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Uncommitted (naive) murine CD4+ T helper cells (Thp) can be induced to differentiate towards T helper 1 (Th1), Th2, Th17 and regulatory (Treg) phenotypes according to the local cytokine milieu. This can be demonstrated most readily both in vitro and in vivo in murine CD4+ T cells. The presence of interleukin (IL)-12 [signalling through signal transduction and activator of transcription (STAT)-4] skews towards Th1, IL-4 (signalling through STAT-6) towards Th2, transforming growth factor (TGF)-β towards Treg and IL-6 and TGF-β towards Th17. The committed cells are characterized by expression of specific transcription factors, T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for Tregs and RORγt for Th17 cells. Recently, it has been demonstrated that the skewing of murine Thp towards Th17 and Treg is mutually exclusive. Although human Thp can also be skewed towards Th1 and Th2 phenotypes there is as yet no direct evidence for the existence of discrete Th17 cells in humans nor of mutually antagonistic development of Th17 cells and Tregs. There is considerable evidence, however, both in humans and in mice for the importance of interferon (IFN)-γ and IL-17 in the development and progression of inflammatory and autoimmune diseases (AD). Unexpectedly, some models of autoimmunity thought traditionally to be solely Th1-dependent have been demonstrated subsequently to have a non-redundant requirement for Th17 cells, notably experimental allergic encephalomyelitis and collagen-induced arthritis. In contrast, Tregs have anti-inflammatory properties and can cause quiescence of autoimmune diseases and prolongation of transplant function. As a result, it can be proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD or acute transplant rejection in humans. Blocking critical cytokines in vivo, notably IL-6, may result in a shift from a Th17 towards a regulatory phenotype and induce quiescence of AD or prevent transplant rejection. In this paper we review Th17/IL-17 and Treg biology and expand on this hypothesis. [ABSTRACT FROM AUTHOR]

Introduction Maternal antibody interference of the infant's humoral immune responses raises some concern to the strategy of maternal Tdap (tetanus, diphtheria, acellular pertussis [aP]) vaccination. This study assessed the impact of maternal Tdap antibodies on the infant's pertussis-specific T lymphocyte responses following infant vaccination with an aP containing vaccine, in a term and preterm born cohort. Methods Heparin samples (±0.5 mL) were conveniently drawn from infants of a Belgian prospective cohort study (N = 79, NCT02511327), including Tdap vaccinated (Boostrix®) and nonvaccinated women (no Tdap vaccine in the last 5 years) that delivered at term or prematurely. Sampling was performed before and 1 month after primary (8-12-16 weeks) and booster vaccination (13 or 15 months) with DTaP-IPV-HB-PRP~T vaccine (Hexyon®). Pertussis toxin (PT)-specific CD3+, CD3+ CD4+ and CD3+ CD8+ lymphoblasts and their cytokine secretions were measured using a flow cytometric assay on whole blood (FASCIA) and multiplex technology (Meso Scale Discovery), respectively. Results In total, 57% of all infants were considered PT-specific CD3+ CD4+ lymphoblasts responders after primary and booster vaccination, whereas 17% were CD3+ CD8+ lymphoblast responders. Interferon (IFN)-γ, interleukin (IL)-13, IL-17A, and IL-5 cytokine secretions after primary and booster vaccination were indicative of a mixed T helper (Th) 1/Th2/Th17 cell profile. Lymphoblast and cytokine levels were comparable between term and preterm infants. Nonresponders for IL-13 after booster vaccination had higher maternal PT immunoglobulin G (IgG) levels at birth when compared to responders. Conclusions Term and preterm born infants are capable of inducing Th1, Th2, and Th17 responses after aP vaccination, yet maternal vaccination modulate these responses. Evaluation of this effect in larger trials is needed. [ABSTRACT FROM AUTHOR]

T cell lines with defined cytokine profiles are an invaluable tool for assessing the control of immune responses both in vitro and in vivo. Production of such cell lines can be complex and time-consuming. Here we present a powerful technique to assay the cytokines produced by T cells activated polyclonally or with specific antigens. This paper presents a detailed methodology for the identification and isolation of cytokine-producing T cells activated with the artificial superantigen, CytoStim, or viral and fungal antigens. These cells can be analysed for different cytokines simultaneously, or cultured further to rapidly establish T cell lines making known cytokine types. We highlight the enumeration, isolation and phenotype of interleukin-17-producing T cells, and the rapid generation of virus-specific Th1 T cell lines. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β (TGF-β) has been shown to play an essential role in the suppression of inflammation, yet recent studies have revealed the positive roles of TGF-β in inflammatory responses. For example, TGF-β induces Foxp3-positive regulatory T cells (iTregs) in the presence of interleukin-2 (IL-2), while in the presence of IL-6, it induces pathogenic IL-17 producing Th17 cells. TGF-β inhibits the proliferation of immune cells as well as cytokine production via Foxp3-dependent and -independent mechanisms. Little is known about molecular mechanisms involved in immune suppression via TGF-β; however, Smad2/3 have been shown to play essential roles in Foxp3 induction as well as in IL-2 and IFN-γ suppression, whereas Th17 differentiation is promoted via the Smad-independent pathway. Interaction between TGF-β and other cytokine signaling is important in establishing the balance of immunity and tolerance. [ABSTRACT FROM PUBLISHER]

OTHER ARTICLES PUBLISHED IN THIS MINI-REVIEW SERIES ON Th17 CELLS Function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04037.x Are T helper 17 cells really pathogenic in autoimmunity? Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04039.x CD4+ T helper cells: functional plasticity and differential sensitivity to regulatory T cell-mediated regulation. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04040.x Development of mouse and human T helper 17 cells. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04041.x Uncommitted (naive) CD4+ T helper cells (Thp) can be induced to differentiate to specific lineages according to the local cytokine milieu, towards T helper type 1 (Th1), Th2, Th17 and regulatory T cell (Treg) phenotypes in a mutually exclusive manner. Each phenotype is characterized by unique signalling pathways and expression of specific transcription factors, notably T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for Tregs and receptor-related orphan receptor (ROR)α and RORγt for Th17 cells. Tregs and Th17 cells have been demonstrated to arise from common precursors in a reciprocal manner based on exposure to transforming growth factor (TGF)-β or TGF-β plus interleukin (IL)-6 and carry out diametrically opposing functions, namely suppression or propagation of inflammation, respectively. However, while epigenetic modifications in Th1 and Th2 differentiated cells prevents their conversion to other phenotypes, Th17 cells generated in vitro using TGF-β and IL-6 are unstable and can convert to other phenotypes, especially Th1, both in vitro and in vivo. Tregs are generated from naive precursors both in the thymus (natural, nTregs) and in the periphery (induced, iTregs). The highly suppressive function of Tregs enables them to control many inflammatory diseases in animals and makes them particularly attractive candidates for immunotherapy in humans. The stability of the Treg phenotype is therefore of paramount importance in this context. Recent descriptions of Treg biology have suggested that components of pathogens or inflammatory mediators may subvert the suppressive function of Tregs in order to allow propagation of adequate immune responses. Unexpectedly, however, a number of groups have now described conversion of Tregs to the Th17 phenotype induced by appropriate inflammatory stimuli. These observations are particularly relevant in the context of cell therapy but may also explain some of the dysregulation seen in autoimmune diseases. In this paper, we review Treg to Th17 conversion and propose some potential mechanisms for this phenomenon. [ABSTRACT FROM AUTHOR]

OTHER ARTICLES PUBLISHED IN THIS MINI-REVIEW SERIES ON Th17 CELLS Function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04037.x Induction of interleukin-17 production by regulatory T cells. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04038.x Are T helper 17 cells really pathogenic in autoimmunity? Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04039.x CD4+ T helper cells: functional plasticity and differential sensitivity to regulatory T cell-mediated regulation. Clin Exp Immunol 2009; doi:10.1111/j.1365-2249.2009.04040.x There has been a considerable amount of interest in the immunological community about new phenotypic subsets of CD4+ T cells, particularly cells that produce the cytokine interleukin (IL)-17 [named T helper type 17 (Th17) cells]. While the initial discovery of Th17 cells and the pathways that controlled their development was in the mouse, recent attention has shifted to the existence of these cells and the relevant upstream cytokine signals in humans. While it is clear that CD4+ T cells producing IL-17 exist in vivo, their relevance to disease pathogenesis is only just being understood. In this paper, we review the data regarding the generation of human Th17 cells in vitro and the evidence that this effector population is important in human disease states. [ABSTRACT FROM AUTHOR]

IL-23 is a cytokine member of the IL-12 superfamily. These heterodimeric cytokines offer broad immune regulatory activity with potential effector function in inflammatory arthritis. IL-23 is a pro-inflammatory cytokine secreted by dendritic cells and macrophages. It plays a key role in both innate and adaptive immunity. By promoting and maintaining T cell differentiation into Th17 T cells, IL-23 is a key player in the pathogenesis of rheumatic diseases. Data from pre-clinical IL-23 knockout models show the major importance of IL-23 in development of arthritis. The induction and maintenance of type 17 cells, which secrete IL-17A and other pro-inflammatory cytokines, contributes to local synovial inflammation and skin inflammation in PsA, and perhaps in RA. Commensurate with this, therapeutic strategies targeting IL-23 have proven efficient in PsA in several studies, albeit not yet in RA. [ABSTRACT FROM AUTHOR]

Background: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in young infants. However, it is also a significant pathogen in older adults. Validated biomarkers of RSV disease severity would benefit diagnostics, treatment decisions, and prophylactic interventions. This review summarizes knowledge of biomarkers for RSV disease in adults.Methods: A literature review was performed using Ovid Medline, Embase, Global health, Scopus, and Web of Science for articles published 1946-October 2016. Nine articles were identified plus 9 from other sources.Results: From observational studies of natural infection and challenge studies in volunteers, biomarkers of RSV susceptibility or disease severity in adults were: (1) lower anti-RSV neutralizing antibodies, where neutralizing antibody (and local IgA) may be a correlate of susceptibility/severity; (2) RSV-specific CD8+ T cells in bronchoalveolar lavage fluid preinfection (subjects with higher levels had less severe illness); and (3) elevated interleukin-6 (IL-6), IL-8, and myeloperoxidase levels in the airway are indicative of severe infection.Conclusions: Factors determining susceptibility to and severity of RSV disease in adults have not been well defined. Respiratory mucosal antibodies and CD8+ T cells appear to contribute to preventing infection and modulation of disease severity. Studies of RSV pathogenesis in at-risk populations are needed. [ABSTRACT FROM AUTHOR]

Objective This study was designed to investigate the role of mucosal-associated invariant T (MAIT) cells in gouty arthritis (GA) and their effects on osteoclastogenesis. Methods Patients with GA (n  = 61), subjects with hyperuricaemia (n  = 11) and healthy controls (n  = 30) were enrolled in this study. MAIT cells, cytokines, CD69, programmed death-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) levels were measured by flow cytometry. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells in the presence of M-CSF and RANK ligand. Results Circulating MAIT cell levels were significantly reduced in GA patients. However, their capacities for IFN-γ, IL-17 and TNF-α production were preserved. Expression levels of CD69, PD-1 and LAG-3 in MAIT cells were found to be elevated in GA patients. In particular, CD69 expression in circulating MAIT cells was increased by stimulation with MSU crystals, suggesting that deposition of MSU crystals might contribute to MAIT cell activation. Interestingly, MAIT cells were found to be accumulated in synovial fluid and infiltrated into gouty tophus tissues within joints. Furthermore, activated MAIT cells secreted pro-resorptive cytokines (i.e. IL-6, IL-17 and TNF-α) and facilitated osteoclastogenesis. Conclusion This study demonstrates that circulating MAIT cells are activated and numerically deficient in GA patients. In addition, MAIT cells have the potential to migrate to inflamed tissues and induce osteoclastogenesis. These findings provide an important role of MAIT cells in the pathogenesis of inflammation and bone destruction in GA patients. [ABSTRACT FROM AUTHOR]

Objectives PD-1+CXCR5−CD4+T peripheral helper (Tph) cells, a recently identified T cell subset, are proven to promote B cell responses and antibody production in rheumatoid arthritis, but their role in the pathogenesis of SLE is unknown. We explored the role of Tph in lupus disease development. Methods This cohort study included 68 patients with SLE and 41 age- and sex-matched healthy individuals. The frequency of PD-1+CXCR5−CD4+T cells was analysed in peripheral blood by flow cytometry. Inducible T-cell costimulator, CD38, MHC-II, IL-21, CXCR3 and CCR6 expression were measured in Tph cells. Comparisons between the two groups were performed, and correlations between Tph cells and other parameters were investigated. Results We revealed a markedly expanded population of Tph cells (8.31 ± 5.45 vs 2.86 ± 1.31%, P < 0.0001) in the circulation of patients with SLE (n = 68), compared with healthy controls (n = 41). Tph cells were much higher in the active group than in the inactive group (14.21 ± 5.21 vs 5.49 ± 2.52%, P < 0.0001). Tph cells were significantly associated with SLEDAI score (r = 0.802), ESR (r = 0.415), IgG (r = 0.434), C3 (r = −0.543), C4 (r = −0.518) and IL-21 level (r = 0.628), and ANA titre (r = 0.272). Furthermore, Tph cells were much higher in lupus patients with arthritis, nephritis, rash, alopecia, pleuritis, pericarditis and haematological involvement. Tph cells were associated with CD138+/CD19+ plasma cells (r = 0.518). Furthermore, MHC-II, inducible T-cell costimulator, CD38, and IL-21 expression were all higher in Tph cells from SLE patients compared with healthy controls. CXCR3+CCR6−Tph (Tph1) cells were expanded in the SLE patients. Conclusion Our data show that relative number of Tph cells is correlated with disease measures in patients with SLE, suggesting an important role in lupus disease development. [ABSTRACT FROM AUTHOR]

The author comments on the article "Early- and late-onset psoriasis: a cross-sectional clinical and immunocytochemical investigation," by E. Theodorakopoulou and colleagues. Topics discussed include subtypes of chronic plaque psoriasis such as type I and type II psoriasis, the link of interleukins with early-onset psoriasis (EOP) and late-onset psoriasis (LOP), and the impact of T-cell infiltration for psoriasis

Impairment of the suppressive function of regulatory T (Treg) cells has been reported in myasthenia gravis (MG). In this study, cytokine-related mechanisms that may lead to the defect of Treg were investigated in patients with anti-acetylcholine receptor antibody-positive MG (AChR + MG). Proliferation and cytokine production of responder T (Tresp) cells in response to polyclonal activation were measured in a suppression assay. The effect of interleukin (IL)-21 on suppression was evaluated in vitro in co-culture. IL-21 increased the proliferation of Tresp cells in Tresp/Treg co-cultures. Tresp cells from patients with MG secreted significantly lower levels of IL-2. In patients with MG, IL-2 levels did not change with the addition of Treg to cultures, whereas it decreased significantly in controls. In Tresp/Treg co-cultures, IL-4, IL-6 and IL-10 production increased in the presence of Treg in patients. Interferon (IFN)-γ was decreased, whereas IL-17A was increased in both patient and control groups. IL-21 inhibited the secretion of IL-4 in MG and healthy controls (HC), and IL-17A in HC only. The results demonstrated that IL-21 enhances the proliferation of Tresp cells in the presence of Treg. An effect of IL-21 mainly on Tresp cells through IL-2 is implicated. [ABSTRACT FROM AUTHOR]

Objective. TNF-α-induced protein 3 (TNFAIP3) is one of the major SLE susceptibility genes involved in the regulation of inflammatory responses through modulation of the nuclear factor-κB (NF-κB) pathway. We aim to assess TNFAIP3 expression in CD4+T cells and the molecular mechanism underlying TNFAIP3 regulation in the pathogenesis of SLE. Methods. The expression and epigenetic regulation of TNFAIP3 in CD4+T cells from SLE patients and normal controls (NCs) were investigated by RT-quantitative PCR, western blot and chromatin immuno-precipitation. The functional effect of TNFAIP3 was further evaluated by knockdown or overproduction of TNFAIP3 in CD4+T cells from SLE patients and NCs. Results. TNFAIP3 mRNA was significantly downregulated in the CD4+T cells of SLE patients compared with NCs. The reduced expression of TNFAIP3 was associated with the reduction of H3K4me3 in the gene promoter region. Functional blockage of TNFAIP3 in normal CD4+T cells using small interfering RNA increased the expression of IFN-y and IL-17, but not IL-2, IL-4 and IL-5. Nevertheless, overexpression of TNFAIP3 in CD4+T cells from SLE patients resulted in the suppression of IFN-γ and IL-17 production. Conclusion. The downregulation of TNFAIP3 in CD4+T cells of SLE was potentially regulated by demethy-lation of histone H3K4, which led to a decreased amount of H3K4me3 in the promoter of the TNFAIP3 gene. The dysregulation of TNFAIP3 in CD4+T cells may contribute to the pathogenesis of SLE by over-production of inflammatory cytokine IFN-γ and IL-17. TNFAIP3 may serve as a promising target for the treatment of SLE in clinical practice. [ABSTRACT FROM AUTHOR]

We have reported previously that T cells from patients with multi-drug-resistant tuberculosis (MDR-TB) express high levels of interleukin (IL)-17 in response to the MDR strain M (Haarlem family) of Mycobacterium tuberculosis ( M. tuberculosis). Herein, we explore the pathways involved in the induction of Th17 cells in MDR-TB patients and healthy tuberculin reactors [purified protein derivative healthy donors (PPD+ HD)] by the M strain and the laboratory strain H37Rv. Our results show that IL-1β and IL-6 are crucial for the H37Rv and M-induced expansion of IL-17+interferon (IFN)-γ- and IL-17+IFN-γ+ in CD4+ T cells from MDR-TB and PPD+ HD. IL-23 plays an ambiguous role in T helper type 1 (Th1) and Th17 profiles: alone, IL-23 is responsible for M. tuberculosis-induced IL-17 and IFN-γ expression in CD4+ T cells from PPD+ HD whereas, together with transforming growth factor (TGF-β), it promotes IL-17+IFN-γ- expansion in MDR-TB. In fact, spontaneous and M. tuberculosis-induced TGF-β secretion is increased in cells from MDR-TB, the M strain being the highest inducer. Interestingly, Toll-like receptor (TLR)-2 signalling mediates the expansion of IL-17+IFN-γ- cells and the enhancement of latency-associated protein (LAP) expression in CD14+ and CD4+ T cells from MDR-TB, which suggests that the M strain promotes IL-17+IFN-γ- T cells through a strong TLR-2-dependent TGF-β production by antigen-presenting cells and CD4+ T cells. Finally, CD4+ T cells from MDR-TB patients infected with MDR Haarlem strains show higher IL-17+IFN-γ- and lower IL-17+IFN-γ+ levels than LAM-infected patients. The present findings deepen our understanding of the role of IL-17 in MDR-TB and highlight the influence of the genetic background of the infecting M. tuberculosis strain on the ex-vivo Th17 response. [ABSTRACT FROM AUTHOR]

SLE is an autoimmune disease characterized by multiple organ damage mediated by autoantibodies and autoreactive T cells. Approaches utilizing genetically engineered mice as well as genome-wide association studies have identified a number of lupus-related genes. Recently, early growth response gene 2 (Egr2) and Egr3 have emerged as regulatory molecules that suppress excessive immune responses. Mice deficient for Egr2 and Egr3 develop a lupus-like disease with dysregulated activation of effector T cells. Furthermore, Egr2 and Egr3 confer suppressive activity to CD4+ T cells and regulate the production of inhibitory cytokines such as IL-10 and TGF-β1. These findings may have implications for a wide range of immune-related pathologies and suggest the possibility that efforts exploiting Egr2 and Egr3 could aid in the development of therapeutic applications. This review summarizes the recent advances regarding the roles of Egr2 and Egr3 on T cells in the control of autoimmunity. [ABSTRACT FROM AUTHOR]

Obesity and aging share an impaired immune system and oxidative and inflammatory stress. Therefore, the hypothesis of obesity as a possible model of premature immunosenescence has been proposed. In this study, we investigated whether adult obese mice, as a consequence of being fed with a fat-rich diet during their adolescence, showed premature immunosenescence and if this was aggravated with aging. Peritoneal cell suspensions were obtained when ICR/CD1 obese female mice were adults (28 weeks) and old (72 weeks), and several functions and antioxidant defenses were evaluated. The results showed that the chemotaxis of both macrophages and lymphocytes, phagocytosis of macrophages, activity of natural killer cells, proliferative response of lymphocytes, interleukin-1β, tumor necrosis factor-alpha, interleukin-6, interleukin-2, and interleukin-10 released in leukocyte cultures, as well as antioxidant and oxidant capacity were significantly impaired in adult obese mice with respect to adult nonobese mice, with values similar to those in chronologically old mice. When these obese animals grew older, although having been fed with a standard diet, they showed a higher deterioration of their immune functions in comparison with the old control group. In conclusion, these results demonstrate that a high fat intake during adolescence can produce an obesity state in adult age associated with a premature immunosenescence, which is aggravated through aging. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Treg) are functionally defective in patients with RA. Restoring their function may not only control inflammation but also restore tolerance in these patients. Biologic therapies have been tremendously successful in treating RA. Here we review numerous reports suggesting that these immunomodulatory therapies have an impact on Treg and that this may contribute to their beneficial effects. Better understanding of their mode of action may not only lead to improvements in therapies and sustained remission but also enable the development of biomarkers of response, which would be the first steps towards personalized medicine. [ABSTRACT FROM AUTHOR]

SS is a chronic systemic autoimmune disease characterized by decreased exocrine gland function. A variety of other disease manifestations may also be present, including general constitutional symptoms and extraglandular features. A multidisciplinary approach focused on both local and systemic medical therapies is needed as the disease has a wide clinical spectrum. The current treatment for SS is mainly symptomatic. However, there is evidence that systemic drugs are effective in controlling extraglandular manifestations of the disease. Overall evidence for the role of conventional immunosuppressive therapy is limited. A number of attempts to use biologic therapies have led to variable results. Biologic agents targeting B cells, such as rituximab, epratuzumab and belimumab, have shown promising results, but further studies are needed to validate the findings. Early-phase studies with abatacept and alefacept proved that T cell stimulation inhibition is another potentially effective target for SS treatment. Modulation or inhibition of other targets such as IFN, IL-6 and Toll-like receptor are also currently being investigated. We have summarized the available evidence regarding the efficacy of biologic treatments and discuss other potential therapies targeting pathways or molecules recognized as being involved in the pathogenesis of SS. [ABSTRACT FROM PUBLISHER]

Background Recent reports have revealed the therapeutic potential of cell-mediated immunity in neoplasms such as cutaneous squamous cell carcinoma ( SCC). Objectives To define the antigenic coexpression of regulatory T cells (Tregs) and plasmacytoid dendritic cells ( pDCs) and assess the CD8+/Foxp3+CD25+ cell ratio at peritumoral and intratumoral levels in order to investigate a correlation with the aggressiveness of SCC tumours. Methods We evaluated the content and distribution of Foxp3+CD25+ Treg and CD123+ pDC infiltration and assessed CD8+/Foxp3+CD25+ cell ratio at peritumoral and intratumoral levels in 40 SCCs (20 well-differentiated, G1; and 20 moderately to poorly differentiated, G2-G3) to investigate a correlation with their aggressiveness. We determined the profiles of Tregs and CD123+ cells; immunostained for CD4, CD8, CD123, interleukin (IL)-1 and transforming growth factor (TGF)-β1; and unequivocally double stained for Foxp3CD25. Results Peritumorally, CD4, CD8 and Foxp3 expression showed no difference between the two groups. CD123+ cells were fewer in G2-G3 ( P = 0·0005), while Foxp3+ CD25+ cells were more numerous ( P = 0·0005). The Foxp3+ CD25+/Foxp3+ ratio was higher in G2-G3 cases ( P = 0·0005), confirming the trend in this group of activated T lymphocytes towards total Treg Foxp3+ cells, while the CD8+/Foxp3+ CD25+ ratio was higher in G1 ( P = 0·0005). Intratumorally, CD4+ and CD8+ cells infiltrated G2-G3 ( P = 0·048) more than G1 ( P = 0·004), whereas almost all cells were CD123 negative. Regarding Foxp3 CD25, TGF-β1 and IL-10, they were less expressed in G1, whereas they were positive in G2-G3 ( P < 0·05). The CD8+/Foxp3+ CD25+ ratio was similar to that observed in peritumoral infiltration. Conclusions Our data suggest that intratumoral recruitment of Tregs, high expression of TGF-β1 and IL-10, almost negative CD123+, and a low CD8+/Foxp3+ CD25+ T-cell ratio may contribute to the aggressiveness of cutaneous SCC, as already evidenced for other solid tumours. [ABSTRACT FROM AUTHOR]

The mechanism underlying late-phase allergic reactions (LPR) remains incompletely understood. This study aimed to investigate the role of a newly described subset of T cells, interleukin (IL)-9 IL-10 T cells, in the pathogenesis of LPR. Using a T helper type 2 (Th2) inflammatory mouse model, we examined the frequency of IL-9 IL-10 T cells in the jejunum by immunohistochemistry. The LPR in the jejunum was observed afterwards. The cytokine profile of IL-9 IL-10 T cells was characterized and the major cytokine that plays the critical role in the initiation of LPR was investigated. Abundant IL-9 IL-10 T cells as well as inflammatory cell extravasation in the jejunal sections were observed in sensitized mice 48 h after specific antigen challenge. IL-9 IL-10 T cells expressed high levels of macrophage inflammatory protein 1 (MIP1) that could be enhanced by T cell receptor activation. MIP1 facilitated macrophage extravasation in local tissue. Macrophage-derived MIP2 contributed to neutrophil infiltration in the intestine in LPR. Pretreatment with anti-MIP antibody inhibited the LPR in the intestine. IL-9 IL-10 T cells play an important role in LPR. This subset of T cells has the potential to be a novel therapeutic target in the treatment of LPR and LPR-related inflammation. [ABSTRACT FROM AUTHOR]

Multiple sclerosis is a T cell-mediated demyelinating disease of the central nervous system. Interleukin-17-producing T helper cells, named Th17 cells, represent a novel CD4+ T cell effector subset involved in the response against extracellular pathogens. In addition, Th17 cells are pathogenic in several animal models of autoimmune disease, including the animal model for multiple sclerosis, but their function in multiple sclerosis remains to be elucidated. In this study, we analysed the frequency and the phenotype of Th17 cells in the cerebrospinal fluid and peripheral blood of multiple sclerosis patients. We show that the frequency of Th17 cells is significantly higher in the cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis during relapse, in comparison to relapsing-remitting patients in remission or to patients with other non-inflammatory neurological diseases. Similarly, in patients with clinically isolated syndrome during their first neurological episode, Th17 cells are more abundant than in clinically isolated syndrome patients with no acute symptoms. Patients with inflammatory neurological diseases other than multiple sclerosis also showed increased frequency of Th17 cells compared to patients with no inflammatory diseases. To assess a potential pathological impact of Th17 cells in disease, we generated T cell clones from the cerebrospinal fluid and peripheral blood of patients with multiple sclerosis. We found that Th17 clones expressed higher basal levels of the activation markers CD5, CD69, CD2 and human leukocyte antigen-DR as well as of the CD28-related family of co-stimulatory molecules, when compared to Th1 clones, and confirmed these findings with ex vivo human T cells. Molecules involved in T cell adhesion to endothelium, such as CD49d, CD6 and the melanoma cell adhesion molecule, were also more abundant on the Th17 than on the Th1 cells. Furthermore, functional assays showed that Th17 clones were more prone than Th1 clones to melanoma cell adhesion molecule-mediated adhesion to endothelial cells, and that Th17 cells had a higher proliferative capacity and were less susceptible to suppression than Th1 cells. Altogether our data suggest that Th17 cells display a high pathogenic potential and may constitute a relevant pathogenic subset in multiple sclerosis. [ABSTRACT FROM PUBLISHER]

An imbalance of immunoregulatory factors and/or cells contributes to uncontrolled mucosal T cell activation and inflammation in Crohn's disease (CD). Bioactive interleukin (IL)-18 has been shown to be produced by macrophages in CD lesions. We report here that T cells freshly isolated from inflamed tissue of CD patients (and not T cells from control intestinal tissue) were responsive to IL-18. In the presence of IL-18, these T cells produced more interferon (IFN)- γ and less IL-10. To analyse further the role of IL-18 in this disease, an acute and a chronic model of murine colitis were used. IL-18 mRNA was significantly enhanced in trinitrobenzene sulphonic acid (TNBS) induced colitis, and treatment with IL-18 binding protein (IL-18BPa), which neutralizes IL-18 bioactivity, significantly reduced the severity of colitis. However, IL-18BPa did not affect the course of chronic colitis in CD45RBhighCD4+ T cell reconstituted SCID mice. Production of IFN- γ in lamina propria mononuclear cell cultures from IL-18BPa-treated SCID mice was decreased, but at the same time fewer lamina propria CD4+ T cells harvested from IL-18BPa-treated mice compared to non-treated mice were in apoptosis. We conclude that IL-18 clearly has a modulatory role in the inflammatory cascade of CD and experimental colitis by affecting IFN- γ and IL-10 production, and apoptosis. In view of the divergent effects of IL-18 neutralization in the two different murine colitis models, it is unlikely that IL-18 is at the top of this cascade. [ABSTRACT FROM AUTHOR]

CD30 is expressed on activated T cells that, as has been suggested, preferentially produce IFN-γ . Interleukin 12 increases antigen-induced CD30 expression on T cells and IFN-γ production. Synthesis of IFN-γ can be augmented further by IL-18. The aim of our study was to investigate whether IL-18 affects the IL-12 induced CD30 expression and cytokine production by allergen or PPD specific T cells. Mononuclear cells of healthy or atopic volunteers were stimulated with PPD or allergen, respectively, to obtain specific T cell lines. T cells were restimulated with appropriate antigen and antigen-presenting cells in the presence of IL-12, IL-18 or a combination of these cytokines. After 3 days, expression of CD30 was investigated on CD4 and CD8 T cells and IFN-γ and IL-4 cytokine production was estimated in the culture supernatants. Flow cytometric analyses showed no effect of IL-18 on CD30 expression during IL-12 co-stimulation. At the same time after the optimal stimulation for CD30 expression, the levels of IFN-γ were high in PPD-stimulated cell lines but have not been up-regulated by IL-18. IFN-γ levels were much lower in allergen-stimulated T cells and although they were up-regulated by IL-12 there was no additional or synergistic effect from IL-18. IL-18, however, increased production of IL-4 in allergen-stimulated cell lines. Our studies provide new information about IL-18 activity on human cells and question its exclusive role in Th1 mediated responses. [ABSTRACT FROM AUTHOR]

We have previously demonstrated that exogenous Nef protein induced activation of normal human T cells up-regulating IL-15 production by monocytes. Since HIV-1 infection results in the early impairment of immune functions we decided to evaluate if Nef is able to modulate the induction of a specific antibody response. Human peripheral blood mononuclear cells from healthy donors were induced in vitro to mount a specific antibody response to the Candida albicans antigen. We show that Nef inhibited, in a dose-dependent manner, the induction of the anti-C. albicans antibody response. The ability of an anti-Nef antibody to prevent such inhibition indicates that the effect was indeed Nef-specific. In the Nef-treated cultures an early increase of IL-15 production was observed and the addition of anti-IL-15 antibody abrogated the Nef-induced inhibitory effect. Moreover the addition of IL-15 to the cultures inhibited, as well as Nef, the induction of the specific antibody response. Thus, our results suggest that Nef may inhibit the induction of a specific antibody response by an early up-regulation of IL-15 production. A better comprehension of this phenomenon may be important for unravelling some aspects of the B cell defects in HIV infection. [ABSTRACT FROM AUTHOR]

Lymphocytes from normal individuals with the histocompatibility antigens HLA-B8 and DR3 have impaired proliferative responses when stimulated with suboptimal concentrations of mitogens. We have previously shown that an important factor in the impaired response is a failure to produce normal quantities of interleukin-2 (IL-2). To examine the mechanism of decreased responsiveness further, we measured interleukin-1 (IL-1) production of tow responder subjects compared with controls. The peripheral blood mononuclear cells of five low responder individuals with HLA-B8/ DR3 stimulated with 0.05 μg/ml of phytohaemagglutinin (PHA) accumulated only 0.036 U/ml of IL-1 compared with 0.32 U/ml for normal responders. There was a highly significant correlation between the PHA-stimulated IL-1 concentration at 12 hand the subsequent IL-2 concentration at 48 h (r =0-89, P<0.0001) suggesting a role of decreased IL-l production in the impaired response. A study of unfractionated or column-fractionated culture supernatants revealed no evidence that the decreased IL-I activity in the supernatants of low responder subjects was related to increased IL-1 inhibitor concentrations. These results suggest that impaired IL-2 production and lymphocyte proliferation in healthy subjects with HLA-B8/DR3 may be mediated at least in part by decreased IL-1 production, and implicates a defect of a very early event in lymphocyte activation. [ABSTRACT FROM AUTHOR]

A number of investigators have reported that human serum inhibits the proliferation of IL-2-dependent mouse cells in IL-2 bioassays, but the mechanism of inhibition has not been carefully examined. We noticed that IL-2-dependent mouse cells (CTLL-2) are killed within 30 mm in the presence of a 1/10 dilution of human serum. However, CTLL-2 cells totally deprived of IL-2 did not begin to die until at least 6 h in culture. Thus, even complete inhibition of IL-2 by human serum could not account for the rapid cytotoxicity caused by human serum. Since humans have 'natural' antibodies which react with mouse cells, it seemed possible that the cytotoxicity was due to antibody/complement-mediated cell lysis. This was supported by the observation that EDTA (at a concentration sufficient to inhibit complement) protected CTLL-2 cells from the cytotoxic effects of human sera from four normal donors. In addition, preincubation of CTLL-2 cells with heat- inactivated human sera at 4°C rendered them much more susceptible to lysis with rabbit complement than cells which were preincubated with complete culture medium. The cytotoxicity of human serum is not limited to IL-2-dependent mouse cells hut was also observed with EL4 and Ag8.653 cells as well as normal splenocytes. The cytotoxic effect of human serum was lost upon removal of IgM, but not upon removal of IgG. These results strongly suggest that the inhibition of proliferation of IL-2-dependent mouse cells by human serum is due to antibody, complement-mediated lysis of those cells. In addition, non-heat-inactivated human serum did not inhibit the IL-2-mediated proliferation of human PHA blasts, indicating that there is no inherent inhibitory activity in human serum apart from the cytotoxic effect on xenogeneic cells. Thus the reported IL-2 inhibitory activity of whole human serum is probably not biologically relevant. [ABSTRACT FROM AUTHOR]

Patients with acquired hypogammaglobulinaemia usually have near normal numbers of B cells and normal T cell function. When hypogammaglobulinaemia occurs in association with thymoma, then B cell numbers have been reported as low, and distinctive T cells are present which inhibit immunoglobulin production by normal cells. It has been suggested that these T cells are responsible for the observed hypogammaglobulinaemia. We report a patient with thymoma and hypogammaglobulinaemia who lacks these distinctive suppressor cells and has normal B cell numbers. It is therefore incorrect to propose a single pathogenic mechanism for hypogammaglobulinaemia in association with thymoma. [ABSTRACT FROM AUTHOR]

Cell-mediated immunity may be depressed during pregnancy. We used the two way mixed lymphocyte reaction as an in vitro model of cell mediated immunity and studied the effect of pregnancy sera on this system by the amount of tritiated thymidine taken up by activated lymphocytes. We found that: (1) pregnancy sera contain a factor inhibiting the mixed lymphocyte reaction; (2) the inhibition of the mixed lymphocyte reaction induced by sera could be reversed by the addition of the supernatant from allogeneic mixed lymphocyte reaction; (3) pure interleukin-1 could not reverse the inhibitory effect and (4) recombinant interleukin-2 (IL-2) completely reversed the inhibitory effect of pregnancy sera on the mixed lymphocyte reaction. We conclude that a factor (or factors) present in serum from pregnant women is capable of inhibiting the generation of IL-2 during lymphocyte activation. [ABSTRACT FROM AUTHOR]

B lymphocyte differentiation into immunoglobulin secreting cells is a process depending on the presence of functionally mature B lymphocytes, monocytes and regulatory T lymphocytes. Cord blood B lymphocytes present in isolated cord blood mononuclear cell (MNC) preparations are normally unable to differentiate into immunoglobulin secreting plaque forming cells (PFC) when cultured in the presence of pokeweed mitogen (PWM) alone or killed Staphylococcus aureus Cowan 1 (SACl) alone. However, each one of these activators induces PFC formation by B lymphocytes in adult MNC cultures. In the present study we show that these two activators can act synergisticaily to induce a significant in vitro PFC response in cord blood MNC's. The synergism of PWM and SACl exhibits a requirement for a specific sequence of addition in order to induce a positive response in neonatal cells. If both activators are not added simultaneously at the initiation of culture. only the initial addition of SACI followed by PWM will result in increased PFC production. The action of PWM and SACl on cord blood MNC can each be replaced by conditioned media. Supernatants from monocyte cultures containing soluble factors such as interleukin-1 (IL-I) can substitute for the activity of SACl while supernatants containing soluble T-cell factors (interleukin-2 [IL-2], T cell replacing factor (TRF), B cell differentiation factor (BCDF), etc) can replace PWM in (he cord blood MNC cultures. The results suggest that the synergistic effect of these two activators overcomes a partial immaturity or an excessive suppressor activity of human cord blood MNC. [ABSTRACT FROM AUTHOR]

The article presents the study which analyzed the normal frequencies of IFN-ϒ producing (Th1) and IL-17 producing T-cells (T-17) in patients with giant cell arteritis (GCA) in stimulated whole blood samples as of May 2014.

RA is a progressive inflammatory autoimmune disease with articular and systemic effects. Its exact cause is unknown, but genetic and environmental factors are contributory. T cells, B cells and the orchestrated interaction of pro-inflammatory cytokines play key roles in the pathophysiology of RA. Differentiation of naïve T cells into Th 17 (TH17) cells results in the production of IL-17, a potent cytokine that promotes synovitis. B cells further the pathogenic process through antigen presentation and autoantibody and cytokine production. Joint damage begins at the synovial membrane, where the influx and/or local activation of mononuclear cells and the formation of new blood vessels cause synovitis. Pannus, the osteoclast-rich portion of the synovial membrane, destroys bone, whereas enzymes secreted by synoviocytes and chondrocytes degrade cartilage. Antigen-activated CD4+ T cells amplify the immune response by stimulating other mononuclear cells, synovial fibroblasts, chondrocytes and osteoclasts. The release of cytokines, especially TNF-α, IL-6 and IL-1, causes synovial inflammation. In addition to their articular effects, pro-inflammatory cytokines promote the development of systemic effects, including production of acute-phase proteins (such as CRP), anaemia of chronic disease, cardiovascular disease and osteoporosis and affect the hypothalamic–pituitary–adrenal axis, resulting in fatigue and depression. [ABSTRACT FROM PUBLISHER]

Recent data from several groups demonstrate high levels of IL-7 in the joints of RA patients, but much lower levels in OA. In contrast, circulating levels of IL-7 in RA remain a point of debate. IL-7 has many roles in T cell, dendritic cell and bone biology in humans. Reduced levels of circulating IL-7 probably underlie a number of the dysfunctions associated with circulating T cells in RA and may provide a mechanism for some of the unexplained systemic manifestations of the disease. However, IL-7 in the joint may have a more sinister role, contributing to a vicious cycle perpetuating inflammation. Typically, IL-1β and TNF-α increase the stromal production of IL-7 and in turn, IL-7 up-regulates the production of TNF-α by macrophages. Most importantly, IL-7 induces the production of osteoclastogenic cytokines by T cells, leading to the maturation of osteoclasts and therefore bone destruction. By linking the stroma with innate and adaptive immunity in RA, IL-7 may be directing the cellular network, leading to chronic inflammation and joint destruction. Blocking IL-7 may well therefore be of therapeutic value. [ABSTRACT FROM AUTHOR]