Th1 Polarization Research Articles

Dendritic cell mineralocorticoid receptor controls blood pressure by regulating T helper 17 differentiation: role of the Plcβ1/4-Stat5-NF-κB pathway.

Dendritic cells (DCs) are closely related to blood pressure (BP) regulation. Mineralocorticoid receptor (MR) is an important drug target for antihypertensive treatment. However, the role of DC MR in the pathogenesis of hypertension has not been fully elucidated. This study aimed to determine the role of DC MR in BP regulation and to explore the mechanism. Renal biopsy and peripheral blood samples were collected from hypertensive patients (HTN) for immunostaining and flow cytometry. Dendritic cell MR knockout (DCMRKO) mice, DC MR overexpressing (DCMROV) mice, DCMROV/IL-17A knockout (DCMROV/IL-17AKO) mice and finerenone-treated C57BL/6 mice were infused with angiotensin II (Ang II) to establish hypertensive models. Western blotting, chromatin immunoprecipitation, co-immunoprecipitation, and in vivo DC depletion or adoptive transfer were used to delineate the functional importance of DC MR in hypertension development. Mineralocorticoid receptor antagonists (spironolactone and finerenone) suppressed DC aggregation and activation, as well as hypertension in HTN and mice. Compared with littermate control (LC) mice, dendritic cell MR knockout mice had strikingly decreased BPs and attenuated target organ damage after Ang II infusion. Flow cytometry showed that DC MR deficiency mitigated Ang II-induced DC activation and T helper 17 (Th17) cell differentiation. RNA sequencing revealed that MR-deficient DCs had elevated expression of Plcβ1 and Plcβ4, knockdown of which reversed the inhibitory effect of MR deficiency on DC activation and Th17 differentiation. Adoptive transfer of MR-deficient DCs protected Ang II-induced hypertension, whereas knockdown of Plcβ1/4 eliminated the protective effects. At the molecular level, MR negatively regulated Plcβ1/4, which recruited SHP-1 to inactivate of Stat5 activity, resulting in enhanced NF-κB activation and Th17 polarization. Furthermore, DCMROV mice manifested more elevated BPs and target organ damage than control mice after Ang II infusion, and these differences were abolished in DCMROV/IL-17AKO mice. Finally, MR antagonists decreased the aggregation of Th17 in HTN and mice. Dendritic cell MR plays important roles in the pathogenesis of hypertension by regulating Th17 through Plcβ1/4-Stat5-NF-κB signalling, and blockade of DC MR is beneficial for treating hypertension.

Piezo1 restrains proinflammatory response but is essential in T cell-mediated immunopathology.

Piezo1 is a mechanosensitive, nonselective Ca2+ channel which is broadly expressed in CD4+ T cells. Using lineage-specific Piezo1 knockout mice (Piezo1cKO), we show that loss of Piezo1 in CD4+ T cells significantly increased IFNγ and IL-17 production in vitro under TH1 and TH17 polarizing conditions, respectively. Despite their intrinsic proinflammatory phenotype, Piezo1cKO T cells are incapable of establishing disease in vivo in three separate adoptive transfer (AT) T cell-mediated inflammatory mouse models, including experimental autoimmune encephalomyelitis, inflammatory bowel disease (IBD), and graft versus-host disease. These phenomena coincided with a decreased effector memory (CD44hiCD62Llo) CD4+ T cell pool derived from donor Piezo1cKO T cells, an observation that is related to intrinsic T-cell fitness, as co-transfer IBD mouse model revealed a deficiency in the CD4+ effector memory population derived only from the naïve Piezo1cKO but not co-infused Piezo1WT CD4+ T cell source. Taken together, our results support Piezo1 as restraining proinflammatory T cell differentiation while contributing to the generation and persistence of the effector memory pool during CD4+ T cell-mediated immunopathology.

Acquired immunostimulatory phenotype of migratory CD103+ DCs promotes alloimmunity following corneal transplantation.

After transplantation, Th1-mediated immune rejection is the predominant cause of graft failure. Th1 cell sensitization occurs through complex and context-dependent interaction among antigen-presenting cell subsets, particularly CD11b+ DCs (DC2) and CD103+ DCs (DC1). This interaction necessitates further investigation in the context of transplant immunity. We used well-established preclinical models of corneal transplantation and identified distinct roles of migratory CD103+ DC1 in influencing the outcomes of the grafted tissue. In recipients with uninflamed corneal beds, migratory CD103+ DC1 demonstrate a tolerogenic phenotype that modulates the immunogenic capacity of CD11b+ DC2 primarily mediated by IL-10, suppressing alloreactive CD4+ Th1 cells via the PD-L1/PD-1 pathway and enhancing Treg-mediated tolerance via αvβ8 integrin-activated TGF-β1, thus facilitating graft survival. Conversely, in recipients with inflamed and vascularized corneal beds, IFN-γ produced by CD4+ Th1 cells induced migratory CD103+ DC1 to adopt an immunostimulatory phenotype, characterized by the downregulation of regulatory markers, including αvβ8 integrin and IL-10, and the upregulation of IL-12 and costimulatory molecules CD80/86, resulting in graft failure. The adoptive transfer of ex vivo induced tolerogenic CD103+ DC1 (iDC1) effectively inhibited Th1 polarization and preserved the tolerogenic phenotype of their physiological counterparts. Collectively, our findings underscore the essential role played by CD103+ DC1 in modulating host alloimmune responses.

Th1 polarization in Bordetella pertussis vaccine responses is maintained through a positive feedback loop.

Outbreaks of Bordetella pertussis (BP), the causative agent of whooping cough, continue despite broad vaccination coverage and have been increasing since vaccination switched from whole-BP (wP) to acellular BP (aP) vaccines. wP vaccination has been associated with more durable protective immunity and an induced Th1 polarized memory T cell response. Here, a multi-omics approach was applied to profile the immune response of 30 wP and 31 aP-primed individuals and identify correlates of T cell polarization before and after Tdap booster vaccination. We found that transcriptional changes indicating an interferon response on day 1 post-booster along with elevated plasma concentrations of IFN-γ and interferon-induced chemokines that peaked at day 1-3 post-booster correlated best with the Th1 polarization of the vaccine-induced memory T cell response on day 28. Our studies suggest that wP-primed individuals maintain their Th1 polarization through this early memory interferon response. This suggests that stimulating the interferon pathway during vaccination could be an effective strategy to elicit a predominant Th1 response in aP-primed individuals that protects better against infection.

Transient High Salt Intake Promotes T-Cell-Mediated Hypertensive Vascular Injury.

Dietary high salt (HS) intake has a strong impact on cardiovascular diseases. Here, we investigated the link between HS-aggravated immune responses and the development of hypertensive vascular disease. ApolipoproteinE-deficient mice were transiently treated with HS (1% NaCl) via drinking water for 2 weeks, followed by a washout period, and subsequent Ang II (angiotensin II) infusion (1000 ng/kg per min for 10 days) to induce abdominal aortic aneurysms/dissections and inflammation. While transient HS intake alone triggered nonpathologic infiltration of activated T cells into the aorta, subsequent Ang II infusion increased mortality and the incidence of abdominal aortic aneurysms/dissections and atherosclerosis compared with hypertensive control mice. There were no differences in blood pressure between both groups. In transient HS-treated hypertensive mice, the aortic injury was associated with increased inflammation, accumulation of neutrophils, monocytes, CD69+CD4+ T cells, as well as CD4+ and CD8+ memory T cells. Mechanistically, transient HS intake increased expression levels of aortic RORγt as well as splenic CD4+TH17 and CD8+TC1 T cells in Ang II-treated mice. Isolated aortas of untreated mice were incubated with supernatants of TH17, TH1, or TC1 cells polarized in vitro under HS or normal conditions which revealed that secreted factors of HS-differentiated TH17 and TC1 cells, but not TH1 cells accelerated endothelial dysfunction. Our data suggest that transient HS intake induces a subclinical T-cell-mediated aortic immune response, which is enhanced by Ang II. We propose a 2-hit model, in which HS acts as a predisposing factor to enhance hypertension-induced TH17 and TC1 polarization and aortic disease.

Tumor draining lymph nodes connected to cold triple-negative breast cancers are characterized by Th2-associated microenvironment

Tumor draining lymph nodes (TDLN) represent a key component of the tumor-immunity cycle. There are few studies describing how TDLNs impact lymphocyte infiltration into tumors. Here we directly compare tumor-free TDLNs draining “cold” and “hot” human triple negative breast cancers (TDLNCold and TDLNHot). Using machine-learning-based self-correlation analysis of immune gene expression, we find unbalanced intranodal regulations within TDLNCold. Two gene pairs (TBX21/GATA3-CXCR1) with opposite correlations suggest preferential priming of T helper 2 (Th2) cells by mature dendritic cells (DC) within TDLNCold. This is validated by multiplex immunofluorescent staining, identifying more mature-DC-Th2 spatial clusters within TDLNCold versus TDLNHot. Associated with this Th2 priming preference, more IL4 producing mast cells (MC) are found within sinus regions of TDLNCold. Downstream, Th2-associated fibrotic TME is found in paired cold tumors with increased Th2/T-helper-1-cell (Th1) ratio, upregulated fibrosis growth factors, and stromal enrichment of cancer associated fibroblasts. These findings are further confirmed in a validation cohort and public genomic data. Our results reveal a potential role of IL4+ MCs within TDLNs, associated with Th2 polarization and reduced immune infiltration into tumors.

FACS aids in the differentiation of Th17 polarization in a patient with atopic dermatitis.

FACS aids in the differentiation of Th17 polarization in a patient with atopic dermatitis.

The Contribution of the Skin Microbiome to Psoriasis Pathogenesis and Its Implications for Therapeutic Strategies.

Psoriasis is a common chronic inflammatory skin disease, associated with significant morbidity and a considerable negative impact on the patients' quality of life. The complex pathogenesis of psoriasis is still incompletely understood. Genetic predisposition, environmental factors like smoking, alcohol consumption, psychological stress, consumption of certain drugs, and mechanical trauma, as well as specific immune dysfunctions, contribute to the onset of the disease. Mounting evidence indicate that skin dysbiosis plays a significant role in the development and exacerbation of psoriasis through loss of immune tolerance to commensal skin flora, an altered balance between Tregs and effector cells, and an excessive Th1 and Th17 polarization. While the implications of skin dysbiosis in psoriasis pathogenesis are only starting to be revealed, the progress in the characterization of the skin microbiome changes in psoriasis patients has opened a whole new avenue of research focusing on the modulation of the skin microbiome as an adjuvant treatment for psoriasis and as part of a long-term plan to prevent disease flares. The skin microbiome may also represent a valuable predictive marker of treatment response and may aid in the selection of the optimal personalized treatment. We present the current knowledge on the skin microbiome changes in psoriasis and the results of the studies that investigated the efficacy of the different skin microbiome modulation strategies in the management of psoriasis, and discuss the complex interaction between the host and skin commensal flora.

JNK Pathway-Associated Phosphatase Deficiency Facilitates Atherosclerotic Progression by Inducing T-Helper 1 and 17 Polarization and Inflammation in an ERK- and NF-κB Pathway-Dependent Manner.

JNK pathway-associated phosphatase (JKAP) regulates T cell-mediated immunity and inflammation, which are involved in atherosclerosis pathogenesis. This study investigated the effects of JKAP on T-helper (Th) cell polarization, inflammation, and atherosclerotic progression. Serum JKAP levels were measured in 30 patients with coronary heart disease (CHD) and 30 controls. CHD blood naïve CD4＋ T cells were acquired, followed by JKAP overexpression and knockdown with or without treatment with PD98059 (ERK inhibitor) or BAY-11-7082 (NF-κB inhibitor) in vitro. CD4＋ T-cell conditional JKAP ablation mice were established in vivo, followed by the construction of an atherosclerosis model. JKAP was reduced and negatively correlated with the Gensini score, CRP, Th1 cells, Th17 cells, and proinflammatory cytokines in patients with CHD. In vitro, JKAP overexpression suppressed Th1 and Th17 cell differentiation and proinflammatory cytokines, whereas JKAP knockdown exerted the opposite effect; however, JKAP modification did not affect Th2 cell differentiation. Interestingly, JKAP negatively regulated the ERK and NF-κB pathways; meanwhile, the PD98059 and BAY-11-7082 treatments repressed Th1 and Th17 cell differentiation, and attenuated the effect of JKAP knockdown on these indices. In vivo, conditional CD4＋ T-cell JKAP ablation increased Th1 and Th17 cell polarization in the spleen, lymph node, blood, and/or aortic root. Furthermore, CD4＋ T-cell conditional JKAP ablation exaggerated atherosclerotic lesions in the aorta, elevated CD4+ cell infiltration and proinflammatory cytokines in the aortic root, and activated the ERK and NF-κB pathways in the aortic root. JKAP ablation facilitates atherosclerosis progression by promoting Th1 and 17 polarization and inflammation through regulation of the ERK and NF-κB pathways.

In vivo edited eosinophils reconcile antigen specific Th2 response and mitigate airway allergy

BackgroundImprovement is needed in the remedies used to control Th2 polarization. Bioengineering approaches have modified immune cells that have immunosuppressive functions. This study aims to generate modified eosinophils (Meos) in vivo and use Meos to balance Th2 polarization and reduce airway allergy.MethodsA cell editor was constructed. The editor contained a peptide carrier, an anti-siglec F antibody, MHC II, ovalbumin, and LgDNA (DNA extracted from a probiotic, Lactobacillus rhamnosus GG). Which was designated as Cedit. Meos are eosinophils modified using Cedits. An airway Th2 polarization mouse model was established used to test the effect of Meos on suppressing airway allergy.ResultsThe Cedits remained physically and chemically stable in solution (pH7.2) for at least 96 h. Cedits specifically bound to eosinophils, which are designated as Meos. Meos produced programmed death ligand-1 (PD-L1); the latter induced antigen specific CD4+ T cell apoptosis. Administration of Cedits through nasal instillations generated Meos in vivo, which significantly reduced the frequency of antigen specific CD4+ T cells in the airways, and mitigated airway Th2 polarization.ConclusionsWe constructed Cedit, which could edit eosinophils into Meos in vivo. Meos could induce antigen specific CD4+ T cell apoptosis, and reconcile airway Th2 polarization.

A nonadjuvanted HLA-restricted peptide vaccine induced both T and B cell immunity against SARS-CoV-2 spike protein

During COVID-19 pandemic, cases of postvaccination infections and restored SARS-CoV-2 virus have increased after full vaccination, which might be contributed to by immune surveillance escape or virus rebound. Here, artificial linear 9-mer human leucocyte antigen (HLA)-restricted UC peptides were designed based on the well-conserved S2 region of the SARS-CoV-2 spike protein regardless of rapid mutation and glycosylation hindrance. The UC peptides were characterized for its effect on immune molecules and cells by HLA-tetramer refolding assay for HLA-binding ability, by HLA-tetramer specific T cell assay for engaged cytotoxic T lymphocytes (CTLs) involvement, by HLA-dextramer T cell assay for B cell activation, by intracellular cytokine release assay for polarization of immune response, Th1 or Th2. The specific lysis activity assay of T cells was performed for direct activation of cytotoxic T lymphocytes by UC peptides. Mice were immunized for immunogenicity of UC peptides in vivo and immunized sera was assay for complement cytotoxicity assay. Results appeared that through the engagement of UC peptides and immune molecules, HLA-I and II, that CTLs elicited cytotoxic activity by recognizing SARS-CoV-2 spike-bearing cells and preferably secreting Th1 cytokines. The UC peptides also showed immunogenicity and generated a specific antibody in mice by both intramuscular injection and oral delivery without adjuvant formulation. In conclusion, a T-cell vaccine could provide long-lasting protection against SARS-CoV-2 either during reinfection or during SARS-CoV-2 rebound. Due to its ability to eradicate SARS-CoV-2 virus-infected cells, a COVID-19 T-cell vaccine might provide a solution to lower COVID-19 severity and long COVID-19.

Design of a potent and selective dual JAK1/TYK2 inhibitor

Janus kinase (JAK) inhibitors have gathered interest as treatments for several inflammatory and autoimmune diseases. The four first marketed inhibitors target JAK1, with varying selectivity towards other JAK family members, but none inhibit tyrosine kinase-2 (TYK2) at clinically relevant doses. TYK2 is required for the signaling of the interleukin (IL)-12 and IL-23 cytokines, which are key to the polarization of TH1 and TH17 cells, respectively; two cell subtypes that play major roles in inflammatory diseases. Herein, we report our effort towards the optimization of a potent and selective dual JAK1/TYK2 inhibitor series starting from a HTS hit. Structural information revealed vectors required to improve both JAK1 and TYK2 potency as well as selectivity towards JAK2. The potent inhibition of both JAK1 (3.5 nM) and TYK2 (5.7 nM) in biochemical assays by our optimized lead compound, as well as its notable selectivity against JAK2, were confirmed in cellular and whole blood assays. Inhibition of TYK2 by the lead compound was demonstrated by dose-dependent efficacy in an IL-23 induced psoriasis-like inflammation mouse model.

Spatial transcriptomics reveals organized and distinct immune activation in cutaneous granulomatous disorders

BackgroundNon-infectious (inflammatory) cutaneous granulomatous disorders include cutaneous sarcoidosis (CS), granuloma annulare (GA), necrobiosis lipoidica (NL), and necrobiotic xanthogranuloma (NXG). These disorders share macrophage predominant inflammation histologically, but the inflammatory architecture and the pattern of extracellular matrix alteration varies. The underlying molecular explanations for these differences remain unclear. ObjectiveTo understand spatial gene expression characteristics in these disorders. MethodsWe performed spatial transcriptomics in cases of CS, GA, NL, and NXG to compare patterns of immune activation and other molecular features in a spatially resolved fashion. ResultsCS is characterized by a polarized, spatially organized T helper (Th) 1 predominant response with classical macrophage activation. GA is characterized by a mixed, but spatially organized pattern of Th1 and Th2 polarization with both classical and alternative macrophage activation. NL showed concomitant activation of Th1, Th2, and Th17 immunity with a mixed pattern of macrophage activation. Activation of type 1 immunity was shared among, CS, GA, and NL and included upregulation of IL-32. NXG showed upregulation of CXCR4-CXCL12/14 chemokine signaling and exaggerated alternative macrophage polarization. Histologic alteration of extracellular matrix correlated with hypoxia and glycolysis programs and type 2 immune activation. ConclusionsInflammatory cutaneous granulomatous disorders show distinct and spatially organized immune activation that correlate with hallmark histologic changes.

NKT cells promote Th1 immune bias to dengue virus that governs long-term protective antibody dynamics.

NKT cells are innate-like T cells, recruited to the skin during viral infection, yet their contributions to long-term immune memory to viruses are unclear. We identified granzyme K, a product made by cytotoxic cells including NKT cells, as linked to induction of Th1-associated antibodies during primary dengue virus (DENV) infection in humans. We examined the role of NKT cells in vivo using DENV-infected mice lacking CD1d-dependent (CD1ddep) NKT cells. In CD1d-KO mice, Th1-polarized immunity and infection resolution were impaired, which was dependent on intrinsic NKT cell production of IFN-γ, since it was restored by adoptive transfer of WT but not IFN-γ-KO NKT cells. Furthermore, NKT cell deficiency triggered immune bias, resulting in higher levels of Th2-associated IgG1 than Th1-associated IgG2a, which failed to protect against a homologous DENV rechallenge and promoted antibody-dependent enhanced disease during secondary heterologous infections. Similarly, Th2 immunity, typified by a higher IgG4/IgG3 ratio, was associated with worsened human disease severity during secondary infections. Thus, CD1ddep NKT cells establish Th1 polarity during the early innate response to DENV, which promotes infection resolution, memory formation, and long-term protection from secondary homologous and heterologous infections in mice, with consistent associations observed in humans. These observations illustrate how early innate immune responses during primary infections can influence secondary infection outcomes.

Hedgehog signaling pathway regulates Th17 cell differentiation in asthma via IL-6/STAT3 signaling

Asthma is the most prevalent chronic inflammatory disease of the airways in children. The most prevalent phenotype of asthma is eosinophilic asthma, which is driven by a Th2 immune response and can be effectively managed by inhaled corticosteroid therapy. However, there are phenotypes of asthma with Th17 immune response that are insensitive to corticosteroid therapy and manifest a more severe phenotype. The treatment of this corticosteroid-insensitive asthma is currently immature and requires further attention. The objective of this study is to elucidate the regulation of the Hedgehog signaling pathway in Th17 cell differentiation in asthma. The study demonstrated that both Smo and Gli3, key components of the Hedgehog signaling pathway, were upregulated in Th17 polarization in vitro and in a Th17-dominant asthma model in vivo. Inhibiting Smo with a small molecule inhibitor or genetically knocking down Gli3 was found to suppress Th17 polarization. Smo was found to increase in Th1, Th2, Th17 and Treg polarization, while Gli3 specifically increased in Th17 polarization. ChIP-qPCR analyses indicated that Gli3 can directly interact with IL-6 in T cells, inducing STAT3 phosphorylation and promoting Th17 cell differentiation. Furthermore, the study demonstrated a correlation between elevated Gli3 expression and IL-17A and IL-6 expression in children with asthma. In conclusion, the study demonstrated that the Hedgehog signaling pathway plays an important role in the pathogenesis of asthma, as it regulates the differentiation of Th17 cells through the IL-6/STAT3 signaling. This may provide a potential therapeutic target for corticosteroid-insensitive asthma driven by Th17 cells.

IL-4 acts on skin-derived dendritic cells to promote the TH2 response to cutaneous sensitization and the development of allergic skin inflammation

Atopic dermatitis is characterized by scratching and a TH2-dominated local and systemic response to cutaneously encountered antigens. Dendritic cells (DCs) capture antigens in the skin and rapidly migrate to draining lymph nodes (dLNs) where they drive the differentiation of antigen-specific naive T cells. We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the TH2 response to cutaneously encountered antigen and allergic skin inflammation. DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD4+ T cells. Skin inflammation following epicutaneous sensitization of tape-stripped skin was assessed by flow cytometry of skin cells and real-time quantitative PCR of cytokines. Cytokine secretion and antibody levels were evaluated by ELISA. Scratching upregulated IL4 expression in human skin. Similarly, tape stripping caused rapid basophil-dependent upregulation of cutaneous Il4 expression in mouse skin. Invitro treatment of DCs from skin dLNs with IL-4 promoted their capacity to drive TH2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4-/- mice and CD11c-CreIl4rflox/- mice, which lack IL-4Rα expression in DCs (DCΔ/Δll4ra mice), were impaired in their capacity to drive TH2 polarization compared with DCs from controls. Importantly, OVA-sensitized DCΔ/Δll4ra mice demonstrated impaired allergic skin inflammation and OVA-specific systemic TH2 response evidenced by reduced TH2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls. Mechanical skin injury causes basophil-dependent upregulation of cutaneous IL-4. IL-4 acts on skin DCs that capture antigen and migrate to dLNs to promote their capacity for TH2 polarization and drive allergic skin inflammation.

A further examination of growth factors, T helper 1 polarization, and the gut microbiome in major depression: Associations with reoccurrence of illness, cognitive functions, suicidal behaviors, and quality of life

Growth factors, T helper (Th)1 polarization, and the microbiome are involved in the pathophysiology of major depression (MDD). It remains unclear whether the combination of these three pathways could enhance the accuracy of predicting the features of MDD, including recurrence of illness (ROI), suicidal behaviors and the phenome. We measured serum stem cell factor (SCF), stem cell growth factor (SCGF), stromal cell-derived factor-1 (SDF-1), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), macrophage-colony stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF), the ratio of serum Th1/Th2 cytokines (zTh1-zTh2), and the abundances of gut microbiome taxa by analyzing stool samples using 16S rDNA sequencing from 32 MDD patients and 37 healthy controls. The results show that serum SCF is significantly lower and VEGF increased in MDD. Adverse childhood experiences (ACE) and ROI are significantly associated with lowered SCF and increasing VEGF. Lifetime and current suicidal behaviors are strongly predicted (63.5%) by an increased VEGF/SCF ratio, Th1 polarization, a gut microbiome enterotype indicating gut dysbiosis, and lowered abundance of Dorea and Faecalobacterium. Around 80.5% of the variance in the phenome's severity is explained by ROI, ACEs, and lowered Parabacteroides distasonis and Clostridium IV abundances. A large part of the variance in health-related quality of life (54.1%) is explained by the VEGF/SCF ratio, Th1 polarization, ACE, and male sex. In conclusion, key features of MDD are largely predicted by the cumulative effects of ACE, Th1 polarization, aberrations in growth factors and the gut microbiome with increased pathobionts but lowered beneficial symbionts.

IL-9 secreted by leukemia stem cells induces Th1-skewed CD4+ T cells, which promote their expansion

AbstractIn acute myeloid leukemia (AML), leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) interact with various cell types in the bone marrow (BM) microenvironment, regulating their expansion and differentiation. To study the interaction of CD4+ and CD8+ T cells in the BM with LSCs and LPCs, we analyzed their transcriptome and predicted cell-cell interactions by unbiased high-throughput correlation network analysis. We found that CD4+ T cells in the BM of patients with AML were activated and skewed toward T-helper (Th)1 polarization, whereas interleukin-9 (IL-9)–producing (Th9) CD4+ T cells were absent. In contrast to normal hematopoietic stem cells, LSCs produced IL-9, and the correlation modeling predicted IL9 in LSCs as a main hub gene that activates CD4+ T cells in AML. Functional validation revealed that IL-9 receptor signaling in CD4+ T cells leads to activation of the JAK-STAT pathway that induces the upregulation of KMT2A and KMT2C genes, resulting in methylation on histone H3 at lysine 4 to promote genome accessibility and transcriptional activation. This induced Th1-skewing, proliferation, and effector cytokine secretion, including interferon gamma (IFN-γ) and tumor necrosis factor α (TNF-α). IFN-γ and, to a lesser extent, TNF-α produced by activated CD4+ T cells induced the expansion of LSCs. In accordance with our findings, high IL9 expression in LSCs and high IL9R, TNF, and IFNG expression in BM–infiltrating CD4+ T cells correlated with worse overall survival in AML. Thus, IL-9 secreted by AML LSCs shapes a Th1-skewed immune environment that promotes their expansion by secreting IFN-γ and TNF-α.

IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease.

IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease whose pathomechanisms remain poorly understood. Here, we identified gene variants in familial IgG4-RD and determined their functional consequences. All 3 affected members of the family shared variants of the transcription factor IKAROS, encoded by IKZF1, and the E3 ubiquitin ligase UBR4. The IKAROS variant increased binding to the FYN promoter, resulting in higher transcription of FYN in T cells. The UBR4 variant prevented the lysosomal degradation of the phosphatase CD45. In the presence of elevated FYN, CD45 functioned as a positive regulatory loop, lowering the threshold for T cell activation. Consequently, T cells from the affected family members were hyperresponsive to stimulation. When transduced with a low-avidity, autoreactive T cell receptor, their T cells responded to the autoantigenic peptide. In parallel, high expression of FYN in T cells biased their differentiation toward Th2 polarization by stabilizing the transcription factor JunB. This bias was consistent with the frequent atopic manifestations in patients with IgG4-RD, including the affected family members in the present study. Building on the functional consequences of these 2 variants, we propose a disease model that is not only instructive for IgG4-RD but also for atopic diseases and autoimmune diseases associated with an IKZF1 risk haplotype.

Akt2 deficiency impairs Th17 differentiation, augments Th2 differentiation, and alters the peripheral response to immunization.

Akt1 and Akt2, isoforms of the serine threonine kinase Akt, are essential for T cell development. However, their role in peripheral T cell differentiation remains undefined. Using mice with germline deletions of either Akt1 or Akt2, we found that both isoforms are important for Th17 differentiation, although Akt2 loss had a greater impact than loss of Akt1. In contrast to defective IL-17 production, Akt2 -/- T cells exhibited enhanced IL-4 production in vitro under Th2 polarizing conditions. In vivo , Akt2 -/- mice displayed significantly diminished IL-17A and GM-CSF production following immunization with myelin oligodendrocyte glycoprotein (MOG). This dampened response was associated with further alterations in Th cell differentiation including decreased IFNγ production but preserved IL-4 production, and preferential expansion of regulatory T cells compared to non-regulatory CD4 T cells. Taken together, we identify Akt2 as an important signaling molecule in regulating peripheral CD4 T cell responses.