to asthma, quantitatively outlines effects of available biologics on biomarkers, and summarizes data and challenges from clinical trials that address non-T2 mechanisms of asthma.

The pathogenesis of inflammatory bowel disease (IBD) involves the dysregulation of multiple inflammatory pathways. The understanding of these mechanisms allows their selective targeting for therapeutic purposes. The discovery of Tumor Necrosis Factor-alpha's (TNF-α) role in mucosal inflammation ushered an exciting new era of drug development which now comprises agents targeting multiple pro-inflammatory signaling pathways, integrins, and leukocyte trafficking regulators.

This review provides an overview of the main molecular players of IBD, their translation into therapeutic targets and the successful development of the advanced agents modulating them. We combine basic science with clinical trials data to present a critical review of both the successful and failed drug development programs. A PubMed literature search was conducted to delve into the available literature and clinical trials.

The treatment landscape for IBD has rapidly expanded, particularly with the development of biologics targeting TNF-α, integrins, and S1P modulators, as well as newer agents such as IL-12/IL-23 inhibitors and JAK inhibitors, offering robust efficacy and safety profiles. However, challenges persist in understanding and effectively treating difficult-to-treat IBD, highlighting the need for continued research to uncover novel therapeutic targets and optimize patient outcomes.

T cells are the main effectors involved in anti-tumor immunity, mediating most of the adaptive response towards cancer. After priming in lymph nodes, tumor antigens-specific naïve T lymphocytes proliferate and differentiate into effector CD4+ and CD8+ T cells that migrate from periphery into tumor sites aiming to eliminate cancer cells. Then while most effector T cells die, a small fraction persists and recirculates as long-lived memory T cells which generate enhanced immune responses when re-encountering the same antigen. A number of T (and non-T) cell subsets, stably resides in non-lymphoid peripheral tissues and may provide rapid immune response independently of T cells recruited from blood, against the reemergence of cancer cells. When tumor grows, however, tumor cells have evaded immune surveillance of effector cells (NK and CTL cells) which are exhausted, thus favoring the local expansion of T (and non-T) regulatory cells. In this review, the current knowledge of features of T cells present in the tumor microenvironment (TME) of solid adult and pediatric tumors, the mechanisms upregulating immune-checkpoint molecules and transcriptional and epigenetic landscapes leading to dysfunction and exhaustion of T effector cells are reviewed. The interaction of T cells with cancer- or TME non-neoplastic cells and their secreted molecules shape the T cell profile compromising the intrinsic plasticity of T cells and, therefore, favoring immune evasion. In this phase regulatory T cells contribute to maintain a high immunosuppressive TME thus facilitating tumor cell proliferation and metastatic spread. Despite the advancements of cancer immunotherapy, many tumors are unresponsive to immune checkpoint inhibitors, or therapeutical vaccines or CAR T cell-based adoptive therapy: some novel strategies to improve these T cell-based treatments are lastly proposed.

Probiotics are live microorganisms that, when administered in adequate amounts, can bring health benefits to the host. Most of these organisms are found naturally in the human gastrointestinal tract. Escherichia coli strains Nissle 1917 (EcN), and CEC15 have shown beneficial effects in murine models of intestinal inflammation, such as colitis and mucositis. The present study evaluated the effects as postbiotic of heat-inactivated and cell-free supernatant preparations of EcN and CEC15 in attenuating 5-fluorouracil (5-FU)-induced intestinal mucositis in mice and compared them with the probiotic effects of the live preparations. BALB/c mice were fed, by daily gavage, with 1010 CFU of live or inactivated bacteria or with 300 µL of cell-free supernatant for 12 days. On the 10th day, all animals, except for the control group, received an intraperitoneal injection of 5-FU (300 mg/kg). After 72 h of 5-FU administration, animals were euthanized, and the ileum and blood were collected for analysis. Treatments with live and heat-inactivated CEC15 mitigated weight loss, preserved intestinal length, reduced histological damage, maintained goblet cells, decreased neutrophil infiltration, and modulated expression of inflammatory and barrier genes when compared to 5-FU mucositis controls. EcN showed more limited effects. CEC15 upregulated mRNA expression of the mucin MUC2 and tight junction protein TJP1. CEC15 demonstrated protective effects against 5-FU-induced mucositis, whether administered with live, heat-inactivated, or cell-free supernatant. This suggests that CEC15 mediates a protective response via secreted metabolites and does not require viability. The postbiotic forms of CEC15 present advantages for use in immunocompromised patients. This study elucidates the anti-inflammatory and barrier-protective effects of CEC15 against intestinal mucositis.

There is substantial evidence indicating that cytokines play a role in the immune defense against tuberculosis. This study aims to evaluate the levels of various cytokines in pleural effusion to ditinguish between tuberculosis pleurisy and malignant pleurisy.

A total of 82 participants with pleural effusion were included in the training cohort, and 76 participants were included in the validation cohort. The individuals were divided into tuberculosis and malignant pleurisy groups. The concentrations of interleukin-1β (IL-1β), IL-4, IL-6, IL-10, IL-17 A, IL-17 F, IL-21, IL-22, IL-25, IL-31, IL-33, interferon-γ (IFN-γ), soluble CD40 ligand (sCD40L) and tumor necrosis factor-α (TNF-α) in pleural effusion were measured using a multiplex cytokine assay. The threshold values were calculated according to the receiver operating characteristic (ROC) curve analysis to aid in diagnosing tuberculosis pleurisy. Furthermore, the combined measure was validated in the validation cohort.

The levels of all 14 cytokines in pleural effusion were significantly higher in participants with tuberculosis compared to those with malignant pleurisy (all P < 0.05). The area under the curve (AUC) was ≥ 0.920 for the IL-22, sCD40L, IFN-γ, TNF-α and IL-31, which were significantly increased in tuberculous pleural effusion (TPE) compared to MPE in the training cohort. Threshold values of 95.80 pg/mL for IFN-γ, 41.80 pg/mL for IL-31, and 18.87 pg/mL for IL-22 provided ≥ 90% sensitivity and specificity in distinguishing between tuberculosis pleurisy and malignant pleurisy in the training cohort. Among these, IL-22 combined with sCD40L showed the best sensitivity and specificity (94.0% and 96.9%) for diagnosing tuberculosis pleurisy, and this finding was validated in the validation cohort.

We demonstrated that the levels of IL-1β, IL-4, IL-6, IL-10, IL-17 A, IL-17 F, IL-21, IL-22, IL-25, IL-31, IL-33, IFN-γ, sCD40L and TNF-α in pleural effusion had significant difference between tuberculosis pleurisy and malignant pleurisy. Specifically, IL-22 ≥ 18.87 pg/mL and sCD40L ≥ 53.08 pg/mL can be clinically utilized as an efficient diagnostic strategy for distinguishing tuberculosis pleurisy from malignant pleurisy.

L-arginine metabolism through arginases and inducible nitric oxide synthase (NOS2) constitutes a fundamental axis for the resolution or progression of Chagas disease. Infection with Trypanosoma cruzi can cause a wide spectrum of disease, ranging from acute forms contained by the host immune response to chronic ones, such as the chronic chagasic cardiomyopathy. Here, we analyzed, in an in vitro model, the ability of two T. cruzi isolates, with different degrees of virulence, to regulate the metabolism of L-arginine through arginase 1 (Arg-1) and NOS2 in macrophages and through arginase 2 (Arg-2) and NOS2 in cardiomyocytes. Stimulation of bone marrow-derived macrophages (BMMΦ), obtained from CD1 mice, with TNF-α + IFN-γ induced their polarization into classically activated macrophages (CAMΦ), which expressed functional NOS2, while stimulation with IL-4 induced their polarization into alternatively activated macrophages (AAMΦ), which expressed functional Arg-1. Interestingly, stimulation of cardiomyocytes, obtained from hearts of CD1 neonatal mice, with TNF-α + IFN-γ or IL-4 also resulted in functional NOS2 and arginase expression, as observed in CAMΦ and AAMΦ, but Arg-2 was the arginase isoform expressed instead of Arg-1. We observed that infection of BMMΦ with the more virulent T. cruzi isolate (QRO) importantly diminished NOS2 expression and nitric oxide (NO) production in CAMΦ, allowing parasite survival, while infection with the less virulent isolate (CI2) did not diminish NOS2 activity and NO production in CAMΦ to a great extent, which resulted in parasite killing. Regarding Arg-1, infection of BMMΦ with the QRO isolate significantly induced Arg-1 expression and activity in AAMΦ, which resulted in a higher parasite load than the one in the unstimulated BMMΦ. Even though infection with CI2 isolate did not increase Arg-1 expression and activity in AAMΦ, the parasite load was higher than the one in the unstimulated BMMΦ but at a lesser magnitude than that observed during infection with the QRO isolate. On the other hand, infection of cardiomyocytes with either QRO or CI2 isolates and further stimulation with TNF-α + IFN-γ inhibited NOS2 expression and NO production, leading to amelioration of infection. Surprisingly, infection of cardiomyocytes with either QRO or CI2 isolates and further stimulation with IL-4 strongly inhibited Arg-2 expression and function, which resulted in parasite loads similar to those observed in unstimulated cardiomyocytes. Our results suggest that T. cruzi isolates that exhibit variable virulence or pathogenicity degrees differentially regulate L-arginine metabolism through Arg-1/2 and NOS2 in macrophages and cardiomyocytes.

Graves' disease is the leading cause of autoimmune hyperthyroidism. Thyroid hormones are an essential element of the endocrine system, playing a pivotal role in the body's development, especially important in children with intensified growth. Disturbance within thyroid tissue certainly affected the whole body. Nowadays, numerous research studies indicate different factors contributing to the onset of the disease; however, the exact pathomechanism of Graves' disease is still not fully understood, especially in the context of immune-related processes. Th1, Th17, and Th22 effector lymphocytes were found to be crucial participants in the disease outcome, as well as in autoimmune diseases. Here, our study aimed at assessing selected effector T lymphocytes, Th1, Th17, and Th22, in newly diagnosed pediatric Graves' disease patients, together with their association with thyroid-related parameters and the potential outcome of disease management. We indicated significant increases in the frequencies and absolute numbers of selected effector lymphocytes in Graves' disease patients. In addition, their mutual ratios, as well as Th1/Th17, Th/Th22, and Th17/Th22, seem to be significant in those diseases. Notably, low Th17/Th22 ratio values were distinguished as potential prognostic factors for normalizing TSH levels in response to methimazole treatment. To sum up, our research determines the crucial contribution of Th1, Th17, and Th22 cells in the pathogenesis of Graves' disease. Moreover, the mentioned subset of T cells is highly likely to play a substantial role in the potential prediction of therapy outcomes.

Previous studies have suggested a potential correlation between psoriasis (PS) and ulcerative colitis (UC). However, studies exploring the shared mechanisms of both diseases remain limited. Current treatments primarily involve using immunosuppressive drugs, which can lead to potential side effects and drug resistance. Traditional Chinese medicine has demonstrated favorable efficacy in treating UC and PS with fewer side effects. This study aims to elucidate the shared biological mechanisms underlying UC and PS and to predict natural compounds effective for treating both disorders.

We collected and validated differentially expressed genes associated with UC and PS from the Gene Expression Omnibus database. A protein-protein interaction network was constructed using the STRING database, aiding in identifying core targets. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were utilized to analyze the functions and genomic enrichment of the identified core targets. The CIBERSORT method was employed to assess the correlation of core targets with immune cells. Compounds with potential therapeutic values were selected from the Coremine and TCMSP databases, and their therapeutic efficacy was predicted via molecular docking.

In UC and PS, 20 common core targets were identified, with matrix metalloproteinase 9 (MMP9), matrix metalloproteinase 1 (MMP1), cluster of differentiation 274 (CD274), C-X-C motif chemokine ligand 10 (CXCL10), and topoisomerase II alpha (TOP2A) emerging as the most relevant targets shared between both conditions. Elevated levels of macrophages and dendritic cells were observed in UC and PS, with CXCL10 exhibiting the closest association with macrophages. UC and PS shared common signaling pathways, including IL-17, TNF, and chemokine signaling pathways, among others. Molecular docking revealed that quercetin, baicalen, irisolidone, rutaecarpine, epigallocatechin-3-gallate, and others held potential as natural compounds for treating both disorders.

MMP9, MMP1, and CXCL10, central mediators in the inflammatory pathways of UC and PS, establish a shared mechanism by triggering cytokine and chemokine activation, leading to tissue damage and positioning them as promising therapeutic targets for both conditions. Compounds such as quercetin, luteolin, irisolidone, rutaecarpine, and so on may be key drugs for treating both conditions. These findings suggest the potential advancement of therapeutic strategies and the enhancement of patient care by exploring shared mechanisms and predicting promising natural compounds for treating UC and PS.

T helper (Th) cell subsets primarily assist B cells in differentiating into plasma cells in the germinal center. The mechanism of malignant transformation of plasma cells is an important target for the clinical treatment of MM; however, the mechanism remains unclear.

We collected the peripheral blood (PB) and bone marrow (BM) samples of 33 patients with MM. In addition, the PB was also collected from 25 normal healthy controls (HCs). We analyzed the percentages of Th cell subsets in the PB and BM samples of patients with MM.

Tfh/CD4+ were positively correlated with the proportion of myeloma cells in the BM and PB samples (r = 0.592, P = 0.002 and r = 0.510, P = 0.010 respectively), and showed a strong correlation between the BM and PB samples (r = 0.6559, P = 0.0095). In the PB samples, the percentages of Th2/CD4+ and Tfh2/Tfh cells were significantly lower in patients with MM than in HCs (P = 0.00013 and P = 0.0004, respectively), whereas the percentage of Th17/CD4+ and Tfh17/Tfh was significantly higher in newly diagnosed patients with MM than in HCs (P = 0.0037 and P = 0.03, respectively), and all these cells showed a good predictive value for MM (area under the curve [AUC] 0.781, = 0.792, = 0.837, and 0.723 respectively). In the PB samples, all subsets of PD-1+ICOS- Tfh showed a noticeable downward trend in MM from newly diagnosed to non-remission and remission groups. In contrast, all subsets of PD-1-ICOS+ Tfh increased gradually.

Th cell subsets play an important role in the occurrence and development of MM and may provide a fundamental basis for identifying new immunotherapy targets and prognosis.

Chronic obstructive pulmonary disease (COPD) has been linked to immune responses to lung-associated self-antigens. Exposure to cigarette smoke (CS), the main cause of COPD, causes chronic lung inflammation, resulting in pulmonary matrix (ECM) damage. This tissue breakdown exposes collagen V (Col V), an antigen typically hidden from the immune system, which could trigger an autoimmune response. Col V autoimmunity has been linked to several lung diseases, and the induction of immune tolerance can mitigate some of these diseases. Evidence suggests that autoimmunity to Col V might also occur in COPD; thus, immunotolerance to Col V could be a novel therapeutic approach.

The role of autoimmunity against collagen V in COPD development was investigated by analyzing the effects of Col V-induced tolerance on the inflammatory response and lung remodeling in a murine model of CS-induced COPD.

Male C57BL/6 mice were divided into three groups: one exposed to CS for four weeks, one previously tolerated for Col V and exposed to CS for four weeks, and one kept in clean air for the same period. Then, we proceeded with lung functional and structural evaluation, assessing inflammatory cells in bronchoalveolar lavage fluid (BALF) and inflammatory markers in the lung parenchyma, inflammatory cytokines in lung and spleen homogenates, and T-cell phenotyping in the spleen.

CS exposure altered the structure of elastic and collagen fibers and increased the pro-inflammatory immune response, indicating the presence of COPD. Col V tolerance inhibited the onset of emphysema and prevented structural changes in lung ECM fibers by promoting an immunosuppressive microenvironment in the lung and inducing Treg cell differentiation.

Induction of nasal tolerance to Col V can prevent inflammatory responses and lung remodeling in experimental COPD, suggesting that autoimmunity to Col V plays a role in COPD development.

The immune system is an intricate network of cellular components that safeguards against pathogens and aberrant cells, with CD4+ T cells playing a central role in this process. Human space travel presents unique health challenges, such as heavy ion ionizing radiation, microgravity, and psychological stress, which can collectively impede immune function. The aim of this research was to examine the consequences of simulated space stressors on CD4+ T cell activation, cytokine production, and gene expression.

CD4+ T cells were obtained from healthy individuals and subjected to Fe ion particle radiation, Photon irradiation, simulated microgravity, and hydrocortisone, either individually or in different combinations. Cytokine levels for Th1 and Th2 cells were determined using multiplex Luminex assays, and RNA sequencing was used to investigate gene expression patterns and identify essential genes and pathways impacted by these stressors.

Simulated microgravity exposure resulted in an apparent Th1 to Th2 shift, evidenced on the level of cytokine secretion as well as altered gene expression. RNA sequencing analysis showed that several gene pathways were altered, particularly in response to Fe ions irradiation and simulated microgravity exposures. Individually, each space stressor caused differential gene expression, while the combination of stressors revealed complex interactions.

The research findings underscore the substantial influence of the space exposome on immune function, particularly in the regulation of T cell responses. Future work should focus expanding the limited knowledge in this field. Comprehending these modifications will be essential for devising effective strategies to safeguard the health of astronauts during extended space missions.

The effects of simulated space stressors on CD4+ T cell function are substantial, implying that space travel poses a potential threat to immune health. Additional research is necessary to investigate the intricate relationship between space stressors and to develop effective countermeasures to mitigate these consequences.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gastrointestinal tract. The introduction of biologics, particularly anti-interleukin (IL) agents, has revolutionized IBD treatment. This review summarizes the role of ILs in IBD pathophysiology and describes the efficacy and positioning of anti-IL therapies. We discuss the functions of key ILs in IBD and their potential as therapeutic targets. The review then discusses anti-IL therapies, focusing primarily on ustekinumab (anti-IL-12/23), risankizumab (anti-IL-23), and mirikizumab (anti-IL-23). Clinical trial data demonstrate their efficacy in inducing and maintaining remission in Crohn's disease and ulcerative colitis. The safety profiles of these agents are generally favorable. However, long-term safety data for newer agents are still limited. The review also briefly discusses emerging therapies such as guselkumab and brazikumab. Network meta-analyses suggest that anti-IL therapies perform well compared to other biological agents. These agents may be considered first- or second-line therapies for many patients, especially those with comorbidities or safety concerns. Anti-IL therapies represent a significant advancement in IBD treatment, offering effective and relatively safe options for patients with moderate to severe disease.

Targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) with specific antibody offers long-term benefits for cancer immunotherapy but can cause severe adverse effects in the heart. This study aimed to investigate the role of anti-CTLA-4 antibody in pressure overload-induced cardiac remodeling and dysfunction. Transverse aortic constriction (TAC) was used to induce cardiac hypertrophy and heart failure in mice. Two weeks after the TAC treatment, mice received anti-CTLA-4 antibody injection twice a week at a dose of 10 mg/kg body weight. The administration of anti-CTLA-4 antibody exacerbated TAC-induced decline in cardiac function, intensifying myocardial hypertrophy and fibrosis. Further investigation revealed that anti-CTLA-4 antibody significantly elevated systemic inflammatory factors levels and facilitated the differentiation of T helper 17 (Th17) cells in the peripheral blood of TAC-treated mice. Importantly, anti-CTLA-4 mediated differentiation of Th17 cells and hypertrophic phenotype in TAC mice were dramatically alleviated by the inhibition of interleukin-17A (IL-17A) by an anti-IL-17A antibody. Furthermore, the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100, also reversed anti-CTLA-4-mediated cardiotoxicity in TAC mice. Overall, these results suggest that the administration of anti-CTLA-4 antibody exacerbates pressure overload-induced heart failure by activating and promoting the differentiation of Th17 cells. Targeting the CXCR4/Th17/IL-17A axis could be a potential therapeutic strategy for mitigating immune checkpoint inhibitors-induced cardiotoxicity.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease characterized by irreversible progressive airflow limitation, often manifested by persistent cough, sputum production and other respiratory symptoms that pose a serious threat to human health and affect the quality of life of patients. The disease is associated with chronic inflammation, which is associated with the onset and progression of COPD, but anti-inflammatory therapy is not first-line treatment. Inflammation has multiple manifestations and phenotypes, and this heterogeneity reveals different patterns of inflammation, making treatment difficult. This paper aims to explore the direction of more effective anti-inflammatory treatment by analyzing the nature of inflammation and the molecular mechanism of disease occurrence and development in COPD patients, and to provide new ideas for the treatment of COPD patients.

Graft-versus-host disease is among the most common clinical complications following allogeneic hematopoietic stem cell transplantation. It causes inflammation-mediated destruction and dysfunction of various organ systems including ocular tissues in 60-90% of the patients and is termed ocular GVHD (oGVHD). In oGVHD, donor-derived T-cells recognize host antigens as foreign, resulting in immune dysregulation, inflammation and fibrosis of lacrimal glands, meibomian glands, cornea, and conjunctiva. The clinical presentation in oGVHD patients range from mild dry eye symptoms to catastrophic inflammation mediated pathological changes which can cause corneal perforation and blindness. In this review article, we provide detailed insights into the impact of mucosal barrier disruption, the afferent and efferent phases of immunological response involving activation of antigen presenting cells and T cells, respectively. We evaluate the evidence outlining the effector phase of the disease leading to cellular destruction and eventually fibrosis in patients with oGVHD. Finally, we discuss the well-established criteria for the diagnosis of oGVHD.

Non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat within the cytoplasm of hepatocytes (exceeding 5% of liver weight) in individuals without significant alcohol consumption, has rapidly evolved into a pressing global health issue, affecting approximately 25% of the world population. This condition, closely associated with obesity, type 2 diabetes, and the metabolic syndrome, encompasses a spectrum of liver disorders ranging from simple steatosis without inflammation to non-alcoholic steatohepatitis (NASH) and cirrhotic liver disease. Recent research has illuminated the complex interplay between metabolic and immune responses in the pathogenesis of NASH, underscoring the critical role played by T and B lymphocytes. These immune cells not only contribute to necroinflammatory changes in hepatic lobules but may also drive the onset and progression of liver fibrosis. This narrative review aims to provide a comprehensive exploration of the effector mechanisms employed by T cells, B cells, and their respective subpopulations in the pathogenesis of NASH. Understanding the immunological complexity of NASH holds profound implications for the development of targeted immunotherapeutic strategies to combat this increasingly prevalent and burdensome metabolic liver disease.

For decades, the Th1/2 paradigm has been used to classify immune responses as either Th1 or Th2-biased. However, in recent years, a staggering amount of evidence has emerged to support rejection of the classical Th1/Th2 paradigm, such as the discoveries of new helper T cell subsets, helper T cell plasticity and protective mixed-Th1/Th2 responses. This opinion piece investigates the shortcomings of classical Th1/Th2 paradigm in the context of recent works, with the goal of facilitating the development of newer models to represent the diversity of Th cells.

Pleurisy can be categorized as primary or secondary, arising from immunological, tumorous, or microbial conditions. It often results in lung structure damage and the development of various respiratory issues. Among the different types, tuberculous pleurisy has emerged as a prominent focus for both clinical and scientific investigations. The IL-10 family, known for its anti-inflammatory properties in the human immune system, is increasingly being studied for its involvement in the pathogenesis of pleurisy. This review aims to present a detailed overview of the intricate role of IL-10 family members (specifically IL-10, IL-22, and IL-26) in human and animal pleuritic diseases or relevant animal models. These insights could serve as valuable guidance and references for further studies on pleurisy and potential therapeutic strategies.

This study aimed to develop and optimize karanjin-loaded ethosomal nanogel formulation and evaluate its efficacy in alleviating symptoms of psoriasis in an animal model induced by imiquimod. These karanjin-loaded ethosomal nanogel, were formulated to enhance drug penetration into the skin and its epidermal retention. Karanjin was taken to formulate ethosomes due to its potential ani-psoriatic activity. Ethosomes were formulated using the cold method using 32full factorial designs to optimize the formulation components. 9 batches were prepared using two independent variablesX1: concentration of ethanol andX2: concentration of phospholipid whereas vesicle size (Y1) and percentage entrapment efficiency (Y2) were selected as dependent variables. All the dependent variables were found to be statistically significant. The optimized ethosomal suspension (B3) exhibited a vesicle size of 334 ± 2.89 nm with an entrapment efficiency of 94.88 ± 1.24% and showed good stability. The morphology of vesicles appeared spherical with smooth surfaces through transmission electron microscopy analysis. X-ray diffraction analysis confirmed that the drug existed in an amorphous state within the ethosomal formulation. The optimized ethosome was incorporated into carbopol 934 to develop nanogel for easy application on the skin. The nanogel underwent characterization for various parameters including spreadability, viscosity, pH, extrudability, and percentage drug content. The ethosomal formulation remarkably enhanced the skin permeation of karanjin and increased epidermal retention of the drug in psoriatic skin compared to marketed preparation and pure drug. A skin retention study showed that ethosomal nanogel formulation has 48.33% epidermal retention in 6 h.In vivo,the anti-psoriatic activity of karanjin ethosomal nanogel demonstrated significant improvement in psoriasis, indicated by a gradual decrease in skin thickness and scaling as reflected in the Psoriasis Severity Index grading. Therefore, the prepared ethosomal nanogel is a potential vehicle for improved topical delivery of karanjin for better treatment of psoriasis.

As lower vertebrates, fish have both innate and adaptive immune systems, but the role of the adaptive immune system is limited, and the innate immune system plays an important role in the resistance to pathogen infection. C-type lectins (CLRs) are one of the major pattern recognition receptors (PRRs) of the innate immune system. CLRs can combine with pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) to trigger NF-κB signaling pathway and exert immune efficacy. In this study, Ssclec12b and Ssclec4e of the C-type lectins, were found to be significantly up-regulated in the transcripts of Sebastes schlegelii macrophages stimulated by bacteria. The identification, expression and function of these lectins were studied. In addition, the recombinant proteins of the above two CLRs were obtained by prokaryotic expression. We found that rSsCLEC12B and rSsCLEC4E could bind to a variety of bacteria in a Ca2+-dependent manner, and promoted the agglutination of bacteria and blood cells. rSsCLEC12B and rSsCLEC4E assisted macrophages to recognize PAMPs and activate the NF-κB signaling pathway, thereby promoting the expression of inflammatory factors (TNF-α, IL-1β, IL-6, IL-8) and regulating the early immune inflammation of macrophages. These results suggested that SsCLEC12B and SsCLEC4E could serve as PRRs in S. schlegelii macrophages to recognize pathogens and participate in the host antimicrobial immune process, and provided a valuable reference for the study of CLRs involved in fish innate immunity.

Ulcerative colitis (UC) is a complicated and recurrent intestinal disease. Currently available drugs for UC treatment are scarce, therefore, novel therapeutic drugs for the UC are urgently to be developed. Gingerenone A (GA) is a phenolic compound known for its anti-inflammatory effect, but its effect on UC remains unknown. Here, it is shown that GA protects mice against UC, which is closely associated with inhibiting intestinal mucosal inflammation and enhancing intestinal barrier integrity in vivo and in vitro. Of note, RNA sequencing analysis demonstrates an evident correlation with IL-17 signaling pathway after GA treatment, and this effect is further corroborated by Western blot. Mechanistically, GA directly interacts with IL-17RA protein through pull-down, surface plasmon resonance analysis and molecular dynamics simulation. Importantly, lentivirus-mediated IL-17RA/Act1 knock-down or GA co-treatment with brodalumab/ixekizumab significantly impairs the protective effects of GA against DSS-induced inflammation and barrier dysfunction, suggesting a critical role of IL-17RA signaling for GA-mediated protection against UC. Overall, these results indicate that GA is an effective agent against UC mainly through the direct binding of IL-17RA to inhibit inflammatory signaling activation.

Multiple sclerosis (MS) is an autoimmune demyelinating disease affecting the central nervous system (CNS). T helper (Th) 17 cells are involved in the pathogenesis of MS and its animal model of experimental autoimmune encephalomyelitis (EAE) by infiltrating the CNS and producing effector molecules that engage resident glial cells. Among these glial cells, astrocytes have a central role in coordinating inflammatory processes by responding to cytokines and chemokines released by Th17 cells. In this study, we examined the impact of pathogenic Th17 cells on astrocytes in vitro and in vivo. We identified that Th17 cells reprogram astrocytes by driving transcriptomic changes partly through a Janus Kinase (JAK)1-dependent mechanism, which included increased chemokines, interferon-inducible genes, and cytokine receptors. In vivo, we observed a region-specific heterogeneity in the expression of cell surface cytokine receptors on astrocytes, including those for IFN-γ, IL-1, TNF-α, IL-17, TGFβ, and IL-10. Additionally, these receptors were dynamically regulated during EAE induced by adoptive transfer of myelin-reactive Th17 cells. This study overall provides evidence of Th17 cell reprogramming of astrocytes, which may drive changes in the astrocytic responsiveness to cytokines during autoimmune neuroinflammation.

Although preclinical investigations have shown notable efficacy in solid tumor models utilizing in vitro-differentiated Th17 cells for adoptive cell therapy (ACT), the potential benefits of this strategy in enhancing ACT efficacy in hematological malignancies, such as chronic lymphocytic leukemia (CLL), remain unexplored. CLL is a B-cell malignancy with a clinical challenge of increased resistance to targeted therapies. T-cell therapies, including chimeric antigen receptor (CAR) T cells, have demonstrated limited success in CLL, which is attributed to CLL-mediated T-cell dysfunction and skewing toward immunosuppressive phenotypes. Herein, we illustrate the feasibility of polarizing CD4+ T cells from the Eμ-TCL1 murine model, the most representative model for human CLL, into Th17 phenotype, employing a protocol of T-cell activation through the inducible co-stimulator (ICOS) alongside a polarizing cytokine mixture. We demonstrate augmented memory properties of in vitro-polarized IL-17-producing T cells, and preliminary in vivo persistence in leukemia-bearing mice. Our findings gain translational relevance through successful viral transduction of Eμ-TCL1 CD4+ T cells with a CD19-targeted CAR construct during in vitro Th17 polarization. Th17 CAR T cells exhibited remarkable persistence upon encountering antigen-expressing target cells. This study represents the first demonstration of the potential of in vitro-differentiated Th17 cells to enhance ACT efficacy in CLL.