The Ly49E receptor inhibits the immune control of acute Trypanosoma cruzi infection

The protozoan parasite Trypanosoma cruzi circulates in the blood upon infection and invades various cells. Parasites intensively multiply during the acute phase of infection and persist lifelong at low levels in tissues and blood during the chronic phase. Natural killer (NK) and NKT cells play an important role in the immune control of T. cruzi infection, mainly by releasing the cytokine IFN-gamma that activates the microbicidal action of macrophages and other cells and shapes a protective type 1 immune response. The mechanisms by which immune cells are regulated to produce IFN-gamma during T. cruzi infection are still incompletely understood. Here, we show that urokinase plasminogen activator (uPA) is induced early upon T. cruzi infection and remains elevated until day 20 post-infection. We previously demonstrated that the inhibitory receptor Ly49E, which is expressed, among others, on NK and NKT cells, is triggered by uPA. Therefore, we compared wild type (WT) to Ly49E knockout (KO) mice for their control of experimental T. cruzi infection. Our results show that young, i.e., 4- and 6-week-old, Ly49E KO mice control the infection better than WT mice, indicated by a lower parasite load and less cachexia. The beneficial effect of Ly49E depletion is more obvious in 4- week-old male than in female mice and weakens in 8-week-old mice. In young mice, the lower T. cruzi parasitemia in Ly49E KO mice is paralleled by higher IFN-gamma production compared to their WT controls. Our data indicate that Ly49E receptor expression inhibits the immune control of T. cruzi infection. This is the first demonstration that the inhibitory Ly49E receptor can interfere with the immune response to a pathogen in vivo

Increased Incidence of Urethane Induced Lung Adenomata by Autosensitized Lymphocytes

The present work investigates the influence of autosensitized lymphocytes on the carcinogenic response of the host. Urethane treated SWR mice received 6 fortnightly injections of lymphocytes sensitized in vitro against syngeneic fibroblasts. An increased incidence of lung adenomata was found in these mice compared with controls injected with unsensitized lymphoid cells or with lymphoid cells sensitized against unrelated transplantation antigens. Autosensitized lymphocytes also modified the response of host lymphoid cells to concanavalin A or to stimulation in a mixed lymphocyte culture assay. These results indicate that autoimmune lymphocytes may increase susceptibility of a host to the induction of tumours

Immunotherapy of neurodegenerative diseases: is it time to change paradigm?

Prion diseases belong to the family of neurodegenerative disorders. They are characterized by the presence, in the central nervous system, of host proteins that by changing conformation and forming soluble multimeric aggregates, and fibrillar amyloid plaques become neurotoxic. To date, there is no treatment capable of deeply modifying the dramatic and lethal course of those diseases. Accumulating clinical and experimental data have nevertheless shown that innate and adaptive immune agents could slow down the course of neurodegenerative pathologies. Immunotherapy has become a promising therapeutic tool, despite the fact that the outcome of the first clinical trials has not fulfilled all promises. First, we will review currently developed strategies, most of them based on the use of antibodies directed against pathogenic proteins. Then, we will discuss alternative strategies relying on cellular immunity, and we will present our latest results involving the adoptive transfer of T lymphocytes. We will conclude by discussing pending issues and questions in the quest for safe and efficient treatments against neurodegenerative diseases.Les maladies à prions appartiennent à la famille des maladies neurodégénératives. Celles-ci se caractérisent par la présence, dans le système nerveux central, de protéines constitutives de l'hôte qui en changeant de conformation et en formant, dans un premier temps, des agrégats multimériques solubles, puis secondairement des dépôts fibrillaires de type amyloïde, deviennent neurotoxiques. Il n'existe à ce jour aucun traitement de fond capable de modifier le cours dramatique et inexorable de ces pathologies. Des données cliniques et expérimentales se sont cependant récemment accumulées montrant que des effecteurs de l'immunité innée et adaptative pouvaient freiner leur développement. L'immunothérapie est devenue l'une des voies les plus prometteuses de traitement, même si les premiers résultats ne sont pas encore à la hauteur des espérances. Nous commencerons par une évaluation critique des stratégies actuellement développées, essentiellement fondées sur la mise en jeu d'anticorps dirigés contre les protéines pathogènes. Nous discuterons ensuite de l'opportunité de mettre en œuvre des approches alternatives reposant sur l'immunité cellulaire, et présenterons nos derniers résultats concernant le transfert adoptif de lymphocytes T. Nous conclurons enfin sur une liste de questions ouvertes dont il ne sera sans doute pas possible de faire l'économie pour parvenir à des solutions thérapeutiques sûres et efficaces

Differential tumor surveillance by natural killer (NK) and NKT cells

Natural tumor surveillance capabilities of the host were investigated in six different mouse tumor models where endogenous interleukin (IL)-12. does or does not dictate the efficiency of the innate immune response. Gene-targeted and lymphocyte subset-depleted mice were used to establish the relative importance of natural killer (NK) and NK1.1(+) T (NKT) cells in protection from tumor initiation and metastasis. In the models examined, CD3(-) NK cells were responsible for tumor rejection and protection from metastasis in models where control of major histocompatibility complex class I-deficient tumors was independent of IL-12, A protective role for NKT cells was only observed when tumor rejection required endogenous IL-12 activity. In particular, T cell receptor J alpha 281 gene-targeted mice confirmed a critical function for NKT cells in protection from spontaneous tumors initiated by the chemical carcinogen, methylcholanthrene. This is the first description of an antitumor function for NKT cells in the absence of exogenously administered potent stimulators such as IL-12 or alpha-galactosylceramide

Immunoprophylactic and immunotherapeutic prospects in prion diseases

Prion diseases or transmissible subacute spongiform encephalopathies (TSSE) are fatal neurodegenerative conditions, for which there is so far no known treatment or prevention. Promising results achieved in the field of Alzheimer disease give however some reasons to hope that individuals with the disease or individuals at risk might benefit from similar immunoprophylactic or immunotherapeutic approaches. This article reviews current knowledge on the immunology of prion diseases. In the first section we describe the known routes of prion lymphoinvasion from the periphery to the sites of neuroinvasion. The second section focuses on the mediators of innate immunity mobilized within the central nervous system and on their ambivalent role in the pathogenesis of the disease. The final section describes the vaccine approaches aimed at stimulating adaptive immunity and at creating, in association with the mediators of the innate immune system, a defence barrier against prions.Les maladies à prions ou encéphalopathies spongiformes subaiguës transmissibles (ESST) sont des affections neurodégénératives fatales, contre lesquelles il n'existe à ce jour aucun traitement ou prophylaxie connu. Des résultats encourageants obtenus dans la maladie d'Alzheimer, laissent toutefois espérer que des approches immunoprophylactiques ou immunothérapeutiques puissent un jour être mises en oeuvre chez des sujets atteints d'ESST ou chez des sujets à risque. Ce mémoire vise à faire le point dans ce domaine. Dans une première partie, nous décrivons les voies connues de la lymphoinvasion dans les formes acquises de maladie, voies à travers lesquelles les prions progressent au sein même du système lymphoïde, depuis la périphérie jusqu'au sytème nerveux central. Dans une deuxième partie, nous mettons l'accent sur les agents de l'immunité innée mobilisés dans le système nerveux central et sur leur rôle ambivalent dans la pathogénie des ESST. Enfin, la dernière partie est consacrée aux approches vaccinales destinées à stimuler l'immunité adaptative et à construire, en collaboration avec le système immunitaire inné, une barrière défensive contre l'agent pathogène

Syndecan-3 and syndecan-4 are enriched in Schwann cell perinodal processes

BACKGROUND: Nodes of Ranvier correspond to specialized axonal domains where voltage-gated sodium channels are highly concentrated. In the peripheral nervous system, they are covered by Schwann cells microvilli, where three homologous cytoskeletal-associated proteins, ezrin, radixin and moesin (ERM proteins) have been found, to be enriched. These glial processes are thought to play a crucial role in organizing axonal nodal domains during development. However, little is known about the molecules present in Schwann cell processes that could mediate axoglial interactions. The aim of this study is to identify by immunocytochemistry transmembrane proteins enriched in Schwann cells processes that could interact, directly or indirectly, with axonal proteins. RESULTS: We show that syndecan-3 (S3) and syndecan-4 (S4), two proteoglycans expressed in Schwann cells, are enriched in perinodal processes in rat sciatic nerves. S3 labeling was localized in close vicinity of sodium channels as early as post-natal day 2, and highly concentrated at nodes of Ranvier in the adult. S4 immunoreactivity accumulated at nodes later, and was also prominent in internodal regions of myelinated fibers. Both S3 and S4 were co-localized with ezrin in perinodal processes. CONCLUSIONS: Our data identify S3 and S4 as transmembrane proteins specifically enriched in Schwann cell perinodal processes, and suggest that S3 may be involved in early axoglial interactions during development

MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression

Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections. Unlike in mouse models, the mechanisms underlying SAg-associated immunosuppression in humans are ill-defined. In this work, we have identified a population of innate-like T cells, called mucosa-associated invariant T (MAIT) cells, as the most powerful source of pro-inflammatory cytokines after exposure to SAgs. We have utilized primary human peripheral blood and hepatic mononuclear cells, mouse MAIT hybridoma lines, HLA-DR4-transgenic mice, MAIThighHLA-DR4+ bone marrow chimeras, and humanized NOD-scid IL-2Rγnull mice to demonstrate for the first time that: i) mouse and human MAIT cells are hyperresponsive to SAgs, typified by staphylococcal enterotoxin B (SEB); ii) the human MAIT cell response to SEB is rapid and far greater in magnitude than that launched by unfractionated conventional T, invariant natural killer T (iNKT) or γδ T cells, and is characterized by production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-2, but not IL-17A; iii) high-affinity MHC class II interaction with SAgs, but not MHC-related protein 1 (MR1) participation, is required for MAIT cell activation; iv) MAIT cell responses to SEB can occur in a T cell receptor (TCR) Vβ-specific manner but are largely contributed by IL-12 and IL-18; v) as MAIT cells are primed by SAgs, they also begin to develop a molecular signature consistent with exhaustion and failure to participate in antimicrobial defense. Accordingly, they upregulate lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin-3 (TIM-3), and/or programmed cell death-1 (PD-1), and acquire an anergic phenotype that interferes with their cognate function against Klebsiella pneumoniae and Escherichia coli; vi) MAIT cell hyperactivation and anergy co-utilize a signaling pathway that is governed by p38 and MEK1/2. Collectively, our findings demonstrate a pathogenic, rather than protective, role for MAIT cells during infection. Furthermore, we propose a novel mechanism of SAg-associated immunosuppression in humans. MAIT cells may therefore provide an attractive therapeutic target for the management of both early and late phases of severe SAg-mediated illnesses

Harnessing Invariant NKT Cells to Improve Influenza Vaccines: A Pig Perspective

Citation: Yang, G.; Richt, J.A.; Driver, J.P. Harnessing Invariant NKT Cells to Improve Influenza Vaccines: A Pig Perspective. Int. J. Mol. Sci. 2018, 19, 68.Invariant natural killer T (iNKT) cells are an “innate-like” T cell lineage that recognize glycolipid rather than peptide antigens by their semi-invariant T cell receptors. Because iNKT cells can stimulate an extensive array of immune responses, there is considerable interest in targeting these cells to enhance human vaccines against a wide range of microbial pathogens. However, long overlooked is the potential to harness iNKT cell antigens as vaccine adjuvants for domestic animal species that express the iNKT cell–CD1d system. In this review, we discuss the prospect of targeting porcine iNKT cells as a strategy to enhance the efficiency of swine influenza vaccines. In addition, we compare the phenotype and tissue distribution of porcine iNKT cells. Finally, we discuss the challenges that must be overcome before iNKT cell agonists can be contemplated for veterinary use in livestock