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Sjögren syndrome (SS) is an autoimmune disease characterized by chronic inflammatory infiltrates in the salivary and lacrimal glands. Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T-cells, predominantly found in mucosal tissues with crucial role in epithelial homeostasis. Thus, MAIT cells may be implicated in mucosal alterations of SS patients. Activation markers, inflammatory and cytotoxic cytokines were examined in 23 SS patients and compared to 23 healthy controls (HC). Tissular MAIT cells in salivary gland (SG) biopsies were also analyzed. Circulating MAIT cells were decreased in SS patients with a higher expression of CD69 and a higher CD4/CD8 ratio of MAIT cells. MAIT cells showed a higher production of IFNγ, TNFα and GzB in SS compare to HC. Tissular MAIT cells were present within inflamed SG of SS patients, while they were absent in SG of HC. Overall, circulating MAIT cells are decreased in the peripheral blood of SS albeit producing higher amounts of IFNγ, TNFα, and GzB. Tissular MAIT cells are detected in salivary glands from SS with a proinflammatory tissular cytokine environment. MAIT cells with abnormal phenotype, functions and tissular homeostasis may contribute to epithelial damage in SS.

Mucosal associated invariant T (MAIT) cells are unconventional, semi-invariant T lymphocytes that recognize microbial-derived vitamin B2 (riboflavin) biosynthesis precursor derivatives presented by the monomorphic MHC class 1-related (MR1) molecule. Upon microbial infection, MAIT cells rapidly produce cytokines and cytotoxic effectors, and are thus important players in anti-microbial defense. MAIT cells are protective in experimental models of infection and are decreased in the blood of adult patients with bacterial infections, including ( ). In children, the risk of rapid progression to active tuberculosis (TB) following infection is higher than in adults. Whether MAIT cells influence the outcome of infection in children is therefore, an important issue. We analyzed MAIT cell numbers and phenotype in 115 children investigated for pulmonary TB and determined their potential correlation with disease progression. MAIT cells were reduced in numbers and activated in the peripheral blood of children with active TB as compared to those with latent TB infection (LTBI) and healthy children. Moreover, MAIT cells did not accumulate and did not proliferate in the lung of children with active TB. These results suggest that MAIT cells may be important in preventing progression of infection to active TB in children.

Adoptive transfer of immunoregulatory cells can prevent or ameliorate graft-versus-host disease (GVHD), which remains the main cause of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation. Mucosal-associated invariant T (MAIT) cells were recently associated with tissue repair capacities and with lower rates of GVHD in humans. Here, we analyzed the immunosuppressive effect of MAIT cells in an in vitro model of alloreactivity and explored their adoptive transfer in a preclinical xenogeneic GVHD model. We found that MAIT cells, whether freshly purified or short-term expanded, dose-dependently inhibited proliferation and activation of alloreactive T cells. In immunodeficient mice injected with human PBMCs, MAIT cells greatly delayed GVHD onset and decreased severity when transferred early after PBMC injection but could also control ongoing GVHD when transferred at delayed time points. This effect was associated with decreased proliferation and effector function of human T cells infiltrating tissues of diseased mice and was correlated with lower circulating IFN-γ and TNF-α levels and increased IL-10 levels. MAIT cells acted partly in a contact-dependent manner, which likely required direct interaction of their T cell receptor with MHC class I-related molecule (MR1) induced on host-reactive T cells. These results support the setup of clinical trials using MAIT cells as universal therapeutic tools to control severe GVHD or mucosal inflammatory disorders.

Understanding how hepatitis C virus (HCV) induces and circumvents the host's natural killer (NK) cell-mediated immunity is of critical importance in efforts to design effective therapeutics. We report here the decreased expression of the NKG2D activating receptor as a novel strategy adopted by HCV to evade NK-cell mediated responses. We show that chronic HCV infection is associated with expression of ligands for NKG2D, the MHC class I-related Chain (MIC) molecules, on hepatocytes. However, NKG2D expression is downmodulated on circulating NK cells, and consequently NK cell-mediated cytotoxic capacity and interferon-γ production are impaired. Using an endotoxin-free recombinant NS5A protein, we show that NS5A stimulation of monocytes through Toll-like Receptor 4 (TLR4) promotes p38- and PI3 kinase-dependent IL-10 production, while inhibiting IL-12 production. In turn, IL-10 triggers secretion of TGFβ which downmodulates NKG2D expression on NK cells, leading to their impaired effector functions. Moreover, culture supernatants of HCV JFH1 replicating Huh-7.5.1 cells reproduce the effect of recombinant NS5A on NKG2D downmodulation. Exogenous IL-15 can antagonize the TGFβ effect and restore normal NKG2D expression on NK cells. We conclude that NKG2D-dependent NK cell functions are modulated during chronic HCV infection, and demonstrate that this alteration can be prevented by exogenous IL-15, which could represent a meaningful adjuvant for therapeutic intervention.

The contribution of innate immunity to immunosurveillance of the oncogenic Human Herpes Virus 8 (HHV8) has not been studied in depth. We investigated NK cell phenotype and function in 70 HHV8-infected subjects, either asymptomatic carriers or having developed Kaposi's sarcoma (KS). Our results revealed substantial alterations of the NK cell receptor repertoire in healthy HHV8 carriers, with reduced expression of NKp30, NKp46 and CD161 receptors. In addition, down-modulation of the activating NKG2D receptor, associated with impaired NK-cell lytic capacity, was observed in patients with active KS. Resolution of KS after treatment was accompanied with restoration of NKG2D levels and NK cell activity. HHV8-latently infected endothelial cells overexpressed ligands of several NK cell receptors, including NKG2D ligands. The strong expression of NKG2D ligands by tumor cells was confirmed in situ by immunohistochemical staining of KS biopsies. However, no tumor-infiltrating NK cells were detected, suggesting a defect in NK cell homing or survival in the KS microenvironment. Among the known KS-derived immunoregulatory factors, we identified prostaglandin E2 (PGE2) as a critical element responsible for the down-modulation of NKG2D expression on resting NK cells. Moreover, PGE2 prevented up-regulation of the NKG2D and NKp30 receptors on IL-15-activated NK cells, and inhibited the IL-15-induced proliferation and survival of NK cells. Altogether, our observations are consistent with distinct immunoevasion mechanisms that allow HHV8 to escape NK cell responses stepwise, first at early stages of infection to facilitate the maintenance of viral latency, and later to promote tumor cell growth through suppression of NKG2D-mediated functions. Importantly, our results provide additional support to the use of PGE2 inhibitors as an attractive approach to treat aggressive KS, as they could restore activation and survival of tumoricidal NK cells.

Recognition of Human Proinsulin Leader Sequence by Class I–Restricted T-Cells in HLA-A*0201 Transgenic Mice and in Human Type 1 Diabetes Andréa Toma 1 , Taghrid Laïka 1 2 , Samy Haddouk 1 , Sandrine Luce 1 , Jean-Paul Briand 3 , Luc Camoin 4 , Francine Connan 4 , Marion Lambert 1 , Sophie Caillat-Zucman 1 , Jean-Claude Carel 1 , Sylviane Muller 3 , Jeannine Choppin 4 , François Lemonnier 2 and Christian Boitard 1 5 1 Institut National de la Santé et de la Recherche Médicale U561 et Université Paris N, Hôpital Cochin-Saint Vincent de Paul, Paris, France 2 Unité d'Immunité Cellulaire Antivirale, Département d'Immunologie, Institut Pasteur, Paris, France 3 Centre National de la Recherche Scientifique Unité Propre de Recherche 9021, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France 4 Institut National de la Santé et de la Recherche Médicale U567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut Cochin, Université Paris N, Paris, France 5 Service d'Immunologie Clinique, Hôpital Cochin-Saint Vincent de Paul, Paris, France Corresponding author: Dr. Christian Boitard, christian.boitard{at}inserm.fr Abstract OBJECTIVE— A restricted region of proinsulin located in the B chain and adjacent region of C-peptide has been shown to contain numerous candidate epitopes recognized by CD8 + T-cells. Our objective is to characterize HLA class I–restricted epitopes located within the preproinsulin leader sequence. RESEARCH DESIGN AND METHODS— Seven 8- to 11-mer preproinsulin peptides carrying anchoring residues for HLA-A1, -A2, -A24, and -B8 were selected from databases. HLA-A2–restricted peptides were tested for immunogenicity in transgenic mice expressing a chimeric HLA-A*0201/β2-microglobulin molecule. The peptides were studied for binding to purified HLA class I molecules, selected for carrying COOH-terminal residues generated by proteasome digestion in vitro and tested for recognition by human lymphocytes using an ex vivo interferon-γ (IFN-γ) ELISpot assay. RESULTS— Five HLA-A2–restricted peptides were immunogenic in transgenic mice. Murine T-cell clones specific for these peptides were cytotoxic against cells transfected with the preproinsulin gene. They were recognized by peripheral blood mononuclear cells (PBMCs) from 17 of 21 HLA-A2 type 1 diabetic patients. PBMCs from 25 of 38 HLA-A1, -A2, -A24, or -B8 patients produced IFN-γ in response to six preproinsulin peptides covering residues 2–25 within the preproinsulin region. In most patients, the response was against several class I–restricted peptides. T-cells recognizing preproinsulin peptide were characterized as CD8 + T-cells by staining with peptide/HLA-A2 tetramers. CONCLUSIONS— We defined class I–restricted epitopes located within the leader sequence of human preproinsulin through in vivo (transgenic mice) and ex vivo (diabetic patients) assays, illustrating the possible role of preproinsulin-specific CD8 + T-cells in human type 1 diabetes. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 14 November 2008. A.T. and T.L. contributed equally to this study. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 6, 2008. Received May 2, 2008. DIABETES

Purpose - The purpose of this paper is to assess the French reform of employees' access to lifelong learning by addressing the issue of the relationship between corporate training policy and employees' capability to aspire for learning. Design/methodology/approach - The investigation is based on the French linked employer-employee survey DIFES1, which allows for responses from employees and human resource management to be analysed together. From a mixed ascending hierarchical clustering, the paper highlights the different ways in which the reform was applied within firms, and identifies capability-friendly backgrounds. From bivariate probit models, it examines what factors affect employees' capability to aspire. Findings - First, the results identify 10.5 per cent of French firms as capability-friendly. Second, it reveals that the capability to aspire is even more influenced by the environment as shaped by the corporate training policy than by professional pathways, occupational groups and other determinants, whilst training experiences themselves have no influence. Third, it raises the key issue of capability for voice as a matter of fundamental importance. Research limitations/implications - Because of the cross-sectional nature of the survey, the research is not able to address the temporal dynamics of the capability to aspire, how it evolves over time. Practical implications - In contrast to political pronouncements attributing employees' lack of aspiration to a personal inclination, the results show how corporate training policies may increase employees' capability to aspire for training by making it a collective issue and provide insights to combat adaptive preferences. Originality/value - The research provides, for the first time, an understanding of the relationship between corporate training strategies and the capability to aspire.

Purpose - The purpose of this paper is to assess the French reform of employees' access to lifelong learning by addressing the issue of the relationship between corporate training policy and employees' capability to aspire for learning.Design methodology approach - The investigation is based on the French linked employer-employee survey DIFES1, which allows for responses from employees and human resource management to be analysed together. From a mixed ascending hierarchical clustering, the paper highlights the different ways in which the reform was applied within firms, and identifies capability-friendly backgrounds. From bivariate probit models, it examines what factors affect employees' capability to aspire.Findings - First, the results identify 10.5 per cent of French firms as capability-friendly. Second, it reveals that the capability to aspire is even more influenced by the environment as shaped by the corporate training policy than by professional pathways, occupational groups and other determinants, whilst training experiences themselves have no influence. Third, it raises the key issue of capability for voice as a matter of fundamental importance.Research limitations implications - Because of the cross-sectional nature of the survey, the research is not able to address the temporal dynamics of the capability to aspire, how it evolves over time.Practical implications - In contrast to political pronouncements attributing employees' lack of aspiration to a personal inclination, the results show how corporate training policies may increase employees' capability to aspire for training by making it a collective issue and provide insights to combat adaptive preferences.Originality value - The research provides, for the first time, an understanding of the relationship between corporate training strategies and the capability to aspire.

Mucosal-associated invariant T (MAIT) cells are semi-invariant T cells that recognize microbial antigens presented by the highly conserved MR1 molecule. MAIT cells are predominantly localized in the liver and barrier tissues and are potent effectors of antimicrobial defense. MAIT cells are very few at birth and accumulate gradually over a period of about 6 years during the infancy. The cytotoxic potential of MAIT cells, as well as their newly described regulatory and tissue repair functions, open the possibility of exploiting their properties in adoptive therapy. A prerequisite for their use as 'universal' cells would be a lack of alloreactive potential, which remains to be demonstrated. We used ex vivo, in vitro and in vivo models to determine if human MAIT cells contribute to allogeneic responses. We show that recovery of MAIT cells after allogeneic hematopoietic stem cell transplantation recapitulates their slow physiological expansion in early childhood, independent of recovery of non-MAIT T cells. In vitro, signals provided by allogeneic cells and cytokines do not induce sustained MAIT cell proliferation. In vivo, human MAIT cells do not expand nor accumulate in tissues in a model of T-cell-mediated xenogeneic graft-versus-host disease in immunodeficient mice. Altogether, these results provide evidence that MAIT cells are devoid of alloreactive potential and pave the way for harnessing their translational potential in universal adoptive therapy overcoming barriers of HLA disparity. ClinicalTrials.gov number NCT02403089.

The major histocompatibility complex class I related chain (MIC) is a stress-inducible protein modulating the function of immune natural killer (NK) cells, a major leukocyte subset involved in proper trophoblast invasion and spiral artery remodeling. Aim of the study was to evaluate whether upregulation of soluble MIC (sMIC) may reflect immune disorders associated to vascular pregnancy diseases (VPD). sMIC was more frequently detected in the plasma of women with a diagnostic of VPD (32%) than in normal term-matched pregnancies (1.6%, P < 0.0001 ), with highest prevalence in intrauterine fetal death (IUDF, 44%) and vascular intrauterine growth restriction (IUGR, 39%). sMIC levels were higher in preeclampsia (PE) than in IUFD ( P < 0.01 ) and vascular IUGR ( P < 0.05 ). sMIC detection was associated with bilateral early diastolic uterine notches ( P = 0.037 ), thrombocytopenia ( P = 0.03 ), and high proteinuria ( P = 0.03 ) in PE and with the vascular etiology of IUGR ( P = 0.0038 ). Incubation of sMIC-positive PE plasma resulted in downregulation of NKG2D expression and NK cell-mediated IFN-γ production in vitro. Our work thus suggests that detection of sMIC molecule in maternal plasma may constitute a hallmark of altered maternal immune functions that contributes to vascular disorders that complicate pregnancy, notably by impairing NK-cell mediated production of IFN-γ, an essential cytokine favoring vascular modeling.