26 research outputs found
Natural killer cell behavior in lymph nodes revealed by static and real-time imaging
Natural killer (NK) cells promote dendritic cell (DC) maturation and influence T cell differentiation in vitro. To better understand the nature of the putative interactions among these cells in vivo during the early phases of an adaptive immune response, we have used immunohistochemical analysis and dynamic intravital imaging to study NK cell localization and behavior in lymph nodes (LNs) in the steady state and shortly after infection with Leishmania major. In the LNs of naive mice, NK cells reside in the medulla and the paracortex, where they closely associate with DCs. In contrast to T cells, intravital microscopy revealed that NK cells in the superficial regions of LNs were slowly motile and maintained their interactions with DCs over extended times in the presence or absence of immune-activating signals. L. major induced NK cells to secrete interferon-Îł and to be recruited to the paracortex, where concomitant CD4 T cell activation occurred. Therefore, NK cells form a reactive but low mobile network in a strategic area of the LN where they can receive inflammatory signals, interact with DCs, and regulate colocalized T cell responses
Tetrameric Complexes of Human Histocompatibility Leukocyte Antigen (HLA)-G Bind to Peripheral Blood Myelomonocytic Cells
The nonclassical MHC class I molecule human histocompatibility leukocyte antigen (HLA)-G is selectively expressed on fetal trophoblast tissue at the maternalâfetal interface in pregnancy. It has long been suggested that HLA-G may inhibit maternal natural killer (NK) cells through interaction with particular NK cell receptors (KIRs). To investigate interactions of HLA-G, we constructed phycoerythrin-labeled tetrameric complexes of HLA-G refolded with a self-peptide. These HLA-G tetramers failed to bind to NK cells and cells transfected with CD94/NKG2 and killer immunoglobulin-like NK receptors. In contrast, HLA-G tetramers did bind to peripheral blood monocytes, staining a CD16+CD14mid subset with greater intensity. On transfectants, HLA-G tetramers bound to inhibitory immunoglobulin-like transcript (ILT)2 and ILT4 receptors. However, staining in the presence of antibodies reactive with ILT receptors revealed that the interaction of HLA-G tetramers with blood monocytes was largely due to binding to ILT4. These results suggest that the primary role of HLA-G may be the modulation of myelomonocytic cell behavior in pregnancy
HLA-Eâdependent Presentation of Mtb-derived Antigen to Human CD8+ T Cells
Previous studies in mice and humans have suggested an important role for CD8+ T cells in host defense to Mtb. Recently, we have described human, Mtb-specific CD8+ cells that are neither HLA-A, B, or C nor group 1 CD1 restricted, and have found that these cells comprise the dominant CD8+ T cell response in latently infected individuals. In this report, three independent methods are used to demonstrate the ability of these cells to recognize Mtb-derived antigen in the context of the monomorphic HLA-E molecule. This is the first demonstration of the ability of HLA-E to present pathogen-derived antigen. Further definition of the HLA-E specific response may aid development of an effective vaccine against tuberculosis
Natural Killer Cell Signal Integration Balances Synapse Symmetry and Migration
Imaging immune surveillance by natural killer (NK) cells has revealed that integration of activating and inhibitory signals determines whether or not NK cells stop to kill the target cell or retain a migratory configuration
A size and space structured model of tumor growth describes a key role for protumor immune cells in breaking equilibrium states in tumorigenesis
International audienceSwitching from the healthy stage to the uncontrolled development of tumors relies on complicated mechanisms and the activation of antagonistic immune responses, that can ultimately favor the tumor growth. We introduce here a mathematical model intended to describe the interactions between the immune system and tumors. The model is based on partial differential equations, describing the displacement of immune cells subjected to both diffusion and chemotactic mechanisms, the strength of which is driven by the development of the tumors. The model takes into account the dual nature of the immune response, with the activation of both antitumor and protumor mechanisms. The competition between these antagonistic effects leads to either equilibrium or escape phases, which reproduces features of tumor development observed in experimental and clinical settings. Next, we consider on numerical grounds the efficacy of treatments: the numerical study brings out interesting hints on immunotherapy strategies, concerning the role of the administered dose, the role of the administration time and the interest in combining treatments acting on different aspects of the immune response. Such mathematical model can shed light on the conditions where the tumor can be maintained in a viable state and also provide useful hints for personalized, efficient, therapeutic strategies, boosting the antitumor immune response, and reducing the protumor actions.Le passage du stade sain Ă la croissance incontrĂŽlĂ©e des tumeurs repose sur des mĂ©canismes compliquĂ©s et l'activation de rĂ©ponses immunitaires antagonistes, qui peuvent Ă terme favoriser la croissance tumorale. Nous introduisons ici un modĂšle mathĂ©matique destinĂ© Ă dĂ©crire les interactions entre le systĂšme immunitaire et les tumeurs. Le modĂšle est basĂ© sur des Ă©quations aux dĂ©rivĂ©es partielles, dĂ©crivant le dĂ©placement de cellules immunitaires soumises Ă la fois Ă des mĂ©canismes de diffusion et de chimiotactisme, dont la force est dĂ©terminĂ©e par le dĂ©veloppement des tumeurs. Le modĂšle prend en compte la double nature de la rĂ©ponse immunitaire, avec l'activation des mĂ©canismes antitumoraux et protumoraux. La compĂ©tition entre ces effets antagonistes conduit soit Ă des phases d'Ă©quilibre, soit Ă des phases d'Ă©chappement, qui reproduisent les caractĂ©ristiques du dĂ©veloppement tumoral observĂ© dans des contextes expĂ©rimentaux et cliniques. Ensuite, nous considĂ©rons sur des bases numĂ©riques l'efficacitĂ© des traitements : l'Ă©tude numĂ©rique apporte des pistes intĂ©ressantes sur les stratĂ©gies d'immunothĂ©rapie, concernant le rĂŽle de la dose administrĂ©e, le rĂŽle du temps d'administration et l'intĂ©rĂȘt de combiner des traitements agissant sur diffĂ©rents aspects du systĂšme immunitaire. Un tel modĂšle mathĂ©matique peut faire la lumiĂšre sur les conditions dans lesquelles la tumeur peut ĂȘtre maintenue dans un Ă©tat viable et Ă©galement fournir des pistes utiles pour des stratĂ©gies thĂ©rapeutiques personnalisĂ©es et efficaces, renforçant la rĂ©ponse immunitaire antitumorale et rĂ©duisant les actions protumorales
TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide
AbstractBackground: The human major histocompatibility complex (MHC) class lb molecule HLA-E is transcribed in most tissues but little is known about its localisation within the cell. We have recently shown that HLA-E binds signal-sequence-derived peptides from human MHC class I molecules in vitro.Results: Using a newly characterised antibody recognising HLA-E, we show that HLA-E is expressed at the cell surface. We demonstrate that HLA-E surface expression is correlated with the presence of MHC class I molecules which provide suitable leader sequence peptides capable of binding to HLA-E. Further studies on the interaction of HLA-E with molecules in the endoplasmic reticulum revealed that HLA-E associates with the transporter associated with antigen processing (TAP) and calreticulin, and that HLA-E expression is TAP-dependent and tapasin-dependent. In addition, HLA-E dissociates from TAP upon binding of MHC class I leader sequence peptides.Conclusion: These experiments establish that surface expression of HLA-E is regulated by the binding of a restricted pool of peptides from the leader sequence of MHC class I molecules. The correlation between HLA-E and MHC class I surface expression might be relevant to the function of HLA-E. Our results also show that, although these HLA-E binding peptides are derived from signal sequences, they may be released back into the cytosol and subsequently translocated by the TAP complex and loaded onto HLA-E molecules
Current Protocols in Immunology
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