Disproportion of helper T cell subsets in peripheral blood of patients with primary Sjögren's syndrome

We studied the proportions of Th1 and Th2 cells in peripheral blood of 15 patients with primary Sj?gren's syndrome (p-SS), by using a procedure to enumerate the cells synthesizing cytokines such as INF-gamma or IL-4 in cytoplasm of CD4+ lymphocytes. The frequency of Th1 (INF-gamma containing) cells in p-SS patients was significantly reduced as compared to normal control (20.57+/-7.48% vs 28.78+/-11.56%, p < 0.05), while that of Th2 (IL-4 containing) cells was not different from normal control (3.33+/-0.98% vs 2.85+/-1.88%). The ratio of Th1 to Th2 cells in p-SS patients was significantly decreased as compared to normal control (6.60+/-3.15 vs 11.55+/-6.72, p < 0.05). There was no difference in frequency of Th1 or of Th2 cells between 8 patients given small amounts of prednisolone (PSL) and 7 patients not given PSL (21.44+/-9.39% vs 19.57+/-5.05%, 3.12+/-0.80% vs 3.56+/-1.17%). The percentage of Th1 cells was not different between 7 patients with glandular symptoms (G) and 8 patients with extraglandular symptoms (EG) (18.61+/-9.63% vs 22.27+/-5.02%). Although the frequency of Th2 cells was higher in EG-patients than that in G-patients (3.84+/-0.78% vs 2.74+/-0.86%) with tendency of elevated IgG level in sera, the ratio of Th1 to Th2 cells was not different among them (6.26+/-2.84 vs 6.99+/-3.64). These results suggest that the reduced ratio of Th1 to Th2 cells is essential and is related to the dysfunction of cellular immunity in p-SS.     

Regulatory T cells but not T helper 17 cells are modulated in an animal model of Graves’ hyperthyroidism

Graves’ disease (GD) involves auto-immunity against thyroid cell antigens, but the reasons for the induction of auto-immunity are uncertain. We wished to investigate the role of T helper 17 (Th17) and regulatory T cells (Treg) in a mouse model of Graves’ hyperthyroidism. The model was generated by immunizing mice with adenovirus expressing the autoantigen thyroid-stimulating hormone receptor (Ad-TSHR289). The frequencies of splenic Th17 and Treg were determined by flow cytometry. The levels of interleukin-17(IL-17), forkhead box P3 (Foxp3), and orphan retinoic acid nuclear receptor (RORγt) mRNA were determined by real-time PCR. The number of CD4⁺CD25⁺Foxp3⁺ T lymphocyte was significantly reduced in the Ad-TSHR289 group compared with the Ad-control (P < 0.05). mRNA level for Foxp3 was less abundant in Ad-TSHR289 group compared with Ad-control (P < 0.05). However, CD4⁺IL-17⁺ T-cell subpopulation and expression of RORγt mRNA did not differ significantly between Ad-TSHR289 and Ad-control groups (P > 0.05). Nevertheless, in Ad-TSHR289 group, a profound increase in the Th17/Treg ratios was found. The present study demonstrates that Th17 is not involved in promoting Graves’ hyperthyroidism, while Treg and the ratio of Th17/Treg might play a role in the pathogenesis of Graves’ hyperthyroidism.     

T helper type 1 cells in asthma: friend or foe?

A large body of research supports a pathogenic role for T helper 2 cells in asthma, although T helper 1 cell-type responses may also contribute. Using the principle of T helper cell cross-regulation, investigators have attempted to regulate the pathological effects of T helper 2 cells using regimens that may promote T helper 1 cell-type inflammation. In this review, we propose that the use of factors that promote T helper 1 cell differentiation and activation to treat asthma may be counterproductive, and that alternate regulatory approaches should be explored.     

Specific microbiota enhances intestinal IgA levels by inducing TGF-β in T follicular helper cells of Peyer's patches in mice

In humans and mice, mucosal immune responses are dominated by IgA antibodies and the cytokine TGF-β, suppressing unwanted immune reactions but also targeting Ig class switching to IgA. It had been suggested that eosinophils promote the generation and maintenance of mucosal IgA-expressing plasma cells. Here, we demonstrate that not eosinophils, but specific bacteria determine mucosal IgA production. Co-housing of eosinophil-deficient mice with mice having high intestinal IgA levels, as well as the intentional microbiota transfer induces TGF-β expression in intestinal T follicular helper cells, thereby promoting IgA class switching in Peyer's patches, enhancing IgA⁺ plasma cell numbers in the small intestinal lamina propria and levels of mucosal IgA. We show that bacteria highly enriched for the genus Anaeroplasma are sufficient to induce these changes and enhance IgA levels when adoptively transferred. Thus, specific members of the intestinal microbiota and not the microbiota as such regulate gut homeostasis, by promoting the expression of immune-regulatory TGF-β and of mucosal IgA.     

A three-cell model for activation of naïve T helper cells

It is generally assumed that the activation of naïve T helper (Th) cells is the result of a two‐cell interaction between the Th cell and a dendritic cell (DC) and that three signals are required. Signal one or stimulation is the recognition by the T‐cell receptor (TCR) of antigenic peptides presented by major histocompatibility complex (MHC) class II molecules. Signal two or co‐stimulation is mainly provided by the triggering of CD28 on the T cell by CD80 and CD86 molecules on the DC. Signal three or polarization directs T‐cell differentiation into various effector phenotypes such as Th1 and Th2. Both signals, two and three, are often assumed to result from the binding of microbial products or endogenous molecular danger signals to germline‐encoded receptors such as toll‐like receptors (TLR) on the DC. However, recent data challenge this two‐cell model by revealing that Th1 polarization requires the presence of interferon‐γ (IFN‐γ) provided by a third cell. I propose here a three‐cell model for naïve Th‐cell activation. In this model, delivery of signal three by the DC is dependent on help provided by other innate immune cells such as NK cells, NK T cells, γδ T cells, mast cells, eosinophils and basophils. The rationale behind this model is that the innate immune system has been designed by evolution to select an appropriate class of immune response to protect the host.     

Histamine and T helper cytokine–driven epithelial barrier dysfunction in allergic rhinitis

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Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells

Follicular T helper (Tfh) cells provide critical help to B cells for germinal center (GC) formation. Mutations affecting SLAM-associated protein (SAP) prevent GC formation because of defective T?cell-B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in?vitro differentiation of functionally competent "Tfh-like" cells that expressed interleukin-21, Tfh cell markers, and Bcl6 and rescued GC formation in SAP-deficient hosts better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wild-type, yet failed to support GCs in?vivo. Interestingly, both Tfh-like and in?vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, Th1, Th2, and Th17 cells could be reprogrammed to obtain Tfh cell characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3, and Rorc in Tfh-like and ex?vivo Tfh cells and on Bcl6 in non-Tfh cells, supporting the concept of plasticity between Tfh and other Th cell populations.     

Mapping the T helper cell response to acid α-glucosidase in Pompe mice

Pompe disease is a neuromuscular disease caused by an inherited deficiency of the lysosomal enzyme acid α-glucosidase (GAA). The resulting accumulation of glycogen causes muscle weakness with the severe form of the disease resulting in death by cardiorespiratory failure in the first year of life. The only available treatment, enzyme replacement therapy (ERT) with recombinant GAA (rhGAA), is severely hampered by antibody responses that reduce efficacy and cause immunotoxicities. Currently, Pompe mice represent the only pre-clinical model for development of new treatments and for immunological studies. While antibody formation following ERT in this model has been described, the underlying T cell response has not been studied. In order to define the T helper response to rhGAA in Pompe mice, immunodominant CD4(+) T cell epitopes were mapped in GAA(-/-) 129SVE mice using ELISpot. Additionally, cytokine responses and antibody formation against rhGAA during ERT were measured. Among the three CD4(+) T cell epitopes identified, only epitope IFLGPEPKSVVQ, predicted to be the strongest MHC II binder, consistently contributed to IL-4 production. Frequencies of IL-4 producing T cells were considerably higher than those of IL-17 or IFN-γ producing cells, suggesting a predominantly Th2 cell mediated response. This is further supported by IgG1 being the prevalent antibody subclass against rhGAA during ERT and consistent with prior reports on IgE formation and anaphylaxis in this model. These results will facilitate mechanistic studies of the immune response to rhGAA in Pompe mice during development of new therapies and tolerance protocols.     

Enhancement of anti-Aspergillus T helper type 1 response by interferon-��-conditioned dendritic cells

Although data show the importance of type I interferons (IFNs) in the regulation of the innate and adaptive immunity elicited in response to viral, bacterial and parasitic infections, the functional activities of these cytokines during fungal infections are poorly understood. We examined here the impact of IFN‐β on the response of human monocyte‐derived dendritic cells (DCs) infected in vitro with Aspergillus fumigatus. Having found that A. fumigatus‐infected DCs do not express IFN‐β, we evaluated the effect of the exogenous addition of IFN‐β on the maturation of human DCs induced by the infection with A. fumigatus conidia. Although the phagocytosis of the fungus was not affected by IFN‐β treatment, the expression of CD86 and CD83 induced upon A. fumigatus challenge was enhanced in IFN‐β‐conditioned DCs, which also showed an increased expression of IL‐27 and IL‐12p70, members of IL‐12 family. Through these modifications, IFN‐β improved the capacity of DCs to promote an anti‐Aspergillus T helper type 1 response, as evaluated by mixed leucocyte reaction, which plays a crucial role in the control of invasive aspergillosis. Our results identified a novel effect of IFN‐β on anti‐Aspergillus immune responses which, in turn, might open new perspectives on the use of IFN‐β in immunotherapy for fungal infections aimed at enhancing the immunological functions of DCs.     

Hepatitis B-specific T helper cell responses in uninfected infants born to HBsAg+/HBeAg? mothers

Vertically transmitted hepatitis B virus (HBV) usually causes chronic infection. While combined active–passive immunoprophylaxis in neonates of hepatitis B surface antigen-positive (HBsAg⁺) mothers at birth prevents vertical transmission, it is not yet clear whether neonates encounter the virus or its products in the absence of hepatitis B e antigen (HBeAg). This study was undertaken to investigate HBV antigen-specific T-cell responses in vaccinated neonates of HBsAg⁺/HBeAg⁻ mothers. Blood was collected from 46 HBsAg⁺ mothers and their neonates (subjects) as well as 24 age-matched controls. All neonates of HBsAg⁺ mothers received appropriate immunoprophylaxis, and HBsAg and hepatitis B surface antibody (anti-HBs) antibody titers were determined after completion of the vaccination course. Peripheral blood mononuclear cells (PBMCs) from infants at birth, 1 and 6 months of age were stimulated with recombinant HBsAg, hepatitis B core antigen (HBcAg) and mitogen, and interferon (IFN)-γ concentrations were determined by ELISA. HBsAg-induced production of IL-2, IL-5, IL-6 and IL-10 was assessed using a cytometric bead array kit on cells from 6-month-old neonates post-vaccination. All neonates were HBsAg⁻ and responded to vaccination. Increased IFN-γ production following HBcAg stimulation was seen in 30.4% of neonates born to HBsAg⁺/HBeAg⁻ mothers. Subjects demonstrated significantly higher IL-2 production post-HBsAg stimulation, whereas IL-5, IL-6 and IL-10 cytokine responses were not significantly different. Almost one-third of uninfected neonates developed viral antigen-induced IFN-γ production, suggesting that they had been exposed to virions or viral derivatives. This encounter, however, did not impair their T-cell responses to vaccination.     

T helper cell populations: As flexible as the skin?

T helper cells can be defined by the cytokines they produce and are divided into Th1, Th2, Th17, T(FH) or regulatory T cells. Th17 cells have been shown to produce, in addition to IL-17, IL-22. In the current issue of the European Journal of Immunology, an article by Larsen et al. (Eur. J. Immunol. 2011. 41: 2596-2605) provides evidence that human T helper cells, like murine cells, can also express IL-22 in the absence of the other T helper cell signature cytokines. Moreover, they show that these IL-22-producing cells, namely Th22 cells, can be found in the skin of psoriasis patients, where they might contribute to the pathogenesis of this inflammatory skin disease. Finally, they show that, molecularly, Th22 cells are related to Th17 cells, and might therefore be derived from the latter. In this Commentary, the development of the pro-inflammatory T helper populations in the skin are discussed and a model that explains the development of Th22 cells found in the skin of psoriasis patients is proposed.