Lung transplantation (LTx) offers a last resort for patients battling end-stage lung disease. Even though short-term survival has improved, these patients still face several long-term challenges, such as chronic rejection and ischemic bronchial anastomosis. In lung transplant recipients, the bronchial anastomosis is prone to complications-such as poor wound healing, necrosis, stenosis, and dehiscence-due to the marginal blood supply at this site. During peri-LTx, hypoxia and ischemia stimulate fibrotic and inflammatory cytokines at anastomotic sites, leading to abnormal collagen production and excessive granulation, which impair wound healing. Despite meticulous techniques, bronchial anastomosis remains a major cause of morbidity and mortality among lung transplant recipients. After LTx, most bronchial complications are attributed to ischemic insult since normal bronchial blood flow is disrupted, and bronchial revascularization usually takes two to four weeks, making the anastomotic bronchial vessels dependent on pulmonary artery circulation. It is clear that hypoxia, inflammation, oxidative stress, and extracellular matrix remodeling play critical roles in bronchial complications, but there is no small animal model to study them. In the context of LTx, mouse tracheal models are essential tools for studying bronchial complications, particularly ischemia, fibrosis, and stenosis, as well as evaluating potential therapeutic interventions. A well-established mouse model of orthotopic tracheal transplantation (OTT) mimics the anastomosis of the bronchi and the subsequent microvascular injury, providing a pathological correlation with anastomotic complications. A series of previous studies using the OTT model explored the microvascularization, ischemia-reperfusion, airway epithelial injury, and fibrotic remodeling effects after airway anastomosis. This review describes OTT as a model of airway anastomotic complications, which is crucial for understanding the immunological and molecular pathways as seen in clinical bronchial anastomoses, as well as improving anastomotic healing and reducing complications through targeted therapeutic strategies.

Cancer-associated fibroblasts (CAFs) are a multifaceted cell population essential for shaping the tumor microenvironment (TME) and influencing therapy responses. Characterizing the spatial organization and interactions of CAFs within complex tissue environments provides critical insights into tumor biology and immunobiology. In this study, through integrative analyses of over 14 million cells from 10 cancer types across 7 spatial transcriptomics and proteomics platforms, we discover, validate, and characterize four distinct spatial CAF subtypes. These subtypes are conserved across cancer types and independent of spatial omics platforms. Notably, they exhibit distinct spatial organizational patterns, neighboring cell compositions, interaction networks, and transcriptomic profiles. Their abundance and composition vary across tissues, shaping TME characteristics, such as levels, distribution, and state composition of tumor-infiltrating immune cells, tumor immune phenotypes, and patient survival. This study enriches our understanding of CAF spatial heterogeneity in cancer and paves the way for novel approaches to target and modulate CAFs.

Modulation of the gut microbiota composition has been suggested as a potential disease modifying therapy in immune-mediated diseases such as multiple sclerosis (MS). However, a conclusive mechanism linking gut microbiota modulation to peripheral immune responses has remained elusive so far.

In this exploratory cohort study, people with MS (pwMS) and healthy controls (HC) supplemented a lactobacilli-rich probiotic for two or six weeks and were additionally investigated six weeks after the last intake. Immune cell phenotyping was performed in blood samples, complemented by mRNA expression analysis, serum cytokine measurements, and Treg suppression assays. Besides gut microbiota composition analysis, metabolite production was investigated in stool and serum. Links between metabolites and peripheral immune system were investigated in in vitro T cell differentiation assays.

In peripheral blood, Treg cells increased in both groups, while Th1 cells were significantly reduced in pwMS. This promotion of a regulatory immunophenotype was complemented by increased concentrations of IL-10 in serum and higher expression of IL10 and CTLA4. Functional assays revealed an enhanced suppressive capacity of Treg cells due to the probiotic intervention. The tryptophan metabolite indole-3-acetate (IAA) increased in stool and serum samples of pwMS during the probiotic intake. In vitro, IAA specifically enhanced the formation of IL-10 secreting T cells together with CYP1a1 expression. This effect was blocked by addition of an aryl hydrocarbon receptor (AHR) inhibitor.

A lactobacilli-enriched probiotic promotes a regulatory immunophenotype in pwMS, probably by enhancing AHR agonists in the gut. It may be of interest as add-on therapy in immune-mediated diseases such as MS.

This study has in part been funded by Novartis Pharma GmbH and BMBF grant no. 01EJ2202B.

The mechanisms by which the gut microbiome contributes to lupus pathogenesis remain poorly understood. The anaerobe Ruminococcus gnavus (RG) expands in patients with lupus in association with flares. The goal of this study was to determine the mechanisms by which candidate pathobiont lipoglycan-producing RG2 may contribute to autoimmunity and to identify factors promoting its expansion.

The consequences of RG colonization or depletion were evaluated in the B6.Sle1.Sle2.Sle3 triple congenic (TC) lupus model by flow cytometry and enzyme-linked immunosorbent assay. RG lysates were tested on Treg cells in vitro. Fecal microbiota transfers evaluated the contribution of the microbiome origin from lupus or control donors and dietary tryptophan. RG1 and RG2 growth and metabolome were evaluated in response to tryptophan in vitro.

Only RG2 stably colonized TC mice, in which it induced autoantibody production and T cell activation. Depletion of anaerobes had the opposite effect, with an increased Treg frequency. RG2 induced Treg apoptosis in cocultures with dendritic cells. RG is present in TC microbiota, from which it is amplified by tryptophan. The combination of TC microbiota and high dietary tryptophan induced autoimmune activation and intestinal inflammation in healthy control mice. Finally, tryptophan enhanced RG2 growth and production of immunomodulatory metabolites.

RG2 contributes to autoimmune activation, at least by inducing Treg apoptosis. The expansion of this pathobiont is promoted by host genetic factors and tryptophan metabolism. Thus, targeted RG2 depletion may improve disease outcomes in patients with lupus.

STAT3 is an important protein responsible for cellular proliferation, motility, and immune tolerance and is hyperactive in colorectal cancer, instigating metastasis, cellular proliferation, migration, as well as inhibition. It helps in proliferation of myeloid-derived suppressor cells (MDSCs), which within the tumor microenvironment (TME) suppress T cells to encourage tumor growth, metastasis, and resistance to immunotherapy, besides playing dynamic role in regulating macrophages within the tumor. Thus, MDSC is a potential target to augment immune surveillance within the TME. Herein, we report targeting both colorectal cancer and MDSCs using a glucocorticoid receptor (GR)-targeted nanoliposomal formulation carrying GR-ligand, dexamethasone (Dex), and a STAT3 inhibitor, niclosamide (N). Our main objective was to selectively inhibit STAT3, the key immunomodulatory factor in most TME-associated cells including MDSCs, and also repurpose the use of this antihelminthic, low-cost drug N for cancer treatment. The resultant formulation D1XN exhibited better tumor regression and survivability compared to GR nontargeted formulation. Further, bone marrow cell-derived MDSCs were engineered by D1XN treatment ex vivo and were inoculated back to tumor-bearing mice. Significant tumor growth inhibition with enhanced antiproliferative immune cell signatures, such as T cell infiltration, decrease in Treg cells, and increased M1/M2 macrophage ratio within the TME were observed. This reveals the effectiveness of engineered MDSCs to modulate tumor surveillance besides reversing the aggressiveness of the tumor. Therefore, D1XN and D1XN-mediated engineered MDSCs alone or in combination can be considered as potent selective chemo-immunotherapeutic nanoliposomal agent(s) against colorectal cancer.

Intestinal fibrosis is a serious complication of Crohn's disease (CD), often resulting from chronic inflammation. However, the precise mechanisms through which inflammation induces intestinal fibrosis remain inadequately elucidated.

A comprehensive single-cell atlas of full-thickness CD, provided by Dr. Florian Rieder, was subjected to reanalysis. Our study used a DSS-induced chronic colitis model in both wild-type (WT) and Areg-/- mice. Additionally, a CD45RBhi CD4+ T cell adoptive transfer model involving WT and Areg-/- Treg cells (Tregs) was used. The expressions of AREG in CD with or without intestinal fibrosis, Tregs and human intestinal myofibroblasts (MFs) were determined. The effect of AREG on proliferation/migration/activation in human intestinal MFs was determined.

Several types of cells were differentially expressed between stricture and non-stricture CD. Among T cells, Tregs accounted for a larger proportion and were significantly increased in stenotic tissues of stricture CD. Although DSS-induced colitis was more severe in Areg-/- mice, which developed less severe intestinal fibrosis compared with WT mice. The transfer of Areg-/- Tregs resulted in less severe fibrosis in Rag-/- mice than WT Tregs. Moreover, TGF-β stimulated AREG expression in Tregs and human intestinal MFs via activation of Smad3.

These findings demonstrated that AREG derived from Tregs and human intestinal MFs, induced by TGF-β, amplifies intestinal fibrotic reactions in experimental colitis as well as in human CD patients. Thus, the TGF-β-Smad3-AREG pathway could be a potential therapeutic target for treating fibrosis in CD.

The advent of syngeneic mouse tumor models provided the scientific foundation for cancer immunotherapies now in widespread use. However, in many respects, these models do not faithfully recapitulate the interactions between cancer cells and the immune systems of human patients who have solid tumors because they represent a very early stage in the immune response to the newly transplanted cancer cells compared with the relatively mature stage found in human patients at the time of treatment. The lack of translatability of syngeneic models is probably responsible for many failed clinical trials conducted at considerable expense, involving far too many patients with cancer who received no benefit. Better mouse models would substantially accelerate the pace of discovery of new immunotherapies. Until these models emerge, a better understanding of the differences between the existing syngeneic models and human cancers may provide a more efficient path for moving experimental drugs into clinical development. To accomplish this, we must consider mice transplanted with syngeneic tumor cells to be in vivo assays, potentially useful for understanding the mechanism of action of immunotherapies rather than disease models.

The immune system encounters a diverse array of antigens, both self and foreign, necessitating mechanisms to maintain tolerance and prevent harmful inflammatory responses. CD4＋ T cells, crucial in orchestrating immune responses, play a critical role in mediating tolerance to both self and foreign antigens. While the mechanisms of CD4＋ T cell-mediated tolerance to self-antigens are well-documented, the understanding of tolerance to foreign antigens, including those from commensal microbes and food, remains incomplete. This review discusses recent progress in the mechanisms underlying immune tolerance to foreign antigens, with a focus on the role of CD4＋ T cells. We explore how inflammatory and tolerogenic CD4＋ T cell subsets are developed and maintained. Moreover, we delve into the complexities of immune responses to commensal microbes and food antigens by reviewing recent findings, highlighting the immunological contexts that shape immune tolerance. Understanding these mechanisms enhances our comprehension of how immune tolerance is established and sustained, providing insights into potential therapeutic approaches for managing chronic inflammatory diseases resulting from a loss of immune tolerance to foreign antigens. [BMB Reports 2025; 58(4): 158-168].

Fatty acid metabolism (FAM) plays a critical role in tumor progression and therapeutic resistance by enhancing lipid biosynthesis, storage, and catabolism. Dysregulated FAM is a hallmark of prostate cancer (PCa), enabling cancer cells to adapt to extracellular signals and metabolic changes, with the tumor microenvironment (TME) playing a key role. However, the prognostic significance of FAM in PCa remains unexplored.

We analyzed 309 FAM-related genes to develop a prognostic model using least absolute shrinkage and selection operator (LASSO) regression based on The Cancer Genome Atlas (TCGA) database. This model stratified PCa patients into high- and low-risk groups and was validated using the Gene Expression Omnibus (GEO) database. We constructed a nomogram incorporating risk score, clinical variables (T and N stage, Gleason score, age), and assessed its performance with calibration curves. The associations between risk score, tumor mutation burden (TMB), immune checkpoint inhibitors (ICIs), and TME features were also examined. Finally, a hub gene was identified via protein-protein interaction (PPI) networks and validated.

The risk score was an independent prognostic factor for PCa. High-risk patients showed worse survival outcomes but were more responsive to immunotherapy, chemotherapy, and targeted therapies. A core gene with high expression correlated with poor prognosis, unfavorable clinicopathological features, and immune cell infiltration.

These findings reveal the prognostic importance of FAM in PCa, providing novel insights into prognosis and potential therapeutic targets for PCa management.

Crohn's disease (CD) is an immune inflammatory disorder of the gastrointestinal tract arising from a complex interplay of genetic, environmental, microbiome, and immune factors. Regulatory T cells (Tregs), characterized by FoxP3 expression, are crucial for maintaining immune homeostasis through PD-1/PD-L1 interaction, interleukin (IL)-10 release, and granzyme (GrB) production. This study aimed to elucidate the role of FoxP3 positive (+) Tregs in CD.

Segmental colonoscopic biopsies from 46 treatment-naive CD cases (34 adults and 12 children) categorized into noninflamed [n = 32; Nancy histologic index (NHI) 0, 1] and inflamed (n = 100; NHI 2-4) mucosae using NHI. CD4, FoxP3, PD-1, IL-10, and GrB immunoexpression were analyzed by eyeballing and image morphometry. Findings were correlated with activity, granulomas, and skip lesions; and compared with site-matched non-inflammatory bowel disease (IBD) controls (n = 30).

FoxP3+ Tregs, IL-10, PD-1, and GrB expressions were significantly higher in NHI 3-4 mucosae than in NHI 0-1 and controls (P < 0.05). No significant differences were observed between adults and children, whereas those with granulomas had increased expression (P = 0.045). The FoxP3 : CD4 ratio positively correlated with IL-10 (Spearman, r = 0.307, P = 0.002), GrB (r = 0.302, P = 0.002), but not with PD-1 (r = 0.98, P = 0.33).

Our findings point to the possibility of a qualitative defect in FoxP3+ Tregs in CD. The functional arms of Tregs in CD need to be elucidated further in larger prospective cohorts to validate our observations and pave the way for future immunotherapy.

Peri-implant inflammation and periodontitis share a common etiology rooted in periodontopathic bacterial invasion, with periodontitis notably linked to systemic inflammatory comorbidities involving T cells. However, the intricate processes within the peri-implant microenvironment and systemic repercussions of implants, particularly related to implant materials, remain inadequately understood. We aim to elucidate the impact of contact with titanium materials, widely employed in dental implants for their high biocompatibility and excellent corrosion resistance, on diverse T cell subpopulations. This study adopts a comprehensive approach, encompassing (1) transcriptomic profiling of peri-implant epithelium in a rat model, (2) examination of phenotypic and functional changes in T cell immunity in human blood cells cultured on titanium discs, and (3) in vivo validation of T cells in implanted mice. Transcriptomic evidence and functional in vitro results revealed that exposure to titanium materials promoted T cell activation and differentiation towards inflammatory subsets, and escalated the secretion of corresponding cytokines. In vivo results showed that most of the gingiva-extracted T cells were activated in both healthy and implanted mice, the latter exhibiting significant lymphadenitis. High-dimensional flow cytometric findings in the in vivo lymphadenitis model indicated titanium-induced T cell immunity, involving preferential activation of Th1, Th17, and Tc1 cells over Tregs in adjacent lymph nodes within three days after implant placement. These findings highlight the pivotal role of T cells in the initiation of peri-implant inflammation, emphasizing the need to understand extra-periodontal inflammatory complications associated with implant surgeries. Our study provides a foundation for future therapeutic strategies targeting T cell responses to enhance the success and longevity of dental implant treatments.

DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) is a C-type lectin receptor expressed on dendritic cells and M2 macrophages, playing a key role in immune regulation and pathogen recognition. Its ability to mediate anti-inflammatory effects by interacting with specific ligands triggers pathways that suppress pro-inflammatory responses and promote tissue repair, making it a potential therapeutic target for inflammatory and autoimmune diseases. DC-SIGN homologs in various animal species share structural similarities and perform comparable immune functions, offering valuable insights into its broader application across species. By recognizing carbohydrate ligands on pathogens, DC-SIGN facilitates immune modulation, which can be harnessed for developing therapies aimed at controlling inflammation. In veterinary medicine, autoimmune and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, represent significant challenges, and the anti-inflammatory properties of DC-SIGN could provide new therapeutic options to improve disease management and enhance animal health. Future investigations should focus on the structural and functional analysis of DC-SIGN homologs in various species, as well as the development of preclinical models to translate these findings into clinical interventions bridging veterinary and human health.

This study aimed to explore the potential mechanism of Xiexin Tang in improving type 2 diabetes mellitus from the perspective of intestinal barrier function. The results indicated that Xiexin Tang could notably promote the expression of GPRs while suppressing the expression of HDACs in colon epithelial cells, then significantly elevate the levels of TGF-β1 and IL-18 to regulate the differentiation of T cells and further maintain the intestinal immune homeostasis. Meanwhile, it could markedly inhibit the inflammatory signaling pathway to improve intestinal barrier function, relieving type 2 diabetes mellitus.

Omalizumab (XOLAIR®)-assisted multi-food oral immunotherapy (mOIT) has been shown to safely, effectively, and rapidly desensitize patients with multiple food allergies. In our clinical trial (NCT02626611) on omalizumab-assisted mOIT, different desensitization outcomes (success or failure of desensitization) were observed following a period of either continued or discontinued mOIT. However, the association between the immunological changes induced by omalizumab-assisted mOIT and desensitization outcomes has not yet been fully elucidated. In this study, due to the key roles of regulatory T (Treg) cells and the type 2 helper T cell (Th2) pathway in immune tolerance to food allergens, we aimed to characterize their association with the desensitization outcomes of omalizumab-assisted mOIT.

Mass cytometry and multiplex cytokine assays were performed on blood samples obtained from participants with allergies to peanut, cashew, or milk in our phase 2 clinical study (NCT02626611). Comprehensive statistical and bioinformatic analyses were conducted on high-dimensional cytometry-based single-cell data and high-throughput multiplex cytokine data.

Our results demonstrated that the frequency of HLA-DR+ Treg cells, and the production of Th2 cytokines (IL-4, IL-5, IL-13, and IL-9) as well as the immunoregulatory cytokine IL-10 by peripheral blood mononuclear cells (PBMCs) was significantly increased in cultures with allergen compared to cultures with media alone at baseline (Week 0). We also observed increased frequency of allergen responsive HLA-DR+ Treg cells and enhanced production of IL-10 by PBMCs in participants who achieved successful desensitization compared to those with failure of desensitization. However, the production of Th2 cytokines by PBMCs did not show significant differences between participants with different desensitization outcomes (success vs. failure of desensitization), despite omalizumab-assisted mOIT inducing a significant reduction in the production of Th2 cytokines.

We demonstrated that the frequency of HLA-DR+ Treg cells and IL-10 cytokine production by PBMCs are associated with desensitization outcomes of omalizumab-assisted mOIT. These findings suggest potential immunological parameters that could be targeted to enhance desensitization success rates.

Regulatory T (Treg) cells contribute to solid organ cancer progression, except in colorectal cancer (CRC) despite being abundantly present. Here, we demonstrate that two distinct tumoral IL-10⁺ and IL-10⁻ Treg cell subsets exert opposing functions by counteracting and promoting CRC tumor growth, respectively. The tumor restraining activity of IL-10⁺ Treg cells was mediated by their suppression of effector CD4 T cell production of IL-17, which directly stimulates CRC tumor cell proliferation. Consistently, IL-10⁻ Treg cells were more abundant in both mouse and human CRC tumors than in tumor-adjacent normal tissues, whereas IL-10+ Treg cells exhibited the opposite distribution. Furthermore, relative abundance of IL-10⁺ and IL-10⁻ Treg cells correlated with better and worse disease prognoses in human CRC, respectively. This functional dichotomy between Treg cell subsets provides a rationale for therapeutic strategies to selectively target pro-tumoral Treg cells while preserving their anti-tumoral counterparts across barrier tissue cancers that harbor both subsets.

Interleukin-10 (IL-10) is an immunomodulatory cytokine critical for intestinal immune homeostasis. IL-10 is produced by various immune cells but IL-10 receptor signaling in intestinal CX3CR1+ mononuclear phagocytes is necessary to prevent spontaneous colitis in mice. Here, we utilized fluorescent protein reporters and cell-specific targeting and found that Rorc-expressing innate lymphoid cells (ILCs) produce IL-10 in response to anti-CD40-mediated intestinal inflammation. Deletion of Il10 specifically in Rorc-expressing ILCs led to phenotypic changes in intestinal macrophages and exacerbated both innate and adaptive immune-mediated models of experimental colitis. The population of IL-10+ producing ILCs shared markers with both ILC2 and ILC3 with nearly all ILC3s being of the NCR+ subtype. Interestingly, Ccl26 was enriched in IL-10+ ILCs and was markedly reduced in IL-10-deficient ILC3s. Since CCL26 is a ligand for CX3CR1, we employed RNA in situ hybridization and observed increased numbers of ILCs in close proximity to Cx3cr1-expressing cells under inflammatory conditions. Finally, we generated transgenic RorctdTomato reporter mice that faithfully marked RORγt+ cells that could rescue disease pathology and aberrant macrophage phenotype following adoptive transfer into mice with selective Il10 deficiency in ILC3s. These results demonstrate that IL-10 production by a population of ILCs functions to promote immune homeostasis in the intestine possibly via direct effects on intestinal macrophages.

Dysregulated differentiation of naïve CD4+ T cells into T helper 17 (Th17) cells is likely a key factor predisposing to many autoimmune diseases. Therefore, better understanding how Th17 differentiation is regulated is essential to identify novel therapeutic targets and strategies to identify individuals at high risk of developing autoimmunity. Here, we extend our prior work using chemical inhibitors to provide mechanistic insight into a novel regulator of Th17 differentiation, the kinase dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). We generated a conditional knockout mouse model to validate DYRK1A as a regulator of Th17 differentiation that acts in a dose-dependent fashion at least in part by modulating interleukin (IL)-6 signaling through multiple mechanisms. We identified a new role for DYRK1A in regulating surface expression of IL-6 receptor subunits in naïve CD4+ T cells, consistent with DYRK1A's impact on Th17 differentiation. Physiologic relevance is supported by findings in people with Down syndrome, in which increased expression of DYRK1A, encoded on chromosome 21, is linked to increased IL-6 responsiveness. Our findings highlight DYRK1A as a druggable target of broad therapeutic and prognostic interest in autoimmunity and immune function.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by enhanced platelet destruction and impaired platelet production, due to a loss of immune tolerance that leads to targeting of platelets and megakaryocytes by glycoprotein-autoantibodies and/or cytotoxic T cells. There is a high degree of heterogeneity in ITP patients signified by unpredictable disease trajectories and treatment responses. Initial studies in humans have identified intestinal microbiota perturbance in ITP. Recently, gut microbial perturbance has been linked to other autoimmune diseases. Based on these findings, we hypothesize that intestinal microbiota may influence ITP pathophysiology through several mechanisms, including induction of platelet-autoantibody production, increasing complement-dependent platelet cytotoxicity, disturbing T cell homeostasis, impairing megakaryocyte function, and increasing platelet-desialylation and -clearance. The pathophysiological heterogeneity of ITP may, at least in part, be attributed to a perturbed intestinal microbiota. Therefore, a better understanding of intestinal microbiota in ITP may result in a more personalized therapeutic approach.

Liver fibrosis is a well-established risk factor for liver cancer development. Despite extensive mechanistic studies on liver fibrosis, the role of the immune cell network in fibrotic disease remains poorly understood. In this study, we demonstrate that regulatory T cells (Tregs) are involved in preventing liver fibrosis by regulating the mevalonate pathway. Blocking the mevalonate pathway increased the granzyme B secretion from Tregs, while restoring the pathway reduced it. Statin treatment, which inhibits the mevalonate pathway, alleviated liver fibrosis progression and enhanced the immunosuppressive function of Tregs in vivo. Mechanistically, mevalonate products, including geranylgeranyl pyrophosphate, inhibited the phosphorylation and activation of LKB1, that is a key regulator of Treg homeostasis. Furthermore, these products disrupted the interaction between LKB1 and cAMP-dependent protein kinase (PKA), leading to further reduction of LKB1 phosphorylation. These findings suggest that targeting LKB1 in Tregs through statin treatment prevents the progression of liver fibrosis, offering a promising and safe therapeutic strategy for liver disease and liver cancer.

Transcription repressor BACH2 redirects short-lived terminally differentiated effector into long-lived memory cells. We postulate that BACH2-mediated long-lived memory programs promote HIV-1 persistence in gut CD4+ T cells. We coupled single-cell DOGMA-seq and TREK-seq to capture chromatin accessibility, transcriptome, surface proteins, T cell receptor, HIV-1 DNA and HIV-1 RNA in 100,744 gut T cells from ten aviremic HIV-1+ individuals and five HIV-1- donors. BACH2 was the leading transcription factor that shaped gut tissue resident memory T cells (TRMs) into long-lived memory with restrained interferon-induced effector function. We found that HIV-1-infected cells were enriched in TRMs (80.8%). HIV-1-infected cells had increased BACH2 transcription factor accessibility, TRM (CD49a, CD69, CD103) and survival (IL7R) gene expression, and Th17 polarization (RORC, CCR6). In vitro gut CD4+ T cell infection revealed preferential infection and persistence of HIV-1 in CCR6+ TRMs. Overall, we found BACH2-driven TRM program promotes HIV-1 persistence and BACH2 as a new therapeutic target.

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes associated with high mortality and disability rates. Inflammation has emerged as a key pathological mechanism in DKD, prompting interest in novel therapeutic approaches targeting inflammatory pathways. Interleukin-6 (IL-6), a well-established inflammatory cytokine known for mediating various inflammatory responses, has attracted great attention in the DKD field. Although multiple in vivo and in vitro studies highlight the potential of targeting IL-6 in DKD treatment, its exact roles in the disease remains unclear. This review presents the roles of IL-6 in the pathogenesis of DKD, including immunoinflammation, metabolism, hemodynamics, and ferroptosis. In addition, we summarize the current status of IL-6 inhibitors in DKD-related clinical trials and discuss the potential of targeting IL-6 for treating DKD in the clinic.

Despite significant advances in treatments, ovarian cancer (OC) remains one of the most prevalent and lethal gynecological cancers in women. The frequent detection at the advanced stages has contributed to low survival rates, resistance to various treatments, and disease recurrence. Thus, a more effective approach is warranted to combat OC. The cytokine Interleukin-6 (IL6) has been implicated in various stages of OC development. High IL6 levels are also correlated with a lower survival rate in OC patients. In this current review, we summarized the pivotal roles of IL6 in OC, including the initiation, development, invasion, metastasis, and drug resistance mechanisms. This article systematically highlights how targeting IL6 improves OC outcomes by altering various cancer processes and reports the ongoing clinical trials that would further shape the IL6-based targeted therapies. This review also suggests how combining IL6-targeted therapies with other therapeutic strategies could further enhance their efficacy to combat OC.

Pathobionts have evolved many strategies to coexist with the host, but how immune evasion mechanisms contribute to the difficulty of developing vaccines against pathobionts is unclear. Meanwhile, Staphylococcus aureus (SA) has resisted human vaccine development to date. Here we show that prior SA exposure induces non-protective CD4+ T cell imprints, leading to the blunting of protective IsdB vaccine responses. Mechanistically, these SA-experienced CD4+ T cells express IL-10, which is further amplified by vaccination and impedes vaccine protection by binding with IL-10Rα on CD4+ T cell and inhibit IL-17A production. IL-10 also mediates cross-suppression of IsdB and sdrE multi-antigen vaccine. By contrast, the inefficiency of SA IsdB, IsdA and MntC vaccines can be overcome by co-treatment with adjuvants that promote IL-17A and IFN-γ responses. We thus propose that IL-10 secreting, SA-experienced CD4+ T cell imprints represent a staphylococcal immune escaping mechanism that needs to be taken into consideration for future vaccine development.

Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease characterized by keratinized epithelial tunnels that grow deeply into the dermis. Here, we examined the immune microenvironment within human HS lesions. Multi-omics profiling and multiplexed imaging identified tertiary lymphoid structures (TLSs) near HS tunnels. These TLSs were enriched with proliferative T cells, including follicular helper (Tfh), regulatory (Treg), and pathogenic T cells (IL17A+ and IFNG+), alongside extensive clonal expansion of plasma cells producing antibodies reactive to keratinocytes. HS fibroblasts express CXCL13 or CCL19 in response to immune cytokines. Using a microfluidic system to mimic TLS on a chip, we found that HS fibroblasts critically orchestrated lymphocyte aggregation via tumor necrosis factor alpha (TNF-α)-CXCL13 and TNF-α-CCL19 feedback loops with B and T cells, respectively; early TNF-α blockade suppressed aggregate initiation. Our findings provide insights into TLS formation in the skin, suggest therapeutic avenues for HS, and reveal mechanisms that may apply to other autoimmune settings, including Crohn's disease.

Interleukin-10 (IL-10) exerts complex effects on tumor growth, exhibiting both pro- and anti-tumor properties. Recent focus on the anti-inflammatory properties of IL-10 has highlighted its potential anti-tumor properties, particularly through the enhancement of CD8+ T cell activity. However, further research is needed to fully elucidate its other anti-tumor mechanisms. Our study investigates novel anti-tumor mechanisms of IL-10 in a murine mammary carcinoma model (4T1). We found that IL-10 overexpression in mouse 4T1 cells suppressed tumor growth in vivo. This suppression was accompanied by an increase in IFN-γ-secreting CD8+ T cells and a decrease in myeloid-derived suppressor cells (MDSCs) in tumor tissue. In vitro experiments showed that IL-10-rich tumor cell-derived supernatants inhibited myeloid cell differentiation into monocytic and granulocytic MDSCs while reducing MDSCs migration. In addition, IL-10 overexpression downregulated CXCL5 expression in 4T1 cells, resulting in decreased CXCR2+ MDSCs infiltration. Using RAG1-deficient mice and CXCL5 knockdown tumor models, we demonstrated that the anti-tumor effects of IL-10 depend on both CD8+ T cells and reduced MDSC infiltration. IL-10 attenuated the immunosuppressive tumor microenvironment by enhancing CD8+ T cell activity and inhibiting MDSCs infiltration. In human breast cancer, we observed a positive correlation between CXCL5 expression and MDSC infiltration. Our findings reveal a dual mechanism of IL-10-mediated tumor suppression: (1) direct enhancement of CD8+ T cell activity and (2) indirect reduction of immunosuppressive MDSCs through CXCL5 downregulation and inhibition of myeloid cell differentiation. This study provides new insights into the role of IL-10 in anti-tumor immunity and suggests potential strategies for breast cancer immunotherapy by modulating the IL-10-CXCL5-MDSCs axis.

Intricate immune regulation is required at mucosal surfaces to allow tolerance to microbiota and harmless allergens and to prevent overexuberant inflammatory responses to pathogens. The cytokine Interleukin-10 (IL-10) is a key mediator of mucosal immune regulation. While IL-10 can be produced by virtually all cells of the immune system, many of its in vivo functions depend upon its production by regulatory or effector T cell populations and its signalling to macrophages, dendritic cells and specific T cell subsets. In this review, we discuss our current understanding of the role of IL-10 in regulation of immune responses, with a focus on its context-specific roles in intestinal homeostasis, respiratory infection and asthma. We highlight the importance of appropriate production and function of IL-10 for balancing pathogen clearance, control of microbiota and host tissue damage, and that precise modulation of IL-10 functions in vivo could present therapeutic opportunities.

There is insufficient evidence to determine the effectiveness of treating allergic rhinitis with a patch laser affix to the skin as opposed to direct intranasal irradiation of the nasal mucosa. We aimed to evaluate the effect of the microneedle patch laser with multiple wavelengths in an allergic rhinitis (AR) mouse model and its underlying mechanism.

The microneedle patch laser was attached to the skin above the mouse's nasal cavity, transmitting light to the nasal mucosa. For 10 days, the microneedle patch laser administered simultaneous exposure to wavelengths of 670, 780, 850, and 910 nm at either 10 or 20 min each day. Multiple allergic parameters were evaluated following the microneedle patch laser treatment.

Microneedle patch laser treatment decreased allergic symptoms and inhibited OVA-specific IgE levels. Additionally, it significantly reduced eosinophil infiltration, epithelial thickness of the nasal mucosa, and IL-4 cytokine levels.

The light emitted by the microneedle patch laser attached to the skin, penetrated effectively to the nasal mucosa within the nasal cavity, suggesting potential for treating allergic rhinitis in mice and could be extended in clinical applications.

Glioblastoma multiforme (GBM), also known as grade IV astrocytoma, is the most common and deadly brain tumour. It has a poor prognosis and a low survival rate. GBM cells' immunological escape mechanism helps them resist advanced multimodal therapy. In physiological homeostasis, brain astrocytes and microglia suppress infections and clear the potential pathogen from the system. However, in severe pathological conditions like cancer, the immune response fails to eliminate mutated and rapidly over-proliferating GBM cells. The malignant cells' interactions with immune cells and the neoplasm's immunosuppressive environment enable the avoidance and their clearance. Immunotherapy efficiently addresses these difficulties, as shown by sufficient evidence. This review discusses how GBM cells inhibit and elude the immune system. These include MHC molecule expression alteration and PD-L1 and CTLA-4 immune checkpoint overexpression. Without co-stimulation, these changes induce effector T-cell tolerance and anergy. The review also covers how MDSCs, TAMs, Herpes Virus Entry Mediators, and Human cytomegalovirus protein decrease the effector immune response against glioblastoma. The latter part discusses various therapies that are available in the market or under clinical trials which revolves around combating resistance against the available multimodal therapies. The recent trends indicate that there are various monoclonal antibodies and peptide-based vaccines that can be utilized to overcome the immune evasion technique harbored by GBM cells. A strategic development of Immunotherapy considering these hallmarks of immune evasion may help in designing a therapy that may prove to be effective in killing the GBM cells thereby, improving the overall survival of GBM-affected patients.

Gender contributes to differences in incidence and progression of chronic kidney disease (CKD) post-cisplatin therapy. This study aims at investigating the potential effect of G1 compound, a GPER agonist, on attenuating cisplatin-induced CKD. To induce CKD in male, intact female, and ovariectomized (OVX) mice, CKD was induced by injecting two cycles of 2.5 mg/kg cisplatin with a 16-day recovery period between cycles). G1 (50 or 100 μg/kg was administered daily for 6 weeks. Severity of renal damage was more pronounced in males than females. Interestingly, OVX resulted in renal damage that is non-significant compared to males and significantly higher than females. G1 improved renal function and blood flow as evidenced by reduction of serum creatinine and elevation of creatinine clearance, NO production, and reduction of ET1. This renoprotective effect could be attributed to its immunomodulatory effect regulated by TGF-β that shifted the balance to favor anti-inflammatory cytokine production (increased IL-10) rather than pro-inflammatory cytokines (decreased Th17 expression). Reduction of TGF-β activation also inhibited epithelial-to-mesenchymal transition that eventually ameliorated CKD development. Antioxidant potential of G1 has been demonstrated by upregulation of Nrf2 and subsequent antioxidant enzymes. These data suggest that G1 could be a promising therapeutic tool to attenuate CP-induced CKD.

Inflammation in the eye is tightly regulated to prevent vision impairment and irreversible blindness. Emerging evidence shows that immune cells are specifically recruited to the lens capsule in response to autoimmune uveitis, yet the potential that they have a role in regulating this inflammatory disease remained unexplored. Here, an immunolocalization approach combined with high-resolution confocal microscopy was used to investigate whether the immune cells that become stably associated with the lens capsule in the eyes of C57BL/6J mice with experimental autoimmune uveitis (EAU) have an immunoregulatory phenotype. These studies revealed that during the acute phase of uveitis, at day 18 after disease induction, the immune cells specifically recruited to the lens capsule, such as regulatory T cells [forkhead box P3 (FoxP3)+CD4+] and M2 macrophages (CD68+ arginase 1+IL-10+), included those with putative anti-inflammatory, proresolution roles. The frequency of these lens capsule-associated immunomodulatory phenotypes increased at day 35 after induction, during the resolution phase of EAU inflammation. At this later stage of resolution, most of the macrophages expressed CD206, a mannose receptor responsible for removing inflammatory molecules, in addition to arginase 1 and IL-10. These results suggest a previously unknown role for the lens as a site for recruitment of immune cells whose role is to suppress inflammation, promote resolution, and maintain remission of EAU.

T helper (Th) 17 cells, a distinct subset of Th lymphocytes, are known for their prominent interleukin (IL)-17 production and other pro-inflammatory cytokines. These cells exhibit remarkable plasticity, allowing them to exhibit different phenotypes in the cancer microenvironment. This adaptability enables Th17 cells to promote tumor progression by immunosuppressive activities and angiogenesis, but also mediate anti-tumor immune responses through employing immune cells in tumor setting or even by directly converting toward Th1 phenotype and producing interferon-gamma (IFN-γ). This dual role of Th17 cells in cancer makes it a double-edged sword in encountering cancer. In this review, we aim to elucidate the complexities of Th17 cell function in cancer by summarizing recent studies and, ultimately, to design novel therapeutic strategies, especially targeting Th17 cells in the tumor milieu, which could pave the way for more effective cancer treatments.

Lactic acid bacteria (LAB) probiotics are health-promoting but their characteristics, safety profile and functional mechanisms are not fully understood. Hence, this study aimed to characterize some hypothetical proteins of the chicken-isolated Limosilactobacillus reuteri genome and unravel their IL-2 and IL-10-inducing potential to understand mechanisms of their immunological functionality for sustainable applications. The selected proteins were subjected to in silico analyses for transmembrane topology, sub-cellular localization, IL-2 and IL-10-inducing ability and IL-2 and IL-10 gene expression across various conditions. IL-2 and IL-10-inducing mutants were statistically analyzed using a one-way analysis of variance of a general linear model of SAS and statistical significance was set at p < 0.05. The analyzed proteins are stable under a wide temperature range. All the hypothetical proteins are IL-2 and IL-10-inducing but QHPv.2.12, QHPv.2.13 and QHPv.2.15 are non-immunogenic. The evaluated mutants are IL-2 and IL-10-inducers but QHPv.2.13 and QHPv.2.15 are not immunogenic. This study sheds light on understanding the functional mechanisms of chicken-isolated L. reuteri and suggests it or its proteins as potent candidates for feed additive and therapeutic purposes.

Expansion of CD4+CD28null T-lymphocytes is common in chronic heart failure (CHF) patients. Its ability to produce high levels of proinflammatory cytokines is probably the key role of these cells in CHF. IL-10 is a candidate for limiting CD4+CD28null T-lymphocyte responses, whereas tumour necrosis factor (TNF) is the cytokine most closely involved in the loss of CD28 expression. Serum levels of TNF and IL-10 were measured in 65 CHF patients (mean age, 65.2 ± 13.84 years). Patients with an IL-10/TNF ratio ≥1 had significantly lower levels of CD4+CD28null T-lymphocytes than those with a ratio <1. In vitro, IL-10 reduced the frequency of proliferative CD4+CD28null T-lymphocytes stimulated with anti-CD3. Pre-treatment with IL-10 before anti-CD3 stimulation was required for the cytokine to inhibit TNF production by CD4+CD28null T-lymphocytes. In addition to the previously described effect of IL-10 on HLA-DR and ICAM-1 expression, LFA-3 protein and mRNA levels were reduced in the presence of the cytokine in monocytes. IL-10 inhibition on CD4+CD28null T-lymphocytes may be mediated by a reduction in HLA class II and LFA-3 expression because blocking interactions with these costimulators has similar effects to those of IL-10 treatment. Moreover, costimulation through CD2/LFA-3 interaction is enough to induce proliferation and cytokine production in CD4+CD28null T-lymphocytes.

CXCR4 cell surface expression is critical for the homing of T regulatory (Treg) cells to the bone marrow (BM). We hypothesize that CXCR4 enrichment on Tregs cell surface may abbreviate their transit time to reach BM. Umbilical cord-blood CD25+ Tregs underwent CXCR4 dual enrichment and ex vivo expansion using the CRANE process to generate CXCR4-enriched Tregs (TregCXCR4) cells, which showed a faster migration across the Transwell membrane toward CXCL12/stromal cell-derived factor 1α (SDF1α) at 15, 30, and 60 min, when compared to unmanipulated Tregcontrol cells (p < 0.0001). TregCXCR4 exhibited preferential homing to BM in vivo at 12 and 24 h. Metacluster analysis of BM showed a decrease in CD8+ and an increase in CD39 and CD73 and CXCR5 when compared to Tregcontrol. TregCXCR4 decreased plasma TGF-β1/β2 and IFN-γ levels. When compared to control, TregCXCR4 cells decreased in CD8+ T cell, IFN-γ, and TNF-α expression in BM. We conclude that TregCXCR4 show enhanced migration toward CXCL12/SDF1α and a preferential homing to BM resulting in resolution of inflammation.

Lung transplant remains the primary therapeutic option for patients with end-stage lung disease, but long-term survival rates remain suboptimal compared with other solid organ transplants. Acute cellular rejection (ACR) is a significant challenge in lung transplant recipients, with T cell-mediated mechanisms playing a major role. IL-10 is known for its immunoregulatory function, although its specific role in lung allograft rejection remains unclear. Using the mouse orthotopic lung transplant model, we investigated the role of IL-10 in regulating alloeffector T cell responses. Unexpectedly, we found that IL-10 was not required for early costimulation blockade-induced allograft acceptance. However, IL-10 deficiency or blockade resulted in increased CD4+ T cell numbers, proliferation, graft infiltration, and alloeffector responses. In the absence of IL-10, CD4+ T cell responses predominated over CD8 responses during ACR in contrast to wild-type mice. Type 1 immunity (IFN-γ) responses along with elevated CD4+NKG7+ and CD4+CD107a+ responses predominated during ACR, highlighting a critical regulatory role for IL-10 in modulating CD4+ T cell alloimmune responses. We further demonstrated increased colocalization of NKG7 and CD107a in CD4+ T cells from IL-10-deficient allografts, suggesting coordination in cytotoxic activity. Together, our findings highlight a critical role for IL-10 in regulation of cytotoxic CD4+NKG7+ T cells, an effector population that needs further investigation to elucidate their role in lung allograft rejection.

The collapse of immune homeostasis induces type 1 diabetes (T1D). In T1D, uncontrolled immune attacks against islet β cells reduce insulin secretion, resulting in hyperglycaemia and various complications. Type 1 regulatory (Tr1) cell therapy is a promising approach for the treatment of T1D. Tr1 cells are a subset of regulatory T (Treg) cells that are characterised by high interleukin-10 secretion and forkhead box protein P3 non-expression. Tr1 cells are reduced and have impaired function in patients with T1D. Immunotherapy is used to treat various diseases, and Treg cells have been applied to treat T1D in animal models and clinical trials. However, the safety and efficacy of Tr1 cells in treating diabetes and other diseases remain unclear. In this review, we aim to investigate the identification and biological function of Tr1 cells and related studies on immune diseases; additionally, we discuss the feasibility, limitations, and possible solutions of Tr1 cell therapy in T1D. This review shows that T1D is caused by an immune imbalance where defective Tr1 cells fail to control effector T cells, leading to the destruction of islet β cells. However, Tr1 cell therapy is safe and effective for other immune diseases, suggesting its potential for treating T1D.