The mammalian target of rapamycin (mTOR) and the phosphatidylinositol-3-kinase (PI3K)/protein kinase B or Akt (PKB/Akt) signaling pathways are considered as two but somewhat interconnected significant immune pathways which play complex roles in a variety of physiological processes as well as pathological conditions. Aberrant activation of PI3K/Akt/mTOR signaling pathways has been reported to be associated in a wide variety of human diseases. Over the past few years, growing evidence in in vitro and in vivo models suggest that this sophisticated and subtle cascade mediates the orchestration of the immune response in health and disease through exposure to probiotics. An expanding body of literature has highlighted the contribution of probiotics and PI3K/Akt/mTOR signaling pathways in gastrointestinal disorders, metabolic syndrome, skin diseases, allergy, salmonella infection, and aging. However, longitudinal human studies are possibly required to verify more conclusively whether the investigational tools used to understand the regulation of these pathways might provide effective approaches in the prevention and treatment of various disorders. In this Review, we summarize the experimental evidence from recent peer-reviewed studies and provide a brief overview of the causal relationship between the effects of probiotics and their metabolites on the components of PI3K/Akt/mTOR signaling pathways and human disease.

https://www.tandfonline.com/doi/pdf/10.1080/19490976.2021.1886844

Modulation of the PI3K/Akt/mTOR signaling pathway by probiotics as a fruitful target for orchestrating the immune response.

The beneficial effects of probiotics have been described in allergic sensitization and diseases; however, many questions remain unanswered, such as characteristics of the most effective strains in modulation of allergic responses and how orally administered probiotics affect the systemic immune system. In the present work, oral administration of five lactic acid bacteria strains showed variable effects on protection against the allergic reaction in a mouse model of food allergy to shrimp tropomyosin (ST). The most effective anti-allergic strain, Bacillus coagulans 09.712 (Bc), greatly improved epithelial barrier function and increased lymphocytes proliferation. Moreover, Bc suppresses ST sensitization by altering Th1/Th2/Treg balance as a result of strong induction of CD4+Foxp3+Tregs in combination with IL-10 producing. Bc-specific induction of CD4+Foxp3+ Tregs also suppresses Th17 pro-inflammatory response in this mouse model. Finally, the intake of Bc suppresses mTOR activation and thus the phosphorylation of downstream factors. Inhibition of mTOR signaling by Bc further results in FOXP3 up-regulation and GATA-3 down-regulation, which, in turn, facilitate to control Th2-predominant and Th17 pro-inflammatory responses caused by ST. Our work provides further characterization of the anti-allergic effects of probiotic LAB strains, and identifies new targets for preventive and curative treatment of food allergies.

/pdf/lactic-acid-bacteria-specific-induction-of-cd4-foxp3-t-cells-2o0377ns46.pdf

Lactic acid bacteria-specific induction of CD4+Foxp3+T cells ameliorates shrimp tropomyosin-induced allergic response in mice via suppression of mTOR signaling.

Intervention with mesenchymal stem cells (MSCs) reveals a promising therapeutic tool to treat transplantation and autoimmune disease due to their immunoregulation capability. But the mechanisms of action are not fully investigated yet. Transforming growth factor-β1 (TGF-β1) exhibit multiple effects in migration, differentiation, and immunomodulation of MSCs. Glycoprotein A repetitions predominant (GARP) is an important marker of activated Treg (regulatory T cells). GARP binds latent TGF-β1 to regulate its activation, which is the indispensable step in Treg suppressing effector T cells. So far we don't know whether GARP present on MSCs and its association with MSCs function. Our study show that MSCs express GARP which binds latent TGF-β1 on their cell surface. We also found that TGF-β1+/- MSCs produce less TGF-β1 and exhibit reduced capacity in inhibiting T cells. When TGF-β1 signaling pathway was blocked, MSCs show decreased activity in inhibiting T cells. Importantly, silencing GARP expression distinctively damaged the capacity of MSCs to inhibit IFN-γ production. These findings indicated the expression of GARP on MSCs and its functionality in activating LAP, thus demonstrating GARP as a novel biomarker and new target to improve the therapeutic efficacy of MSCs.

/pdf/mesenchymal-stem-cells-inhibit-t-cell-activation-by-4jsxbf66xg.pdf

Mesenchymal stem cells inhibit T cell activation by releasing TGF-β1 from TGF-β1/GARP complex.

Regulatory T cells (Tregs) are a double-edged regulator of the immune system. Aberrations of Tregs correlate with pathogenesis of inflammatory, autoimmune and neoplastic disorders. Phenotypically and functionally distinct subsets of Tregs have been identified in humans and mice on the basis of their extensive portfolios of monoclonal antibodies (mAb) against Treg surface antigens. As an important veterinary species, dogs are increasingly recognised as an excellent model for many human diseases. However, insightful study of canine Tregs has been restrained by the limited availability of mAb. We therefore set out to characterise CD4+CD25high T cells isolated ex vivo from healthy dogs and showed that they possess a regulatory phenotype, function, and transcriptomic signature that resembles those of human and murine Tregs. By launching a cross-species comparison, we unveiled a conserved transcriptomic signature of Tregs and identified that transcript hip1 may have implications in Treg function.

/pdf/phenotypic-characterisation-of-regulatory-t-cells-in-dogs-halbpmmr6g.pdf

Phenotypic characterisation of regulatory T cells in dogs reveals signature transcripts conserved in humans and mice.

Abstract Background To construct a predictive model of immunotherapy efficacy for patients with lung squamous cell carcinoma (LUSC) based on the degree of tumor-infiltrating immune cells (TIIC) in the tumor microenvironment (TME). Methods The data of 501 patients with LUSC in the TCGA database were used as a training set, and grouped using non-negative matrix factorization (NMF) based on the degree of TIIC assessed by single-sample gene set enrichment analysis (GSEA). Two data sets (GSE126044 and GSE135222) were used as validation sets. Genes screened for modeling by least absolute shrinkage and selection operator (LASSO) regression and used to construct a model based on immunophenotyping score (IPTS). RNA extraction and qPCR were performed to validate the prognostic value of IPTS in our independent LUSC cohort. The receiver operating characteristic (ROC) curve was constructed to determine the predictive value of the immune efficacy. Kaplan–Meier survival curve analysis was performed to evaluate the prognostic predictive ability. Correlation analysis and enrichment analysis were used to explore the potential mechanism of IPTS molecular typing involved in predicting the immunotherapy efficacy for patients with LUSC. Results The training set was divided into a low immune cell infiltration type (C1) and a high immune cell infiltration type (C2) by NMF typing, and the IPTS molecular typing based on the 17-gene model could replace the results of the NMF typing. The area under the ROC curve (AUC) was 0.82. In both validation sets, the IPTS of patients who responded to immunotherapy were significantly higher than those who did not respond to immunotherapy ( P = 0.0032 and P = 0.0451), whereas the AUC was 0.95 (95% CI = 1.00–0.84) and 0.77 (95% CI = 0.58–0.96), respectively. In our independent cohort, we validated its ability to predict the response to cancer immunotherapy, for the AUC was 0.88 (95% CI = 1.00–0.66). GSEA suggested that the high IPTS group was mainly involved in immune-related signaling pathways. Conclusions IPTS molecular typing based on the degree of TIIC in the TME could well predict the efficacy of immunotherapy in patients with LUSC with a certain prognostic value. 

/pdf/construction-of-a-predictive-model-for-immunotherapy-1o7ikfl3.pdf

Construction of a predictive model for immunotherapy efficacy in lung squamous cell carcinoma based on the degree of tumor-infiltrating immune cells and molecular typing

Owing to their manifold immune regulatory functions, regulatory T cells (Treg) have received tremendous interest as targets for therapeutic intervention of diverse immunological pathologies or cancer. Directed manipulation of Treg will only be achievable with extensive knowledge about the intrinsic programs that define their regulatory function. We simultaneously analyzed miR and mRNA transcript levels in resting and activated human Treg cells in comparison with non-regulatory conventional T cells (Tcon). Based on experimentally validated miR-target information, both transcript levels were integrated into a comprehensive pathway analysis. This strategy revealed characteristic signal transduction pathways involved in Treg biology such as T-cell receptor-, Toll-like receptor-, transforming growth factor-β-, JAK/STAT (Janus kinase/signal transducers and activators of transcription)- and mammalian target of rapamycin signaling, and allowed for the prediction of specific pathway activities on the basis of miR and mRNA transcript levels in a probabilistic manner. These data encourage new concepts for targeted control of Treg cell effector functions.

MiRNome and transcriptome aided pathway analysis in human regulatory T cells

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MiRNome and transcriptome aided pathway analysis in human regulatory T cells