T-helper Cell Type Research Articles

Type 1 Helper T Cells and FoxP3-positive T Cells in HIV–Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) induced by combination antiretroviral therapy (cART) has been attributed to dysregulated expansion of tuberculin PPD-specific IFN-gamma-secreting CD4(+) T cells. To investigate the role of type 1 helper T cell expansions and regulatory T cells in HIV-TB IRIS. Longitudinal and cross-sectional studies of Mycobacterium tuberculosis-specific IFN-gamma enzyme-linked immunospot responses and flow cytometric analysis of blood cells from a total of 129 adults with HIV-1-associated tuberculosis, 98 of whom were prescribed cART. In cross-sectional analysis the frequency of IFN-gamma-secreting T cells recognizing early secretory antigenic target (ESAT)-6, alpha-crystallins 1 and 2, and PPD of M. tuberculosis was higher in patients with TB-IRIS than in similar patients treated for both HIV-1 and tuberculosis who did not develop IRIS (non-IRIS; P <or= 0.03). The biggest difference was in the recognition of alpha-crystallin molecules: peptide mapping indicated a polyclonal response. Flow cytometric analysis indicated equal proportions of CD4(+) and CD8(+) cells positive for activation markers HLA-DR and CD71 in both patients with TB-IRIS and non-IRIS patients. The percentage of CD4(+) cells positive for FoxP3 (Forkhead box P3) was low in both groups (TB-IRIS, 5.3 +/- 4.5; non-IRIS, 2.46 +/- 2.46; P = 0.13). Eight weeks of longitudinal analysis of patients with tuberculosis who were starting cART showed dynamic changes in antigen-specific IFN-gamma-secreting T cells in both the TB-IRIS and non-IRIS groups: the only significant trend was an increased response to PPD in the TB-IRIS group (P = 0.041). There is an association between helper T-cell type 1 expansions and TB-IRIS, but the occurrence of similar expansions in non-IRIS brings into question whether these are causal. The defect in immune regulation responsible for TB-IRIS remains to be fully elucidated.

Combined Stimulation of Nasal Polyp Fibroblasts With Poly IC, Interleukin 4, and Tumor Necrosis Factor α Potently Induces Production of Thymus- and Activation-Regulated Chemokine

To examine the effects of cytokines and poly IC on the expression of thymus- and activation-regulated chemokine (TARC), a potent chemoattractant for helper T-cell type 2 (T(H)2) cells, in nasal polyp fibroblasts. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis. Academic research. Primary fibroblast lines were established from human nasal polyp biopsy tissue specimens (n = 5) removed at polypectomy. The expression of TARC messenger RNA (mRNA) was evaluated by real-time RT-PCR. The amount of TARC in the supernatants was measured by enzyme-linked immunosorbent assay. Combined stimulation with interleukin 4 (IL-4) and tumor necrosis factor alpha (TNF-alpha) or with poly IC and IL-4 induced TARC production. Combined exposure of cells to poly IC, IL-4, and TNF-alpha resulted in substantial amounts of TARC release into the culture medium. Quantitative RT-PCR analysis revealed that simultaneous stimulation with those 3 compounds induced a tremendous increase in the amount of TARC mRNA in the nasal polyp fibroblasts. Nasal polyp fibroblasts contribute to T(H)2 cell infiltration and RNA virus-induced exacerbation of T(H)2-type airway inflammatory conditions such as allergic chronic sinusitis.

Comparison of DNA- and mRNA-Transfected Mouse Dendritic Cells as Potential Vaccines against the Human Papillomavirus Type 16 associated Oncoprotein E7

Dendritic cells (DCs) mediate the generation of strong cytotoxic T-lymphocyte (CTL) responses by functioning in antigen presentation and exerting adjuvant properties. We compared several activation markers and parameters of biological activity of DNA- and mRNA-transfected DCs in vitro and in vivo. CpG-matured, bone marrow derived C57BL/6 mouse DCs were electroporated either with enhanced green fluorescence protein (EGFP) or human papillomavirus type 16 (HPV16) E7 expression plasmids or in vitro transcribed mRNAs encoding for the codon-optimized E7 or a shuffled version thereof. Activation marker expression and antigen presentation was analysed by fluorescence-activated cell sorting. The migratory behaviour of transfected DCs were investigated by in vitro chemotaxis experiments and cytokine expression by ELISA. CTL-priming capacity of transfected DCs were determined by vaccination of mice. mRNA transfection produced a two- to fourfold increase of the activation markers CD40, CD80, CD86 and MHC I and MHC II molecules. Predominately antigen-expressing DCs migrated after mRNA transfection. Furthermore, mRNA-transfected DCs were capable of inducing a chemokine gradient. After maturation, electroporation and activation with soluble CD40 ligand and interferon-y, DCs displayed a T-helper cell type 2 cytokine expression pattern. Nevertheless, E7-transfected DCs were able to prime E7-specific CTL responses in vivo. The highest E7-specific CTL frequencies were found in mice immunized with mRNA-transfected DCs. The in vitro expanded CTLs exerted functional E7-specific cytotoxic activity. Genetically modified DCs are suitable vehicles for the induction of E7-specific CTL responses in mice and hence could help to eradicate HPV-associated lesions in humans.

Modulation of ozone-induced airway hyperresponsiveness and inflammation by interleukin-13

The present study aimed to determine whether the T-helper cell type 2-derived cytokines, interleukin (IL)-4 and -13, can modulate the lung response to ozone exposure. IL-13(-/-), IL-4/13(-/-) and IL-13-overexpressing transgenic (Tg) mice were exposed to ozone (3 ppm; 3 h) or air. Wild-type (Wt) Balb/c mice and transgenic-negative littermates (IL-13Wt) were used as controls for gene-deficient and IL-13Tg mice, respectively. IL-4/13(-/-) and IL-13(-/-) mice developed a lesser degree of ozone-induced airway hyperresponsiveness (AHR) while IL-13Tg mice developed a greater degree of AHR compared with ozone-exposed wild-type or IL-13Wt mice, respectively. Ozone caused a time-dependent increase of bronchoalveolar lavage (BAL) neutrophils and macrophages in wild-type mice, maximal at 20-24 h, which was attenuated in the IL-13(-/-) and IL-4/13(-/-) mice. In IL-13Tg mice, there was a greater increase in BAL neutrophils after ozone exposure compared with IL-13Wt mice. Using quantitative real-time PCR, ozone-induced mRNA expression for IL-6 and keratinocyte chemokine was further enhanced in IL-13(-/-) and IL-4/13(-/-) mice, and was inhibited in IL-13Tg mice. Macrophage inflammatory protein (MIP)-3alpha/CCL20 expression was enhanced after ozone exposure in wild-type mice, inhibited in IL-13(-/-) and IL-4/13(-/-) mice, while in IL-13Tg mice it was enhanced. A similar pattern of expression was observed with lipopolysaccharide-induced cytokine (LIX/CXCL5/ENA-78) expression. In conclusion, interleukin-13 augments ozone-induced airway hyperresponsiveness and neutrophilic inflammation, possibly through modulation of certain cytokines induced by ozone exposure.

Effects of formoterol and salmeterol on the production of Th1- and Th2-related chemokines by monocytes and bronchial epithelial cells

It is unknown whether formoterol and salmeterol, two long-acting beta(2)-adrenoreceptor agonists, have regulatory functions in the production of T-helper cell (Th) type 2- and Th1-related chemokines by monocytes and bronchial epithelial cells. In the present study, the effects of formoterol and salmeterol on lipopolysaccharide (LPS)-induced expression of the Th2-related chemokine macrophage-derived chemokine (MDC; CCL22) and the Th1-related chemokine interferon-gamma-inducible protein (IP)-10 (CXCL10) were investigated in a monocytic cell line, THP-1, and in human primary monocytes. In addition, their effects on the expression of the Th2-related chemokine thymus- and activation-regulated chemokine (TARC; CCL17) were evaluated in an epithelial cell line, BEAS-2B. Formoterol enhanced MDC but suppressed IP-10 production in monocytes induced by LPS. Higher doses of salmeterol were required to enhance LPS-induced MDC expression in THP-1 cells. Formoterol and salmeterol could significantly suppress TARC expression in BEAS-2B cells. These effects could be reversed by a selective beta(2)-adrenoreceptor antagonist, ICI-118551. Formoterol- and LPS-induced MDC expression was inhibited by budesonide. Both long-acting beta(2)-adrenoreceptor agonists suppressed thymus- and activation-regulated chemokine expression in bronchial epithelial cells mediated via beta(2)-adrenoreceptors. Formoterol at physiological concentrations could suppress lipopolysaccharide-induced T-helper cell type 1-related chemokine (interferon-gamma-inducible protein-10) but enhance T-helper cell type 2-related chemokine (macrophage-derived chemokine) expression in human monocytes. Long-acting beta(2)-adrenoreceptor agonists may increase T-helper cell type 2-related chemokine expression in monocytes and T-helper cell type 2 recruitment and, therefore, long-acting beta(2)-adrenoreceptor agonist monotherapy may not be an appropriate therapeutic option for asthma.

HIV and immune reconstitution disease in the wormy world

In tropical countries, notably sub-Saharan Africa, helminth infections are the most prevalent parasitic infection. These great immunomodulators have the ability to tip the balance towards T-helper cell type 2 immunity, to decrease vaccine responses, and influence the outcome of major tropical killers. For example, intestinal helminths seem to play a protective role against severe malaria by blunting proinflammatory cytokines [1]. On the contrary, there is a negative impact of helminths on the immunity and clinical course of tuberculosis [2]. Several conflicting studies have been published comparing viral loads and CD4 cell counts in HIV-infected individuals with and without helminths. It is currently not known whether helminths have any significant impact on the course of HIV infection. With the scaling up of antiretroviral use in poor countries, a growing number of individuals are undergoing treatment in areas of a high prevalence of helminth infection. When available, HAART is usually started at lower CD4 cell counts than in rich countries, where routine CD4 cell counts usually allow clinicians to start treatment before opportunistic infections occur. Given the poor diagnostic facilities of most health structures in the developing world, a number of patients start HAART while having a latent opportunistic infection. The combination of a very low CD4 cell count and undiagnosed infection at the start of HAART are ideal conditions for immune reconstitution disease (IRD) to occur. This can partly explain the very high mortality rate during the first year of HAART observed in numerous trials conducted in Africa. The incidence and mortality of IRD vary widely between publications. This is attributed to differences in the severity of immunodeficiency, the prevalence and intensity of co-infections when HAART is initiated, and maybe genetic factors [3]. We suggest the wide variation between estimates of the incidence and mortality of IRD could mirror the variation in the prevalence of helminth infections between different study sites. The postulated immune mechanism of IRD involves an imbalance between proinflammatory (IFN-γ) and homeostatic cytokines (IL-10), a mechanism that is significantly affected by helminth infections. Therefore, a simple prediction that would arise from the immunological impact of helminths is that helminth-infected HIV patients starting HAART would have less severe IRD than patients without helminths infected with the same pathogen at equivalent disseminations. Such knowledge may lead to important recommendations regarding the management of helminth infections during HAART initiation.

Th1 polarization of the immune response in uveitis in Behçet's disease

Background: It has been reported that abnormalities in the balance of T-helper cells type 1/2 (Th1/Th2) may account for the pathophysiology of human autoimmune diseases. The purpose of this study was to define the role of the Th1/Th2 balance in the pathogenesis of uveitis in Behçet's disease (BD). Methods: From February 2003 to August 2005, we studied 31 patients with active BD. Of these patients, 21 (12 female, 9 male; mean age 35.5 [SD 10] years) presented with acute uveitis, and 10 (7 female, 3 male; mean age 34 [SD 11] years) presented with inflammatory arthritis but no prior uveitis attack.The control group consisted of 10 (7 female, 3 male; mean age 34.7 [SD 8] years) age-matched, healthy individuals. CD4+ CD26+ and CD4+ CD30+ cell surface expression of the peripheral blood CD4+ T lymphocytes was evaluated by analytic flow cytometry in order to determine percentages of Th1 and Th2 lymphocyte subsets. Results: The mean percentage of CD4+ CD26+ and CD4+ CD30+ cells was 26.27 (SD 6.18) % and 2.56 (SD 0.82) %, 17.42 (SD 5.90) % and 2.86 (SD 0.72) %, and 14.99 (SD 3.96) % and 3.11 (SD 1.25) % in BD with active uveitis, BD with inflammatory arthritis but no prior uveitis attack, and control groups, respectively. T-helper 1 (Th1) cell percentage was significantly higher in the BD with active uveitis group than the BD with arthritis and no prior uveitis attack group ( p = 0.001). With respect to the percentage of CD30+ Th2 cells, there was no statistical difference between the 2 BD groups ( p = 0.529) or among the 3 groups ( p = 0.375). Interpretation: Th1 lymphocyte dominance in peripheral circulating blood may play a role in the pathogenesis of BD uveitis.

Pharmacokinetic/pharmacodynamic profile of mometasone furoate nasal spray: Potential effects on clinical safety and efficacy

Background: Mometasone furoate nasal spray (MFNS) is recommended as a first-line therapy for allergic rhinitis. The purpose of intranasal administration is to deliver maximally effective therapy to the affected nasal tissues while minimizing systemic exposure. Objective: This article reviews the pharmacokinetic and pharmacodynamic properties of MFNS, highlighting the potential clinical relevance of data concerning its glucocorticoid receptor binding, bioavailability, and metabolism, and its role in activating and suppressing transcription of steroid-dependent genes. Methods: A search of the MEDLINE and EMBASE databases (January 1995–July 2007) was undertaken to identify in vitro, preclinical, and clinical studies and review articles concerning MFNS. Searches were also conducted to identify articles on the pharmacokinetics, pharmacodynamics, and adverse effects of the intranasal corticosteroids discussed in this article. Pertinent abstracts from allergy society meetings and data from the author's research experience were also included. Results: The data reviewed indicate that MFNS has a number of qualities that are important in achieving nasal selectivity with minimal systemic adverse effects. For example, MFNS is stable in nasal tissues and is efficiently metabolized in the liver (AUC for a 400-μg dose: 127 fmol/mL · h). Its systemic bioavailability (0.46%is one of the lowest among currently available intranasal corticosteroids. Bioactive glucocorticoid metabolites have not been observed in humans. The results of immunologic studies suggest that MFNS may reverse the exaggerated T-helper cell type 2 (Th2)-related cytokine response seen in allergic disease through preferential inhibition of Th2 over the T-helper cell type 1-related cytokine. Conclusions: MFNS is an intranasal corticosteroid with a low potential for systemic adverse effects. The efficacy and safety profiles of MFNS seen in clinical use are consistent with its pharmacokinetic and pharmacodynamic properties.

Toll-like receptors, Notch ligands, and cytokines drive the chronicity of lung inflammation.

Current dogma supports the concept that the expression of a disease-inducing signature cytokine phenotype is important to the maintenance stage of chronic lung disorders. This cytokine phenotype has been characterized as a polarization toward type 2 cytokines, which are profibrotic and immunoregulatory. The biology of this latter activity could mechanistically explain pathogen-induced exacerbation of chronic lung inflammation, as a skewed cytokine profile in the lung alters dendritic cell function, activates fibroblasts, and facilitates a subsequent "second hit" by an infectious pathogen. In this setting, cytokine biology is also linked to Toll-like receptors (TLRs) in the maintenance of lung immunity, as the activity of this receptor-ligand system by both leukocytes and stromal cells is likely an important component of disease chronicity. The participation of dendritic cells via TLRs in chronic lung disease could facilitate communication circuits established between antigen-presenting cells and lymphocytes. Data suggest that TLR activation via myeloid differentiation factor 88 adaptor protein leads to the induction of a Notch ligand known as Delta-like-4 on dendritic cells that activate the Notch receptor on T cells, promoting a helper T-cell type 1 cytokine response. It is likely that the evolution of host defense signals designed to recognize patterns emitted from a hostile microbial environment may now be superimposed on adaptive immunity and provide the underpinning to support the maintenance of chronic lung disease.

Pulmonary dendritic cells: playing ball in the BAL?

The lung is one of the few organs in the human body where there is a continuous and extensive interaction between the environment and our immune system. With every breath we take, numerous airborne particles, both harmless as well as potentially dangerous, are inhaled into the airways. The big challenge for the pulmonary immune system is to discriminate the good from the bad and to react accordingly. Unnecessary action against harmless particles ( e.g. innocent antigens, self proteins) should be avoided, while a rapid and strong immune response is needed against potentially dangerous microorganisms. Pulmonary dendritic cells (DCs) are ideally suited to maintain this delicate balance between tolerance and active immune responses 1. DCs are antigen-presenting cells that play a central role in host immune defence, by linking innate with adaptive immune responses 2. They recognise danger signals from invading pathogens and are able to prime naive T-cells and to initiate appropriate T-cell immune responses against these microorganisms 3. Indeed, T-lymphocytes themselves are actually “blind” to unprocessed antigens, and require the assistance of antigen presenting cells, such as DCs and macrophages, to be able to recognise antigens. Moreover, by the release of inflammatory cytokines, DCs influence the polarisation of the adaptive T-cell response into either a T-helper cell type (Th)1-, Th2- or a T-regulatory cell-direction 4. This enables them not only to initiate active immune responses, but also to control and dampen these immune responses, as well as to avoid unwanted immune responses against …

Astrocytes stimulate interleukin‐17 and interferon‐γ production in vitro

Astrocytes play important roles in the complex and as yet not very well understood net of interactions among resident and infiltrating cells during central nervous system (CNS) inflammation. In such an intricate network, cytokines represent an essential means for intercellular communication, and astrocytes are able to affect their generation and/or release. Among various cytokines produced by infiltrating cells, interferon (IFN)-gamma and interleukin (IL)-17 are the focus of this research, because they are pivotal cytokines of helper T-cell type 1 (Th1) and helper T-cell type 17 (Th17), respectively. Importantly, both Th1 and Th17 cells, as well as their cytokines, have been shown to be of importance for the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of a prototypical CNS disease with inflammatory pathogenesis, multiple sclerosis. Therefore, the influence of astrocytes on the generation of IFN-gamma and IL-17 in concanavalin A- and myelin basic protein-stimulated lymph node cells of healthy rats and rats with developing EAE, respectively, was investigated in vitro. Astrocytes up-regulated IL-17 and IFN-gamma gene expression and protein synthesis in T cells, which coincided with astrocytes' ability to express IL-23 subunit p19 and common IL-12/IL-23 subunit p40 but not IL-12 subunit p35 in the co-cultivations. These results suggest one more way in which astrocytes could contribute to the complex interactions during CNS inflammation.

Associations of IL-2 and IL-4 gene polymorphisms with psoriasis in the Korean population

Psoriasis is association with an overexpression of T-helper cell type 1(Th1) cytokines and relative underexpression of Th2 cytokines. The cytokine production is under genetic control, and certain allelic variants of cytokine genes are associated with higher or lower cytokine production in vitro and in vivo. We aimed to evaluate association of cytokine genes polymorphisms with psoriasis in the Korean population. We investigated the polymorphisms of IL-2 -330, IL-4 -590, IL-4 receptor +1902, IL-10 -1082 and -819, and IFN-gamma intron 1 in 114 psoriasis patients and 281 healthy normal controls in Korean. IL-2 -330*G and IL-4 -590*C alleles significantly increased in psoriasis patients, especially late-onset group, compared to the control. The combined effect of IL-2 -330*G and IL-4 -590*C showed that the positive combination of IL-2 -330*G and IL-4 -590*C alleles were more significantly associated with the late-onset group of psoriasis patients than the controls. These results suggest that the genetic polymorphisms of IL-2 and IL-4 genes can be susceptible to psoriasis in Korean, especially late-onset psoriasis group.

Aerobic Exercise Decreases Chronic Allergic Lung Inflammation and Airway Remodeling in Mice

Aerobic conditioning improves exercise capacity and decreases symptoms in patients with asthma. However, its benefits in the context of allergic airway inflammation are poorly understood. To evaluate the effects of two intensities of aerobic exercise on airway inflammation and remodeling in a model of chronic allergic lung inflammation. Mice were subjected to chronic ovalbumin (OVA) sensitization and to 4 weeks of low (OVA+Low) or moderate (OVA+Mod) exercise training in a treadmill. Airway inflammation and remodeling and expression of helper T-cell type 1 and 2 cytokines were evaluated. OVA-induced allergic airway inflammation and remodeling were characterized by an increase in collagen (288%), elastic fiber (56%), smooth muscle (380%), and epithelial (402%) contents (P < 0.001) when compared with the control group. OVA+Low and OVA+Mod groups presented a decrease in bronchoalveolar lavage fluid eosinophils (respectively, 84 and 75%; P < 0.01) and airway walls (respectively, 94 and 58%; P < 0.001) when compared with the OVA group. OVA+Low and OVA+Mod groups also presented a reduction in the number of peribronchial inflammatory cells expressing IL-4 (respectively, 85 and 75%; P < 0.01) and IL-5 (respectively, 88 and 89%; P < 0.01) when compared with the OVA group. Aerobic conditioning did not change the expression of either IFN-gamma or IL-2 by inflammatory cells or plasma levels of IgE or IgG1. OVA+Low and OVA+Mod groups presented an increase in the expression of IL-10 (P < 0.001). Low and moderate aerobic conditioning also reduced airway remodeling in OVA-sensitized mice when compared with the OVA group. We concluded that low and moderate aerobic exercise decreases airway inflammation and remodeling in a murine model of asthma.

Suppressive effects of ketotifen on Th1‐ and Th2‐related chemokines of monocytes

Ketotifen is a mast cell stabilizer and useful in younger children with allergic diseases such as asthma and allergic rhinitis. Macrophage-derived chemokine (MDC) is a T-helper cell type 2 (Th2)-related chemokine involved in recruitment of Th2 cells toward allergen-challenged inflammation. However, the Th1-related chemokines, interferon-inducible protein 10 (IP-10)/CXCL10, and the monokine induced by interferon-gamma (MIG)/CXCL9 are also important in allergen-induced asthma in animal models. We investigated the effects of ketotifen on the expression of Th1- and Th2-related chemokines of human monocytes in vitro and ex vivo. Ketotifen (5-50 microM) significantly down-regulated lipopolysaccharide (LPS)-induced MDC, MIG and IP-10 (p < 0.05, each comparison) in THP-1 cells and human primary monocytes in a dose-dependent manner. SB203580 [p38-mitogen-activated protein kinase (MAPK) inhibitor] suppressed LPS-induced MDC and IP-10 expression, and PD98059 (ERK-MAPK inhibitor) could only suppress LPS-induced IP-10, but not MDC expression. LPS-induced pp38 and p-ERK expression of THP-1 monocytic cells was suppressed by ketotifen. These data demonstrate that ketotifen is effective in down-regulating LPS-induced MDC, MIG and IP-10, which play important roles in the pathogenesis of airway inflammation. The suppressive effect on MDC and IP-10 may, at least in part, involve the down-regulation of LPS-induced p38 and ERK-MAPK expression.

The development of sarcoidosis with the use of alemtuzumab – clues to T‐cell immune reconstitution

The development of sarcoidosis with the use of alemtuzumab – clues to T‐cell immune reconstitution

Effect of choline chloride in allergen-induced mouse model of airway inflammation

The incidence of asthma has increased the world over, and current therapies for the disease suffer from potential side-effects. This has created an opportunity to develop novel therapeutic approaches. Here, the anti-inflammatory activity of choline was investigated in a mouse model of allergic airway inflammation. Choline (1 mg.kg(-1)) was administered via oral gavage or intranasally before and after ovalbumin (OVA) challenge in sensitised mice. Airway hyperresponsiveness (AHR) to methacholine was measured in the mice by whole-body plethysmography. Type-2 T-helper cell cytokine and leukotriene levels were estimated in bronchoalveolar lavage fluid (BALF) and spleen culture supernatant by ELISA. Eosinophil peroxidase activity was also determined in the BALF supernatant. Choline treatment in sensitised mice before OVA challenge via oral/intranasal routes significantly inhibited eosinophilic airway inflammation and eosinophil peroxidase activity. It also reduced immunoglobulin E and G1 production and inhibited the release of type-2 T-helper cell cytokines and leukotrienes. However, the development of AHR was prevented effectively by intranasal choline treatment. Most importantly, choline treatment after OVA challenge by both routes could reverse established asthmatic conditions in mice by inhibiting AHR, eosinophilic airway inflammation and other inflammatory parameters. This study provides a new therapeutic approach for controlling as well as preventing asthma exacerbations.

Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death

Regulated glycosylation controls T cell processes, including activation, differentiation and homing by creating or masking ligands for endogenous lectins. Here we show that stimuli promoting T helper type 1 (TH1), TH2 or interleukin 17-producing T helper (TH-17) differentiation can differentially regulate the glycosylation pattern of T helper cells and modulate their susceptibility to galectin-1, a glycan-binding protein with anti-inflammatory activity. Although TH1- and TH-17-differentiated cells expressed the repertoire of cell surface glycans critical for galectin-1-induced cell death, TH2 cells were protected from galectin-1 through differential sialylation of cell surface glycoproteins. Consistent with those findings, galectin-1-deficient mice developed greater TH1 and TH-17 responses and enhanced susceptibility to autoimmune neuroinflammation. Our findings identify a molecular link among differential glycosylation of T helper cells, susceptibility to cell death and termination of the inflammatory response.

Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major

CD4+ T cells have a crucial role in mediating protection against a variety of pathogens through production of specific cytokines. However, substantial heterogeneity in CD4+ T-cell cytokine responses has limited the ability to define an immune correlate of protection after vaccination. Here, using multiparameter flow cytometry to assess the immune responses after immunization, we show that the degree of protection against Leishmania major infection in mice is predicted by the frequency of CD4+ T cells simultaneously producing interferon-gamma, interleukin-2 and tumor necrosis factor. Notably, multifunctional effector cells generated by all vaccines tested are unique in their capacity to produce high amounts of interferon-gamma. These data show that the quality of a CD4+ T-cell cytokine response can be a crucial determinant in whether a vaccine is protective, and may provide a new and useful prospective immune correlate of protection for vaccines based on T-helper type 1 (TH1) cells.

Dynamic changes in histone-methylation 'marks' across the locus encoding interferon-γ during the differentiation of T helper type 2 cells

The 'histone-code' hypothesis proposes that cell fate 'decisions' are achieved through the creation of stable epigenetic histone 'marks' at gene loci. Here we explored the formation of marks of repressive methylation of histone 3 at lysine 9 (H3-K9) and of H3-K27 at the locus encoding interferon-gamma (Ifng locus) during the commitment of naive T cells to the T helper type 1 (TH1) and TH2 lineages. Methylation of H3-K9 across the Ifng locus was rapidly induced in differentiating TH1 and TH2 cells and was sustained in TH1 cells. In contrast, TH2 differentiation caused loss of methylation of H3-K9 and gain of methylation of H3-K27 by mechanisms dependent on the transcription factors GATA-3 and STAT6. Thus, histone-methylation marks at the Ifng locus are highly dynamic, which may ensure higher-order transcriptional regulation during early lineage commitment.

Invasive Cryptococcosis and Adalimumab Treatment

Invasive Cryptococcosis and Adalimumab Treatment