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.
Animals ; Cytokines/metabolism ; Epigenesis, Genetic/*genetics ; Gene Expression Regulation/genetics/physiology ; Humans ; T-Lymphocytes/*metabolism

T cells are an important adaptive immune response arm that mediates cell-mediated immunity. T cell metabolism plays a central role in T cell activation, proliferation, differentiation, and effector function. Specific metabolic programs are tightly controlled to mediate T cell immune responses, and alterations in T cell metabolism may result in many immunological disorders. In this review, we will summarize the main T cell metabolic pathways and the important factors participating in T cell metabolic programming during T cell homeostasis, differentiation, and function.
Animals ; Cell Physiological Phenomena ; Humans ; Immunity, Cellular ; physiology ; Metabolic Networks and Pathways ; immunology ; T-Lymphocytes ; immunology ; metabolism

In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8+T cells rapidly fall into anergy to host cells, while donor CD4+T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8+T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8+T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4+CD25+regulatory T cells (T(reg) cells) are critical in maintaining the donor CD8+T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of T(reg) cells in determining cGVHD versus aGVHD.
T-Lymphocytes, Regulatory/*immunology ; Mice, Inbred DBA ; Mice ; Interleukin-2 Receptor alpha Subunit/*metabolism ; Immune Tolerance/physiology ; Graft vs Host Disease/*immunology ; Female ; Clonal Anergy/*physiology ; Chronic Disease ; CD8-Positive T-Lymphocytes/*immunology ; CD4-Positive T-Lymphocytes/*immunology ; Animals

Current therapies for autoimmune diseases are not cures but merely palliatives, aimed at reducing symptoms. For the most part, these treatments provide nonspecific suppression of the immune system and thus do not distinguish between a pathogenic autoimmune response and a protective immune response. Recently emerging evidence not only has indicated the involvement of members of the TNF receptor/ligand superfamilies but also has revealed exciting innovative strategies for the treatment of autoimmune diseases and other chronic inflammatory diseases without depressing the immune response in general. In this review, we will discuss the regulatory mechanisms of TNF receptor/ligand family members, such as HVEM/ LIGHT, 4-1BB/4-1BBL, and GITR/GITRL that regulate T and B cell functions and participate in the process of inflammatory diseases. We will also discuss how intervening in the costimulatory pathways mediated by these molecules might have some potential as a therapeutic approach to immune disorders.
Animals ; Apoptosis ; Autoimmune Diseases/immunology/metabolism/pathology ; B-Lymphocytes/immunology/physiology ; Dendritic Cells/physiology ; Human ; Inflammation/*immunology ; Lymphocyte Activation/immunology ; Models, Biological ; Receptors, Tumor Necrosis Factor/*physiology ; T-Lymphocytes/immunology/physiology ; Tumor Necrosis Factor/immunology/*physiology

AIMTo provide further evidence for the synthesis of catecholamines (CAs) in lymphocytes and to investigate the effect of the endogenous CAs synthesized by lymphocytes on function of the lymphocytes themselves and the receptor mechanisms involved in the effect.

METHODSRT-PCR was performed to detect the expression of TH mRNA in the lymphocytes from the mesenteric lymph nodes of rats. Different concentrations of pargyline, an inhibitor of monoamine oxydase, and antagonists of alpha1-, alpha2-, beta1-, and beta2-adrenergic receptor (AR) were added to the lymphocyte cultures, and then proliferative response of the lymphocytes to mitogen concanavalin A (Con A) were measured via methyl-thiazole-tetrazolium (MTT) assay.

RESULTSThe lymphocytes could express TH mRNA, and the expression of TH mRNA was significantly higher in the Con A-activated lymphocytes than in the resting ones. The treatment of pargyline of 10(-6) and 10(-5) mol/L (not 10(-7) mol/L) notably attenuated Con A-induced lymphocyte proliferation. Beta2-AR antagonist ICI118551 (10(-7) and 10(-6) mol/L) completely blocked, but alpha1-AR antagonist corynanthine and alpha2-AR antagonist yohimbine (10(-7) and 10(-6) mol/L) partly blocked the suppressive effect of pargyline on the Con A-induced lymphocyte proliferation. Nevertheless, atenolol, an antagonist of beta1-AR, had no blocking effect on pargyline inhibition of lymphocyte proliferation.

CONCLUSIONLymphocytes have the ability to synthesize CAs and the ability is enhanced in the activated lymphocytes. The endogenous CAs synthesized by lymphocytes can inhibit T cell proliferation and the inhibition of T cells by the CAs is mediated predominantly by beta2-AR on the lymphocytes.

Animals ; Catecholamines ; biosynthesis ; physiology ; Cell Proliferation ; drug effects ; Concanavalin A ; pharmacology ; Female ; Lymphocyte Activation ; Lymphocytes ; metabolism ; Male ; Neuroimmunomodulation ; physiology ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta ; physiology ; T-Lymphocytes ; cytology ; immunology ; Tyrosine 3-Monooxygenase ; genetics ; metabolism

Animals ; Gene Expression Profiling ; Gene Silencing ; Hematologic Neoplasms ; genetics ; metabolism ; Hematopoiesis ; genetics ; Humans ; MicroRNAs ; metabolism ; physiology ; Neoplasms ; genetics ; metabolism ; Oligonucleotide Array Sequence Analysis ; T-Lymphocytes ; metabolism

To explore the role of dentritic epidermal T lymphocytes ( DETCs) in immune rejection of skin allograft in mice and its related mechanism. Methods (1) Full-thickness skin was harvested from back of one male wild type (WT) C57BL/6 mouse. Epithelial cells were isolated for detection of the expression of DETCs and their phenotype with flow cytometer. Another male WT C57BL/6 mouse was used to harvest full-thickness skin from the back. Epidermis was isolated for observation of the morphological characteristics of DETCs with immunofluorescence technology. (2) Four male green fluorescence protein (GFP)-marked C57BL/6 mice, 7 female WT C57BL/6 mice (group WT), and 7 female ybT lymphocytes 8 gene knock-out (GK) C57BL/6 mice (group GK) were used. Full-thickness skin in the size of 1.4 cm x 1.4 cm on the back of mice in groups WT and GK were excised, and the wounds were transplanted with full-thickness skin in the size of 1.2 cm x 1.2 cm obtained from male GFP-marked C57BL/6 mice. The survival time of skin grafts was affirmed with small animal in vivo imager and naked eyes and recorded. (3) Two male WT C57BL/6 mice were used to isolate epithelial cells. Cells were inoculated into 48-well plate and divided into activation group (A) and control group (C) according to the random number table, with 4 wells in each group. Cells in group A were treated with 10 pL concanavalin A in the concentration of 2 microg/mL for 24 hours, while those in group C with PBS in the same volume as that in group A. The expression of interferon y in DETCs was detected with flow cytometer. (4) Four male GFP-marked C57BL/6 mice were used as donors. Fourteen female WT C57BL/6 mice were used as receptors and divided into interferon gamma neutralizing group (IN) and control group (C) according to the random number table, with 7 mice in each group. The skin transplantation model of C57BL/6 male to C57BL/6 female was established as in part (2). Before surgery and 72 hours after, mice in group IN were intraperitoneally injected with 200 pL interferon y neutralizing antibody in the concentration of 1 mg/mL, and those in group C with normal saline in the same volume as that in group IN. The survival time of skin grafts was observed and recorded using the methods in part (2), and the result of group IN was compared with that of group GK in part (2). The survival curve of skin grafts was processed with Log-rank ( Mantel-Cox) test. Results (1) The positive expression rate of DETCs in epithelial cells of skin in mouse was 7.27%, and they were all CD3 cells. DETCs were found to be scattered in the epidermis of skin in mouse with dendritic morphology. (2) The survival time of skin grafts of mice in group GK was 22-35 d, obviously longer than that in group WT (12-16 d, y2 = 14. 10 , P < 0.001). (3) Expression of interferon gamma was detected in 22. 70% DETCs in group A, which was obviously higher than that in group C (0.51%). (4) The survival time of skin grafts of mice in group IN was 19-24 d, which was obviously longer than that in group C (12-16 d, chi 2 = 13.60, P < 0.001) but close to that in group GK as in part (2) (chi2 = 0.06, P = 0.810). Conclusions DETCs are involved in promotion of immune rejection of skin allograft probably by secretinf interferon gamma.
Allografts ; Animals ; Epidermis ; Female ; Graft Survival ; immunology ; physiology ; Interferon-gamma ; immunology ; metabolism ; Lymphocytes ; Male ; Mice ; Mice, Inbred C57BL ; Skin ; Skin Transplantation ; T-Lymphocytes ; immunology

The OPG/RANKL/RANK system plays an important role in osteoclastogenesis and represents a great progress in bone biology. RANKL, which expresses on the surface of osteoblast/stromal cells and activated T cells, binds to RANK on the osteoclastic precursors or mature osteoclasts, and promotes osteoclastogenesis and bone resorption. While osteoprotegerin (OPG), which is expressed by osteoblasts/stromal cells, strongly inhibits bone resorption by binding to its ligand RANKL and thereby blocks the interaction between BANKL and RANK. A number of cytokines and hormones exert their effects on bone metabolism by regulating the OPG/RANKL ratio in the bone marrow microenvironment. RANK is also expressed on mammary epithelial cells and RANKL expression in these cells is induced by pregnancy hormones, RANKL and RANK are essential for the formation of the lactating mammary gland and the transmission of maternal calcium to neonates in mammalian species. Modulation of these systems provides a unique opportunity to develop novel therapeutics to inhibit bone loss in osteoporosis, rheumatoid arthritis, and bone metastasis of cancer. Further research should be focused on the cooperation of OPG/RANKL/RANK system with other signal pathways and the interactions among bone remodeling, immune system and endocrinology system. Currently, the development of OPG analogues or compounds which may stimulate OPG expression is becoming an attractive industry which may be profitable to both patients and manufacturers.
Animals ; Bone Resorption ; immunology ; metabolism ; Humans ; Osteoclasts ; cytology ; metabolism ; pathology ; Osteogenesis ; drug effects ; genetics ; immunology ; Osteoprotegerin ; metabolism ; physiology ; RANK Ligand ; metabolism ; physiology ; Receptor Activator of Nuclear Factor-kappa B ; metabolism ; pharmacology ; physiology ; T-Lymphocytes ; drug effects ; immunology

How follicular T-helper (Tfh) cells develop is incompletely understood. We find that, upon antigen exposure in vivo, both naïve and antigen-experienced T cells sequentially upregulate CXCR5 and Bcl6 within the first 24 h, relocate to the T-B border, and give rise to phenotypic Bcl6(+)CXCR5(+) Tfh cells before the first cell division. CXCR5 upregulation is more dependent on ICOS costimulation than that of Bcl6, and early Bcl6 induction requires T-cell expression of CXCR5 and, presumably, relocation toward the follicle. This early and rapid upregulation of CXCR5 and Bcl6 depends on IL-6 produced by radiation-resistant cells. These results suggest that a Bcl6(hi)CXCR5(hi) phenotype does not automatically define a Tfh lineage but might reflect a state of antigen exposure and non-commitment to terminal effector fates and that niches in the T-B border and/or the follicle are important for optimal Bcl6 induction and maintenance.
Animals ; CD40 Ligand ; metabolism ; Cell Differentiation ; physiology ; DNA-Binding Proteins ; metabolism ; Inducible T-Cell Co-Stimulator Protein ; metabolism ; Interleukin-6 ; metabolism ; Mice ; Proto-Oncogene Proteins c-bcl-6 ; Receptors, CXCR5 ; metabolism ; T-Lymphocytes, Helper-Inducer ; metabolism

Sphingosine 1-phosphate (S1P), a bioactive lipid produced by metabolism of sphingolipid, plays an important roles in the regulation of various biological responses. T cell expresses the S1P receptors, including S1P1, S1P2, S1P3, S1P4 and S1P5. Activation of S1P signal regulates multiple immunological functions of T cell, including proliferation, apoptosis, differentiation, migration and cytokine excretion. FTY720, a sphingosine analog, suppresses the S1P signal resulting in redistribution of lymphocytes from circulation to secondary lymphoid tissues, which has been applied as a potent immunosuppressive drug. In this paper, biosythesis and degradation of S1P, S1P receptor and its mediated signal pathway, S1P receptor expression of T-cells, regulation of S1P on T cell functions and immunosuppresion drugs involving S1P signal pathway were reviewed.
Fingolimod Hydrochloride ; Humans ; Immunosuppressive Agents ; pharmacology ; Lysophospholipids ; metabolism ; physiology ; Propylene Glycols ; pharmacology ; Receptors, Lysosphingolipid ; metabolism ; physiology ; Signal Transduction ; drug effects ; Sphingosine ; analogs & derivatives ; metabolism ; pharmacology ; physiology ; T-Lymphocytes ; drug effects ; immunology ; physiology