Microbial Components and Effector Molecules in T Helper Cell Differentiation and Function

The mammalian intestines harbor trillions of commensal microorganisms composed of thousands of species that are collectively called gut microbiota. Among the microbiota, bacteria are the predominant microorganism, with viruses, protozoa, and fungi (mycobiota) making up a relatively smaller population. The microbial communities play fundamental roles in the maturation and orchestration of the immune landscape in health and disease.Primarily, the gut microbiota modulates the immune system to maintain homeostasis and plays a crucial role in regulating the pathogenesis and pathophysiology of inflammatory, neuronal, and metabolic disorders. The microbiota modulates the host immune system through direct interactions with immune cells or indirect mechanisms such as producing short-chain acids and diverse metabolites. Numerous researchers have put extensive efforts into investigating the role of microbes in immune regulation, discovering novel immunomodulatory microbial species, identifying key effector molecules, and demonstrating how microbes and their key effector molecules mechanistically impact the host immune system. Consequently, recent studies suggest that several microbial species and their immunomodulatory molecules have therapeutic applicability in preclinical settings of multiple disorders. Nonetheless, it is still unclear why and how a handful of microorganisms and their key molecules affect the host immunity in diverse diseases. This review mainly discusses the role of microbes and their metabolites in T helper cell differentiation, immunomodulatory function, and their modes of action.

Lactobacillus pentosus Modulates Immune Response by Inducing IL-10 Producing Tr1 Cells

Several gut commensals have been shown to modulate host immune response. Recently, many food derived microbes have also been reported to affect the immune system. However, a mechanism to identify immunostimulatory and immunoregulatory microbes is needed. Here, we successfully established an in vitro screening system and identified an immunoregulatory bacterium, Lactobacillus pentosus KF340 (LP340), present in various fermented foods. LP340 induced a regulatory phenotype in mice Ag presenting cells which, in turn, induced IL-10 and IFN-γ producing Type 1 regulatory T cells (Tr1 cells) from naïve CD4⁺ T cells. Naïve CD4⁺ T cells co-cultured with LP340 treated dendritic cells highly expressed cytokine receptor IL-27R and were CD49b and lymphocyte-activation gene 3 double positive. Oral administration of LP340 in mice with atopic dermatitis reduced cellular infiltration in affected ear lobes and serum IgE levels, thus, ameliorating the disease symptoms. This suggests a systemic immunoregulatory effect of LP340. These findings demonstrate that LP340, a bacterium derived from food, prevents systemic inflammation through the induction of IL-10 producing Tr1 cells.

Erratum: Immune Disorders and Its Correlation with Gut Microbiome

The authors requested a correction in the authorship as JS Hwang to be the sole first author based on their careful re-evaluation of the authors' contribution. This correction does not affect any of the content of the article.

Probiotics as a Potential Immunomodulating Pharmabiotics in Allergic Diseases: Current Status and Future Prospects

The prevalence of allergic disorders has dramatically increased over the past decade, particularly in developed countries. Apart from gastrointestinal disorders, neoplasia, genital and dermatological diseases etc., dysregulation of gut microbiota (dysbiosis) has also been found to be associated with increased risk of allergies. Probiotics are increasingly being employed to correct dysbiosis and, in turn, to modulate allergic diseases. However, several factors like strain variations and effector metabolites or component of them in a bacterial species can affect the efficacy of those as probiotics. On the other hand, host variations like geographical locations, food habits etc. could also affect the expected results from probiotic usage. Thus, there is a glaring deficiency in our approach to establish probiotics as an irrefutable treatment avenue for suitable disorders. In this review, we explicate on the reported probiotics and their effects on certain allergic diseases like atopic dermatitis, food allergy and asthma to establish their utility. We propose possible measures like elucidation of effector molecules and functional mechanisms of probiotics towards establishing probiotics for therapeutic use. Certain probiotics studies have led to very alarming outcomes which could have been precluded, had effective guidelines been in place. Thus, we also propose ways to secure the safety of probiotics. Overall, our efforts tend to propose necessary discovery and quality assurance guidelines for developing probiotics as potential immunomodulatory ‘Pharmabiotics.’

Immune Disorders and Its Correlation with Gut Microbiome

Allergic disorders such as atopic dermatitis and asthma are common hyper-immune disorders in industrialized countries. Along with genetic association, environmental factors and gut microbiota have been suggested as major triggering factors for the development of atopic dermatitis. Numerous studies support the association of hygiene hypothesis in allergic immune disorders that a lack of early childhood exposure to diverse microorganism increases susceptibility to allergic diseases. Among the symbiotic microorganisms (e.g. gut flora or probiotics), probiotics confer health benefits through multiple action mechanisms including modification of immune response in gut associated lymphoid tissue (GALT). Although many human clinical trials and mouse studies demonstrated the beneficial effects of probiotics in diverse immune disorders, this effect is strain specific and needs to apply specific probiotics for specific allergic diseases. Herein, we briefly review the diverse functions and regulation mechanisms of probiotics in diverse disorders.

The expression of Foxp3 protein by retroviral vector-mediated gene transfer of Foxp3 in C57BL/6 mice / 대한수의학회지

The maintenance of peripheral immune tolerance and prevention of chronic inflammation and autoimmune disease require CD4+CD25+ T cells (regulatory T cells). The transcription factor Foxp3 is essential for the development of functional, regulatory T cells, which plays a prominent role in self-tolerance. Retroviral vectors can confer high level of gene transfer and transgene expression in a variety of cell types. Here we observed that following retroviral vector-mediated gene transfer of Foxp3, transductional Foxp3 expression was increased in the liver, lung, brain, heart, muscle, spinal cord, kidney and spleen. One day after vector administration, high levels of transgene and gene expression were observed in liver and lung. At 2 days after injection, transductional Foxp3 expression level was increased in brain, heart, muscle and spinal cord, but kidney and spleen exhibited a consistent low level. This finding was inconsistent with the increase in both CD4+CD25+ T cell and CD4+Foxp3+ T cell frequencies observed in peripheral immune cells by fluorescence-activated cell-sorting (FACS) analysis. Retroviral vector-mediated gene transfer of Foxp3 did not lead to increased numbers of CD4+CD25+ T cell and CD4+Foxp3+ T cell. These results demonstrate the level and duration of transductional Foxp3 gene expression in various tissues. A better understanding of Foxp3 regulation can be useful in dissecting the cause of regulatory T cells dysfunction in several autoimmune diseases and raise the possibility of enhancing suppressive functions of regulatory T cells for therapeutic purposes.

Probiotics as an Immune Modulator for Allergic Disorders / 소아알레르기및호흡기학회지

Allergic disorders such as atopic dermatitis and asthma are common hyperimmune disorders in industrialized countries. Although the exact etiology is unclear, several factors may trigger the disease onset. These include susceptible genetic background, environmental factors and an aberrant gut microbiota with a shift of the Th1/Th2 balance towards a Th2 response. Probiotics confer health benefits through multiple action mechanisms including modification of immune system in both systemic immune system and gut associated lymphoid tissue. Although many human clinical trials and mouse studies demonstrated the beneficial effects of probiotics in diverse allergic disorders, therapeutic efficacy is quite diverse depending on administration dose and types of strains or their mixture. To properly modulate allergic diseases, administration of tailor made probiotics with immune tolerance activity is required. Human clinical trials demonstrate a limited benefit of probiotics in atopic dermatitis in a preventive as well as a therapeutic capacity. In addition, beneficial effect of probiotics treatment is limited in the treatment of bronchial asthma. Identification of specific probiotics that has immune modulating activity and elucidation of the underlying mechanism of action will lead to develop probiotics as an as immune modulator targeting allergic disorders. Herein, we briefly review the diverse functions and regulation mechanisms of probiotics in allergic disorders including atopic dermatitis and asthma.

Molecular Mechanisms Governing IL-24 Gene Expression

Interleukin-24 (IL-24) belongs to the IL-10 family of cytokines and is well known for its tumor suppressor activity. This cytokine is released by both immune and nonimmune cells and acts on non-hematopoietic tissues such as skin, lung and reproductive tissues. Apart from its ubiquitous tumor suppressor function, IL-24 is also known to be involved in the immunopathology of autoimmune diseases like psoriasis and rheumatoid arthritis. Although the cellular sources and functions of IL-24 are being increasingly investigated, the molecular mechanisms of IL-24 gene expression at the levels of signal transduction, epigenetics and transcription factor binding are still unclear. Understanding the specific molecular events that regulate the production of IL-24 will help to answer the remaining questions that are important for the design of new strategies of immune intervention involving IL-24. Herein, we briefly review the signaling pathways and transcription factors that facilitate, induce, or repress production of this cytokine along with the cellular sources and functions of IL-24.

Epigenetic Regulation of Cytokine Gene Expression in T Lymphocytes

The developmental program of T helper and regulatory T cell lineage commitment is governed by both genetic and epigenetic mechanisms. The principal events, signaling pathways and the lineage determining factors involved have been extensively studied in the past ten years. Recent studies have elucidated the important role of chromatin remodeling and epigenetic changes for proper regulation of gene expression of lineage-specific cytokines. These include DNA methylation and histone modifications in epigenomic reprogramming during T helper cell development and effector T cell functions. This review discusses the basic epigenetic mechanisms and the role of transcription factors for the differential cytokine gene regulation in the T helper lymphocyte subsets.