We have previously clarified that emedastine, a second-generation antihistamine drug, inhibits T helper 1(Th1)/Th2 cell differentiation mediated by Langerhans cells (LCs). In addition, although we have recently found that mast cells also function as antigen-presenting cells (APCs) and induce Th1/Th2 cell differentiation, any influence of emedastine on this function remained unclear. Here we investigated the influence of emedastine on Th1/Th2 cell differentiation via mast cells. Mast cells were obtained by long-term culture of murine splenocytes in medium supplemented with tumor necrosis factor (TNF)-α. The mast cells were then incubated in the presence or absence of emedastine, and cultured with naïve CD4+ T cells in the presence of ovalbumin (OVA) peptide. Five days later, Th cells in the culture were stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, and Th1/Th2 cytokine production was examined by enzyme-linked immunosorbent assay. When mast cells treated with emedastine were used as APCs, production of interferon (IFN)-γ and interleukin (IL)-4 from activated Th cells was significantly suppressed. This suppression was associated with inhibition of CD86 expression on mast cells, and mast cells treated with emedastine were shown to obstruct the differentiation of both Th1 and Th2 cells by down-regulating their cell surface expression of CD86. The present data provide additional information that topical application of emedastine to the lesional skin of patients with atopic dermatitis (AD) would reduce not only LC- but also mast cell-mediated skin inflammation.

In this study, we investigated the effects of the artificial photoperiods that mimic summer (16L:8D; 16 h Light: 8 h Dark) and winter (8L:16D) solstices, equinoxes (12L:12D), and the artificial 24-h light regimen (24L:0D) on the leukocyte populations and the T helper and regulatory type responses on rainbow trout (Oncorhynchus mykiss). Using flow cytometry analysis, we found that photoperiod induces changes in head kidney leukocyte subsets. The lymphoid subset increased in the 16L:8D summer solstice regime. The analysis using antibodies against B and T cells showed the increase of CD4-1+ T lymphocytes and other unidentified lymphoid cells, with no changes in the B cells. To investigate the modulatory influence of the photoperiod on the fish T cell response, we quantified in the head kidney the transcript levels of genes involved in the Th1 type response (t-bet, ifn-ƴ, il-12p35, il-12p40c), Th2 type response (gata3, il-4/13a), Th17 response (ror-ƴt, il-17a/f), T regulatory response (foxp3α, il-10a, tgf-β1), and the T cell growth factor il-2. The results showed that the seasonal photoperiod alone has a limited influence on the expression of these genes, as the only difference was observed in il-14/13a and il-10a transcripts of fish kept on the 16L:8D regimen. In addition, the 24L:0D treatment used in aquaculture produces a reduction of il-14/13a and il-17a/f. We also evaluated the effect of photoperiod in the presence of an antigenic stimulus. Thus, in fish immunized with the recombinant viral protein 1 (rVP1) of infectious pancreatic necrosis virus (IPNV), the photoperiod had a striking influence on the type of adaptive immune response. Each photoperiod fosters a unique immune signature of antigenic response. A classical type 1 response is observed in fish subjected to the 16L:8D photoperiod. In contrast, fish in the 12L:12D photoperiod showed only the upregulation of il-12p40c. Furthermore, none of the cytokines were increased in fish maintained on the artificial 24L:0D regimen, and a decrease in the master transcription factors (t-bet, ror-ƴt, and foxp3α) was observed. Thus, fish on the 12L:12D and 24L:0D photoperiod appear hyporesponsive regarding the T cell response. Altogether, this study showed that photoperiods modify the magnitude and quality of the T-helper response in rainbow trout and thus impact essential mechanisms for the generation of immune memory and protection against microorganisms.

Over the past few years, Th17 cells is considered a key player in osteoporosis pathogenesis. Although extensively studied in murine models, comprehensive Th17 cell characterization in osteoporotic women is elusive. We thus aimed to examine peripheral Th17 cells frequency and phenotypes in healthy and osteoporotic women. Our results demonstrated that Th17 cells were primarily CD4+CD45RA-CCR7-HALDR+CCR6lowT-cells. Compared to Pre-N, Post-L showed increased proportion of Th17 with concomitant decrease in Th1 cells. The Th17 cells frequency in effector memory CD4+ T cells was significantly elevated in Post-N with a decrease of Th1 cells in effector memory subsets compared to Pre-N and Post-L. Both Post-N and Post-L had decreased frequency of dual positive Th1-Th17 cells and increased HLA-DR expression on Th17 cells compared to Pre-N. Thus, our study demonstrates increased Th17 cells frequency and reduced Th1 cells frequency with effector memory phenotype in postmenopausal women with estrogen insufficiency and correlates with aging process.

This review offers a systematic understanding about how polyphenols target multiple inflammatory components and lead to anti-inflammatory mechanisms. It provides a clear understanding of the molecular mechanisms of action of phenolic compounds. Polyphenols regulate immunity by interfering with immune cell regulation, proinflammatory cytokines\' synthesis, and gene expression. They inactivate NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and modulate mitogen-activated protein Kinase (MAPk) and arachidonic acids pathways. Polyphenolic compounds inhibit phosphatidylinositide 3-kinases/protein kinase B (PI3K/AkT), inhibitor of kappa kinase/c-Jun amino-terminal kinases (IKK/JNK), mammalian target of rapamycin complex 1 (mTORC1) which is a protein complex that controls protein synthesis, and JAK/STAT. They can suppress toll-like receptor (TLR) and pro-inflammatory genes\' expression. Their antioxidant activity and ability to inhibit enzymes involved in the production of eicosanoids contribute as well to their anti-inflammation properties. They inhibit certain enzymes involved in reactive oxygen species ROS production like xanthine oxidase and NADPH oxidase (NOX) while they upregulate other endogenous antioxidant enzymes like superoxide dismutase (SOD), catalase, and glutathione (GSH) peroxidase (Px). Furthermore, they inhibit phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) leading to a reduction in the production of prostaglandins (PGs) and leukotrienes (LTs) and inflammation antagonism. The effects of these biologically active compounds on the immune system are associated with extended health benefits for different chronic inflammatory diseases. Studies of plant extracts and compounds show that polyphenols can play a beneficial role in the prevention and the progress of chronic diseases related to inflammation such as diabetes, obesity, neurodegeneration, cancers, and cardiovascular diseases, among other conditions.

The interferon-inducible transmembrane (Ifitm/Fragilis) genes encode homologous proteins that are induced by IFNs. Here, we show that IFITM proteins regulate murine CD4+ Th cell differentiation. Ifitm2 and Ifitm3 are expressed in wild-type (WT) CD4+ T cells. On activation, Ifitm3 was downregulated and Ifitm2 was upregulated. Resting Ifitm-family-deficient CD4+ T cells had higher expression of Th1-associated genes than WT and purified naive Ifitm-family-deficient CD4+ T cells differentiated more efficiently to Th1, whereas Th2 differentiation was inhibited. Ifitm-family-deficient mice, but not Ifitm3-deficient mice, were less susceptible than WT to induction of allergic airways disease, with a weaker Th2 response and less severe disease and lower Il4 but higher Ifng expression and IL-27 secretion. Thus, the Ifitm family is important in adaptive immunity, influencing Th1/Th2 polarization, and Th2 immunopathology.

BACKGROUND: Excessive drinkers (ED) and patients with alcoholic liver disease (ALD) are several times more susceptible to bacterial and viral infections and have a decrease in antibody responses to vaccinations. Follicular helper T (TFH) cells are essential to select B cells in the germinal center and to produce antibodies. TFH cells express both a membrane-associated and a soluble form of CD40 ligand (sCD40L); in which the latter form is released to circulation upon T cell activation. The effect of alcohol on TFH cells has not been studied.
OBJECTIVE: The goals of this study are to determine the levels of TFH and T helper 1 (Th1) cells in ED and those with alcoholic cirrhosis (AC) when compared to healthy controls and to determine the prognostic significance of sCD40L in a cohort of patients with AC.
METHODS: Controls, ED, and those with AC were enrolled. Baseline demographic, laboratory tests, and peripheral blood mononuclear cells (PBMCs) were isolated and assessed via flow cytometry for TFH cells. In vitro study was performed to determine the ability of PBMCs to secrete interferon (IFN)-γ upon stimulation. Serum sCD40L were also determined and its prognostic significance was tested in a cohort of AC patients.
RESULTS: The levels of circulating TFH (cTFH) cells were significantly lower in peripheral blood of subjects with ED and AC compared to controls (P<0.05). IFN-γ secretion from PBMCs upon stimulation was also lower in ED and those with cirrhosis. Serum sCD40L was significantly lower in ED and AC when compared to that in controls (P<0.0005). Its level was an independent predictor of mortality.
CONCLUSIONS: Patients with AC had significantly lower level of cTFH and sCD40L. The level of sCD40L was an independent predictor of mortality in these patients.

BACKGROUND: The occurrence of malignant lymphoma after delivery is an extremely rare event. Although several cases of Hodgkin lymphoma and B cell lymphoma and a few cases of peripheral T cell lymphoma (PTCL) after delivery have been reported, there are no report of autopsy cases of PTCL in the puerperal period.
METHODS: A 32-year-old Japanese woman with a past medical history of atopic dermatitis and bronchial asthma presented with generalized eruptions four days after the delivery of her first child; generalized skin induration and lymphadenopathy subsequently emerged. A skin biopsy specimen showed the diffuse proliferation of atypical lymphoid cells that were immunohistochemically-positive for CD4 but negative for CD8. She was diagnosed as PTCL, not otherwise specified (PTCL, NOS). She died one year and three months after the onset of symptoms. At autopsy, the systemic infiltration of lymphoma cells into the whole body was observed. Unexpectedly, these lymphoma cells were immuno-reactive with CD8 but not with CD4.
CONCLUSIONS: The occurrence and development of PTCL after delivery with the shift from CD4 positivity to CD8 positivity may be associated with not only the selection of resistant subclone as a result of chemotherapy but also the changes of immune status before and after delivery.

Adenovirus serotype 5 (Ad5) is one of the most widely used viral vectors and is known to generate potent T cell responses. While many previous studies have characterized Ad5-induced CD8 T cell responses, there is a relative lack of detailed studies that have analyzed CD4 T cells elicited by Ad5 vaccination. Here, we immunized mice with Ad5 vectors encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) and examined GP-specific CD4 T cell responses elicited by Ad5 vectors and compared them to those induced by an acute LCMV infection. In contrast to LCMV infection, where balanced CD4 T helper 1 (Th1) and T follicular helper (Tfh) responses were induced, Ad5 immunization resulted in a significantly reduced frequency of Th1 cells. CD4 T cells elicited by Ad5 vectors expressed decreased levels of Th1 markers, such as Tim3, SLAM, T-bet, and Ly6C, had smaller amounts of cytotoxic molecules like granzyme B, and produced less interferon gamma than CD4 T cells induced by LCMV infection. This defective CD4 Th1 response appeared to be intrinsic for Ad5 vectors and not a reflection of comparing a nonreplicating vector to a live viral infection, since immunization with a DNA vector expressing LCMV-GP generated efficient CD4 Th1 responses. Analysis at early time points (day 3 or 4) after immunization with Ad5 vectors revealed a defect in the expression of CD25 (interleukin-2 [IL-2] receptor alpha chain) on Ad5-elicited CD4 T cells, and administration of exogenous IL-2 following Ad5 immunization partially restored CD4 Th1 responses. These results suggest that impairment of Th1 commitment after Ad5 immunization could be due to reduced IL-2-mediated signaling.IMPORTANCE During viral infection, generating balanced responses of Th1 and Tfh cells is important to induce effective cell-mediated responses and provide optimal help for antibody responses. In this study, to investigate vaccine-induced CD4 T cell responses, we characterized CD4 T cells after immunization with Ad5 vectors expressing LCMV-GP in mice. Ad5 vectors led to altered effector differentiation of LCMV GP-specific CD4 T cells compared to that during LCMV infection. CD4 T cells following Ad5 immunization exhibited impaired Th1 lineage commitment, generating significantly decreased Th1 responses than those induced by LCMV infection. Our results suggest that suboptimal IL-2 signaling possibly plays a role in reduced Th1 development following Ad5 immunization.