γδ T cell-mediated activation of cDC1 orchestrates CD4+ Th1 cell priming in malaria.

γδ T cells facilitate the CD4+ T helper 1 (Th1) cell response against Plasmodium infection by activating conventional dendritic cells (cDCs), although the underlying mechanism remains elusive. Our study revealed that γδ T cells promote the complete maturation and production of interleukin-12 and CXCR3-ligands specifically in type 1 cDCs (cDC1), with minimal impact on cDC2 and monocyte derived DCs (Mo-DCs). During the initial infection phase, γδ T cell activation and temporal accumulation in the splenic white pulp, alongside cDC1, occur via CCR7-signaling. Furthermore, cDC1/γδ T cell interactions in the white pulp are amplified through CXCR3 signaling in γδ T cells, optimizing Th1 cell priming by cDC1. We also demonstrated how transitional Th1 cells arise in the white pulp before establishing their presence in the red pulp as fully differentiated Th1 cells. Additionally, we elucidate the reciprocal activation between γδ T cells and cDC1s. These findings suggest that Th1 cell priming is orchestrated by this reciprocal activation in the splenic white pulp during the early phase of blood-stage Plasmodium infection.

Capecitabine mitigates cardiac allograft rejection via inhibition of TYMS-Mediated Th1 differentiation in mice.

OBJECTIVES: Previous studies elucidated that capecitabine (CAP) works as an anti-tumor agent with putative immunosuppressive effects. However, the intricate mechanisms underpinning these effects remain to be elucidated. In this study, we aimed to unravel the molecular pathways by which CAP exerts its immunosuppressive effects to reduce allograft rejection. METHODS: Hearts were transplanted from male BALB/c donors to male C57BL/6 recipients and treated with CAP for seven days. The rejection of these heart transplants was assessed using a range of techniques, including H&E staining, immunohistochemistry, RNA sequencing, LS-MS/MS, and flow cytometry. In vitro, naïve CD4+ T cells were isolated and cultured under Th1 condition medium with varying treatments, flow cytometry, LS-MS/MS were employed to delineate the role of thymidine synthase (TYMS) during Th1 differentiation. RESULTS: CAP treatment significantly mitigated acute allograft rejection and enhanced graft survival by reducing graft damage, T cell infiltration, and levels of circulating pro-inflammatory cytokines. Additionally, it curtailed CD4+ T cell proliferation and the presence of Th1 cells in the spleen. RNA-seq showed that TYMS, the target of CAP, was robustly increased post-transplantation in splenocytes. In vitro, TYMS and its metabolic product dTMP were differentially expressed in Th0 and Th1, and were required after activation of CD4+ T cell and Th1 differentiation. TYMS-specific inhibitor, raltitrexed, and the metabolite of capecitabine, 5-fluorouracil, could inhibit the proliferation and differentiation of Th1. Finally, the combined use of CAP and the commonly used immunosuppressant rapamycin can induce long-term survival of allograft. CONCLUSION: CAP undergoes metabolism conversion to interfere pyrimidine metabolism, which targets TYMS-mediated differentiation of Th1, thereby playing a significant role in mitigating acute cardiac allograft rejection in murine models.

Th1 cell immune response in Talaromyces marneffei infection with anti-interferon-γ autoantibody syndrome.

Anti-interferon-γ autoantibody (AIGA) syndrome may be the basis of disseminated Talaromyces marneffei infection in human immunodeficiency virus (HIV)-negative adults. However, the pathogenesis of Th1 cell immunity in T. marneffei infection with AIGA syndrome is unknown. A multicenter study of HIV-negative individuals with T. marneffei infection was conducted between September 2018 and September 2020 in Guangdong and Guangxi, China. Patients were divided into AIGA-positive (AP) and AIGA-negative (AN) groups according to the AIGA titer and neutralizing activity. The relationship between AIGA syndrome and Th1 immune deficiency was investigated by using AP patient serum and purification of AIGA. Fifty-five HIV-negative adults with disseminated T. marneffei infection who were otherwise healthy were included. The prevalence of AIGA positivity was 83.6%. Based on their AIGA status, 46 and 9 patients were assigned to the AP and AN groups, respectively. The levels of Th1 cells, IFN-γ, and T-bet were higher in T. marneffei-infected patients than in healthy controls. However, the levels of CD4+ T-cell STAT-1 phosphorylation (pSTAT1) and Th1 cells were lower in the AP group than in the AN group. Both the serum of patients with AIGA syndrome and the AIGA purified from the serum of patients with AIGA syndrome could reduce CD4+ T-cell pSTAT1, Th1 cell differentiation and T-bet mRNA, and protein expression. The Th1 cell immune response plays a pivotal role in defense against T. marneffei infection in HIV-negative patients. Inhibition of the Th1 cell immune response may be an important pathological effect of AIGA syndrome.IMPORTANCEThe pathogenesis of Th1 cell immunity in Talaromyces marneffei infection with anti-interferon-γ autoantibody (AIGA) syndrome is unknown. This is an interesting study addressing an important knowledge gap regarding the pathogenesis of T. marneffei in non-HIV positive patients; in particular patients with AIGA. The finding of the Th1 cell immune response plays a pivotal role in defense against T. marneffei infection in HIV-negative patients, and inhibition of the Th1 cell immune response may be an important pathological effect of AIGA syndrome, which presented in this research could help bridge the current knowledge gap.

hsa_circ_0087100/hsa-miR-6743-5p affects Th1 cell differentiation by regulating STAT1 in diabetic retinopathy.

Objective: To elucidate the role of the competitive endogenous RNA (ceRNA) network in immune infiltration of diabetic retinopathy (DR). Methods: We obtained differentially expressed (DE) circRNAs, miRNAs and mRNAs from the Gene Expression Omnibus database. Then, we identified immune infiltration by CIBERSORT and single-sample gene set enrichment analysis and discovered co-expression genes by weighted gene co-expression network analysis. Furthermore, STAT1-mediated Th1 differentiation was determined in DR cell models, DR patients and DR mouse models. Results: hsa_circ_0087100/hsa-miR-6743-5p/STAT1 was involved in immune infiltration of Th1 cells. Aberrant expression of the ceRNA network and STAT1-mediated Th1 differentiation was thus verified in vitro and in vivo. Conclusion: hsa_circ_0087100/hsa-miR-6743-5p/STAT1 may affect Th1 cell differentiation in DR.

The protease inhibitor E64d might attenuate the development of experimental anti-glomerular basement membrane disease through regulating the activation of Th1 cells.

BACKGROUND: Cathepsins have been recently identified as a regulator in the activation of Th1 and Th17 cells, which play an important role in the pathogenesis of anti-glomerular basement membrane (GBM) disease. Whether cathepsins contribute to the development of anti-GBM disease through regulating the activation of CD4+ T cell is still unclear. METHODS: Rats with experimental anti-GBM disease was established by immunization with the nephritogenic T cell epitope α3127-148. E64d, a cysteine cathepsin inhibitor, was administered in vitro and vivo to evaluate the effect of cathepsins on regulating the activation of antigen specific T cells and the development of anti-GBM disease. RESULTS: In rats with experimental anti-GBM diseases, E64d treatment not only reduced the levels of proteinuria, serum creatinine and anti-GBM antibody, but also ameliorated the kidney injury with less glomerular IgG deposition, a lower percentage of crescents and less infiltration of CD4+ T cells, CD8+ T cells and macrophages, as well as a lower percentage of splenic Th1 cells. In vitro, E64d treatment could significantly reduce the production of IFN-γ in the supernatant which might be produced by the activation of Th1 cells after being recalled with the autoantigen α3127-148. We also found the CD4+ T cells of rats with anti-GBM disease had an increased expression of cathepsin L (Cts-L), and the percentage of CD4+ T cells with extracellular expression of Cts-L was obviously higher, indicating it as a potential key regulator. CONCLUSIONS: E64d might attenuate the development of anti-GBM disease by participating in the activation of Th1 cells, indicating it as a potential drug for anti-GBM disease in the future.

IL-17 and IFN-γ-producing respiratory tissue resident memory CD4†T cells persist for decades in adults immunized as children with whole cell pertussis vaccines.

The objective was to determine if antigen-specific tissue resident memory T (TRM) cells persist in respiratory tissues of adults immunized as children with whole cell pertussis (wP) or acellular pertussis (aP) vaccines. Mononuclear cells from tonsil or nasal tissue cells were cultured with Bordetella pertussis antigens and TRM cells quantified by flow cytometry. Adults immunized with wP vaccines as children had significantly more IL-17A and IFN-y-producing TRM cells that respond to B. pertussis antigens in respiratory tissues when compared with aP-primed donors. Our findings demonstrate that wP vaccines induce CD4 TRM cells that can persist in respiratory tissues for decades.

Effect of Med1 on T cell development and CD4+ T cell differentiation in immune response. / Med1对T细胞发育及CD4+ Tç»†èƒžåœ¨å ç–«åº”ç­”ä¸­åˆ†åŒ–çš„å½±å“.

OBJECTIVES: The differentiation of CD4+ T cells is regulated by a complex and fine signaling pathway composed of many molecules during immune response, and the molecular mechanism for regulating T-bet expression is unclear. Mediator complex subunit 1 (Med1) can combine with a variety of co-factors to regulate gene transcription, promote cell proliferation and survival, and affect invariant natural killer T cell (iNKT) development. This study aims to investigate the effect of Med1 on T cell development and CD4+ T cell differentiation in immune response. METHODS: Mice with T cell-specific knockout of Med1 gene (Med1F/FCD4cre+, KO) were constructed and verified. The percentage and number of CD4+ and CD8+ T cells in thymus, spleen, and lymph nodes of KO mice and control (Con) mice (Med1F/FCD4cre-) were detected by flow cytometry. After 8 days of infection with lymphocytic choriomeningitis virus (LCMV), the percentage and number of CD4+ T cells or antigen-specific (GP66+) CD4+ T cells, the percentage and number of Th1 cells (Ly6c+PSGL1+) in CD4+ T cells or antigen-specific CD4+ T cells were examined in the spleen of mice. Moreover, the fluorescence intensity of T-bet in CD4+ T cells or antigen-specific CD4+ T cells was analyzed. RESULTS: Compared with the Con group, the percentage and number of CD4+ T cells and CD8+ T cells in the thymus, CD4+ T cells in the spleen and lymph nodes of the KO group showed no significant differences (all P>0.05), but the percentage and number of CD8+ T cells in the spleen and lymph nodes of the KO group were diminished significantly (all P<0.05). After 8 days of infection with LCMV, there was no significant difference in the percentage and number of CD4+ T cells or antigen-specific CD4+ T cells in the spleen between the KO group and the Con group (all P>0.05), while in comparison with the Con group, the percentage and number of Th1 cells in CD4+ T cells or antigen-specific CD4+ T cells, and the expression of T-bet in CD4+ T cells or antigen-specific CD4+ T cells were significantly reduced in the spleen of the KO group (all P<0.05). CONCLUSIONS: Specific knockout of Med1 in T cells does not affect the development of CD4+ and CD8+ T cells in the thymus, but does affect the maintenance of peripheral CD8+ T cells. In the immune response, Med1 gene deletion affects the expression of transcription factor T-bet, which in turn to reduce Th1 cell differentiation.

Features of SARS-CoV-2 Replication in Various Types of Reptilian and Fish Cell Cultures.

BACKGROUND: SARS-CoV-2 can enter the environment from the feces of COVID-19 patients and virus carriers through untreated sewage. The virus has shown the ability to adapt to a wide range of hosts, so the question of the possible involvement of aquafauna and animals of coastal ecosystems in maintaining its circulation remains open. METHODS: the aim of this work was to study the tropism of SARS-CoV-2 for cells of freshwater fish and reptiles, including those associated with aquatic and coastal ecosystems, and the effect of ambient temperature on this process. In a continuous cell culture FHM (fathead minnow) and diploid fibroblasts CGIB (silver carp), SARS-CoV-2 replication was not maintained at either 25 °C or 29 °C. At 29 °C, the continuous cell culture TH-1 (eastern box turtle) showed high susceptibility to SARS-CoV-2, comparable to Vero E6 (development of virus-induced cytopathic effect (CPE) and an infectious titer of 7.5 ± 0.17 log10 TCID50/mL on day 3 after infection), and primary fibroblasts CNI (Nile crocodile embryo) showed moderate susceptibility (no CPE, infectious titer 4.52 ± 0.14 log10 TCID50/mL on day 5 after infection). At 25 °C, SARS-CoV-2 infection did not develop in TH-1 and CNI. CONCLUSIONS: our results show the ability of SARS-CoV-2 to effectively replicate without adaptation in the cells of certain reptile species when the ambient temperature rises.

The effect of Jiaweidaochi powder on Th1/Th2 in rats with recurrent aphthous ulcer.

OBJECTIVE: To elucidate the effect of Jiaweidaochi powder on the Th1/Th2 ratio in rats with recurrent aphthous ulcers (RAU). DESIGN: 40 Sprague-Dawley rats were included in this study, randomly divided into a control group, a model group, and three treatment groups (0.5 g/ ml, 1 g/ml, 2 g/ml Jiaweidaochi powder). The RAU model of rats was established by autoantigen injection. The effects of Jiaweidaochi powder on the expression of INFG, IL-4, TBX21, and GATA3 mRNA were detected by real-time PCR. The expression of IFN-γ, IL-4, and IFN-γ/IL-4 proteins in oral ulcer tissue and serum of rats were analyzed by Western blot and ELISA, respectively. The proportion of Th1 cells and Th2 cells in RAU rats was analyzed by flow cytometry. RESULTS: Jiaweidaochi powder reduced the number, diameter, and duration of oral ulcers in RAU rats. Real-time PCR showed that middle and high-dose Jiaweidaochi powder decreased the expression of INFG TBX21 mRNA and increased the expression of IL-4 and GATA3 mRNA in the oral tissue of RAU rats. ELISA and western blot confirmed that the expression of IFN-γ protein was significantly decreased, and the level of IL-4 protein was increased both in oral tissue and serum of RAU rats treated with middle or high doses of Jiaweidaochi powder. Flow cytometry found that the Jiaweidaochi powder decreased the proportion of Th1 cells and increased the proportion of Th2 cells in RAU rats. CONCLUSION: This study found that Jiaweidaochi powder promoted the balance of Th1/Th2 in RAU rats, contributing to the healing of RAU.

The effect of glatiramer acetate, IFNß-1a, fingolimod, and dimethyl fumarate on the expression of T-bet, IFN-γ, and MEG3 in PBMC of RRMS patients.

OBJECTIVE: Multiple sclerosis (MS) is a progressing neurodegenerative disease marked by chronic central nervous system inflammation and degeneration.This study investigates gene expression profiles of T-box transcription factor TBX21 (T-bet), interferon-gamma (IFN-γ), and long non-coding RNA MEG3 in peripheral blood mononuclear cells (PBMCs) from treatment-naïve Relapsing-Remitting Multiple Sclerosis patients (RRMS), healthy controls, and RRMS patients on different Disease Modifying Therapies (DMTs). The aim is to understand the role of T-bet, IFN-γ, and MEG3 in MS pathogenesis and their potential as diagnostic and therapeutic targets. RESULTS: Elevated T-bet expression is observed in treatment-naïve RRMS patients compared to healthy individuals. RRMS patients treated with Interferon beta-1alpha (IFNß-1a) and fingolimod exhibit downregulated T-bet and MEG3 expression levels, respectively, with more pronounced effects in females. Healthy individuals show a moderate positive correlation between T-bet and MEG3 and between IFN-γ and T-bet. In RRMS patients treated with Glatiramer Acetate (GA), a strong positive correlation is observed between MEG3 and IFN-γ. Remarkably, RRMS patients treated with Dimethyl Fumarate (DMF) exhibit a significant positive correlation between T-bet and MEG3. These findings underscore the diagnostic potential of T-bet in RRMS, warranting further exploration of MEG3, T-bet, and IFN-γ interplay in RRMS patients.

Interleukin-12 induces IFN-γ secretion and STAT signaling implying its potential regulation of Th1 cell response in Nile tilapia.

As a pleiotropic cytokine consisting of IL-12p35 and IL-12p40, Interleukin-12 (IL-12) features in inflammation regulation and anti-bacterial immunity. While IL-12 homologs have been identified in non-mammalian species, the precise mechanisms by which IL-12 contributes to early adaptive immune responses in vertebrates remain incompletely understood. Herein, an evolutionary conserved Oreochromis niloticus IL-12 (defined as OnIL-12) was identified by synteny characterization, structural comparisons and phylogenetic pattern of IL-12p35b and IL-12p40a. IL-12p35b and IL-12p40a exhibited widespread expression in lymphoid-related tissues of tilapia, while their mRNA expression in head-kidney demonstrated a significant increase after Edwardsiella piscicida infection. Compared with other lymphocytes, recombinant OnIL-12 (rOnIL-12) displayed stronger affinity binding to T cells. Although stimulation of lymphocytes with the p35b or p40a subunit resulted in a significant induction of IFN-γ expression, rOnIL-12 showed stronger potential to promote IFN-γ expression than these subunits. rOnIL-12 not only elevated the mRNA expression level Th1 cell-associated transcription factor T-bet in lymphocytes, but also increased the proportion of CD4-1+IFN-γ+ lymphocytes. Moreover, the mRNA and phosphorylation levels of STAT1, STAT3, STAT4 and STAT5 were enhanced by rOnIL-12. These findings will offer previous evidence for further exploration into the regulatory mechanisms of Th1 cellular immunity in early vertebrates.

The Function of T Cell Immunity in Lymphedema: A Comprehensive Review.

Lymphedema is a debilitating disease characterized by extremity edema, fibroadipose deposition, impaired lymphangiogenesis, and dysfunctional lymphatics, often with lymphatic injury secondary to the treatment of malignancies. Emerging evidence has shown that immune dysfunction regulated by T cells plays a pivotal role in development of lymphedema. Specifically, Th1, Th2, Treg, and Th17 cells have been identified as critical regulators of pathological changes in lymphedema. In this review, our aim is to provide an overview of the current understanding of the roles of CD4+ T cells, including Th1, Th2, Treg, and Th17 subsets, in the progression of lymphedema and to discuss associated therapies targeting T cell inflammation for management of lymphedema.

Correlation between the intestinal microflora and peripheral blood Th1/Th2 balance in hypothyroidism during the first half of pregnancy.

Objective: This study aimed to investigate the relationship between intestinal microflora characteristics and the peripheral blood T helper cell (Th)1/Th2 balance in patients with hypothyroidism during the first half of pregnancy. Methods: The Th1/Th2 ratios in the peripheral blood of pregnant women in the hypothyroidism and control groups were determined using flow cytometry. The cytometric bead array assay was used to determine the serum levels of interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. Moreover, 16S rRNA amplicon sequencing was used to determine the intestinal microbial composition in the two groups. Finally, the relationships between intestinal microflora, Th1/Th2 cells, cytokines, and clinical indicators were analyzed. Results: C-reactive protein levels were higher in the hypothyroidism group than in the control group. In contrast to the control group, the hypothyroidism group showed an increase in Th1 cells and the Th1/Th2 ratio, and a decrease in Th2 cells. The hypothyroidism group had higher serum IL-2, TNF-α, and IFN-γ levels, and lower IL-10 levels, than the control group. The richness of the intestinal microflora in the hypothyroidism group increased whereas the diversity decreased. The linear discriminant analysis effect size revealed that the hypothyroidism group had a higher abundance of Prevotella and Faecalibacterium, but a lower abundance of Bacteroides, compared to the control group. Prevotella was positively correlated with Th1 cells, the Th1/2 ratio, and TNF-α. Bacteroides was positively correlated with Th2 cells and IL-10, but negatively correlated with Th1 cells, the Th1/2 ratio, TNF-α, and IFN-γ. The thyroid peroxidase antibody level was directly proportional to TNF-α. Conclusion: A Th1/Th2 imbalance occurs in patients with hypothyroidism during the first half of pregnancy. Disorders of the intestinal microflora may lead to hypothyroidism during pregnancy by affecting the Th1/Th2 balance.

P2RX7 signaling drives the differentiation of Th1 cells through metabolic reprogramming for aerobic glycolysis.

Introduction: This study provides evidence of how Th1 cell metabolism is modulated by the purinergic receptor P2X7 (P2RX7), a cation cannel activated by high extracellular concentrations of adenosine triphosphate (ATP). Methods: In vivo analysis was performed in the Plasmodium chabaudi model of malaria in view of the great relevance of this infectious disease for human health, as well as the availability of data concerning Th1/Tfh differentiation. Results: We show that P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-conditioned CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, in vitro ATP synthase blockade and the consequent inhibition of oxidative phosphorylation, which drives cellular metabolism for aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. Conclusion: These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 differentiation and suggest that ATP synthase inhibition is a downstream effect of P2RX7 signaling that potentiates the Th1 response.

Nocardia rubra cell-wall skeleton activates an immune response in cervical tissue via stimulating FPR3 to enhance dendritic cell-mediated Th1 differentiation.

Nocardia rubra cell wall skeleton (Nr-CWS) has proven to be a successful medicine for therapy of cervical human papillomavirus infection. The mechanism of action of Nr-CWS is unclear but may involve a stimulatory effect on the host immune system. We previously found that CD4+ T cells were increased in cervical tissue after Nr-CWS treatment. Microarray data from these cervical tissues revealed the significant upregulation of formylated peptide receptor 3 (FPR3). This study aimed to explore the role of Nr-CWS in immunomodulatory based on these findings. Examination of CD4+ T cell subsets in cervical tissue from patients who received Nr-CWS revealed substantial increases in Th1 cytokines and transcription factors. The regulatory effects of Nr-CWS on the function and phenotype of dendritic cells (DCs) were assessed in comparison with the traditional DC maturation inducer lipopolysaccharide (LPS). Similar to LPS, Nr-CWS potently induced DC maturation and interleukin-12 (IL-12) secretion. Differentiation of T cells induced by Nr-CWS stimulated DCs was assessed using the mixed lymphocyte reaction assay. Significant differentiation towards Th1 was evident. Finally, FPR3 expression in DCs in response to Nr-CWS and LPS was measured. Nr-CWS potently upregulated FPR3 expression, while the LPS did not. Silencing FPR3 in DCs reduced Nr-CWS-induced IL-12 production and Th1 cell polarization in co-cultured T cells. The collective findings indicate that Nr-CWS may target FPR3 on the surface of DC cells and activate a Th1-type immune response. The findings clarify the basis of the antiviral immune effects of Nr-CWS on human papillomavirus.

Induction of liver transplant immune tolerance in an outbred rat strain model using tacrolimus.

BACKGROUND: Orthotopic liver transplantation is the only option for patients with end-stage liver disease and hepatocellular carcinoma. Post-transplant immunosuppressive therapy is important to prevent graft failure. We investigated the effectiveness of tacrolimus (FK506) and their mechanisms for liver transplant immune tolerance in an outbred rat LT model. RESULTS: To investigate the therapeutic effect of the FK506 on outbred rat LT model, FK506 and postoperative therapy were administered subcutaneously once or twice daily to transplanted rats. Histopathological and immunohistochemical analyses were conducted for all groups. The regulation of inflammatory cytokine signaling in the spleen was analyzed by flow cytometry. FK506 attenuated allograft rejection and increased survival in rat orthotopic liver transplantation models. The FK506-treated group had reduced serum levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. Furthermore, FK506 decreased the expression of inflammatory cytokines and the activation of pathogenic Th1 and Th17 cells in the liver. CONCLUSIONS: Taken together, we revealed that FK506 ameliorated strong allograft rejection in outbred liver transplantation model by anti-inflammatory effect and inhibitory peroperty of pathogenic T cells.

Full-length transcriptome sequencing of lymphocytes respond to IFN-γ reveals a Th1-skewed immune response in flounder (Paralichthys olivaceus).

Interferon gamma (IFN-γ), the member of type II interferons, is a major driver and effector cytokine for Th1 cells and plays broad roles in regulating the function of immune cells. Teleost fish represents the oldest living bony vertebrates containing T-lymphocyte subsets. However, whether or how the regulatory mechanisms of IFN-γ on Th1 cells occur in teleost fish remain unknown. In this study, full-length transcriptome sequencing was performed to analyze the differentially expressed genes (DEGs) and signaling pathways in the IFN-γ stimulated lymphocytes of flounder (Paralichthys olivaceus), the data showed 811 genes were upregulated and 1107 genes were downregulated, Th1 and Th2 cell differentiation pathway was remarkably enriched from DEGs, and the genes in the Th1 cell differentiation pathway were upregulated and verified. Accordingly, variations on Th1 cell differentiation marker genes and CD4+ cells were investigated after IFN-γ stimulation, the results confirmed that CD4+ T lymphocytes proliferated significantly after IFN-γ stimulation, accompanied by eight genes significant upregulation and increased T-bet expression in lymphocytes. In conclusion, the results revealed an induction of IFN-γ on Th1-type immune response, providing novel perspectives into the differentiation of CD4+ T lymphocytes in teleost.

Th1-involved immune infiltrates improve neoadjuvant chemoradiotherapy response of esophageal squamous cell carcinoma.

Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is recommended for locally advanced esophageal squamous cell carcinoma (ESCC) treatment. Patients who achieve a pathological complete response (pCR) have better survival. Our study aimed to discover immune-associated predictors of pCR in ESCC. Herein, we found that Th1-cell infiltration inferred from RNA sequencing was higher in the pCR group than in the non-pCR group. Multiplexed immunohistochemistry (mIHC) confirmed that Th1-, CD8+ T-, NK-, NKT-, and dendritic-cell infiltration was positively associated with pCR. The spatial relationships between Th1 cells and CD8+ T, NK, NKT, dendritic, or ESCC cells were significant pCR predictors. The active and desert subtypes were identified based on immune cell infiltration, and showed different pCR rates. In vitro experiments confirmed that Th1 cells inhibited the proliferation and improved the chemosensitivity and radiosensitivity of ESCC cells. Th1 cells upregulated interferon-gamma response signaling and antigen presentation pathways and downregulated lipid metabolism and MAPK pathways of ESCC cells. These findings highlight the important role of Th1 cells as the predictor of pCR and the regulator of chemosensitivity and radiosensitivity of ESCC, and suggest elevating Th1-infiltration as a strategy to improve NCRT response.

Th1-related transcription factors and cytokines in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an inflammatory disorder related to immunity dysfunction. The Th1 cell family including Th1 cells, transcription factor T-bet, and related cytokines IFNγ, TNFα, IL-2, IL-18, TGF-ß, and IL-12 have been widely discussed in autoimmunity, such as SLE. In this review, we will comprehensively discuss the expression profile of the Th1 cell family in both SLE patients and animal models and clarify how the family members are involved in lupus development. Interestingly, T-bet-related age-associated B cells (ABCs) and low-dose IL-2 treatment in lupus were emergently discussed as well. Collection of the evidence will better understand the roles of the Th1 cell family in lupus pathogenesis, especially targeting IL-2 in lupus.