Immune synapse formation promotes lipid peroxidation and MHC-I upregulation in licensed dendritic cells for efficient priming of CD8+ T cells
Diego Calzada‐FraileSalvador IborraMarta Ramírez‐HuescaInmaculada JorgeEnrico DottaElena Hernández‐GarcíaNoa B. Martín‐CófrecesEstanislao Nistal‐VillánEsteban VeigaJesús VázquezGiulia PasqualFrancisco Sánchez‐Madrid
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Abstract Antigen cognate dendritic cell (DC)-T cell synaptic interactions drive activation of T cells and instruct DCs. Upon receiving CD4 + T cell help, post-synaptic DCs (psDCs) are licensed to generate CD8 + T cell responses. However, the cellular and molecular mechanisms that enable psDCs licensing remain unclear. Here, we describe that antigen presentation induces an upregulation of MHC-I protein molecules and increased lipid peroxidation on psDCs in vitro and in vivo. We also show that these events mediate DC licensing. In addition, psDC adoptive transfer enhances pathogen-specific CD8 + T responses and protects mice from infection in a CD8 + T cell-dependent manner. Conversely, depletion of psDCs in vivo abrogates antigen-specific CD8 + T cell responses during immunization. Together, our data show that psDCs enable CD8 + T cell responses in vivo during vaccination and reveal crucial molecular events underlying psDC licensing.Keywords:
Priming (agriculture)
Immunological synapse
Antigen processing and presentation experiments can be done with a wide variety of antigen-presenting cells (APCs). Most experiments will use one of the "professional" APC types: dendritic cells (DCs), macrophages, and B lymphocytes. Other types of cells may be used for antigen presentation in some circumstances. Each type of professional APC has an important antigen-presentation function, but the different APC types contribute to different aspects of the immune response. Therefore, selection of an APC type for study must include consideration of the stage or aspect of immune response that is to be modeled in the experiment. An important technical distinction for some types of experiments is whether the APCs are adherent or nonadherent, since this dictates the procedures that must be used to wash the cells as the medium is changed.
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This chapter contains sections titled: Introduction Dendritic cell terminology and heterogeneity Antigen uptake Antigen presentation Integrated function of dendritic cells in the immune response Role for dendritic cells in allergic sensitization in humans Dendritic cells in allergic asthma Dendritic cells in atopic dermatitis Role of dendritic cells in allergic rhinitis Dendritic cells as drug targets in allergic diseases Origin and function of macrophages Homeostasis in the alveolar compartment is maintained by alveolar macrophages Function of alveolar macrophages in inflammatory conditions and asthma Conclusion References
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Professional antigen-presenting cells (APCs), such as dendritic cells and macrophages, are known for their ability to present exogenous antigens to T cells. However, many other cell types, including endothelial cells, fibroblasts, and lymph node stromal cells, are also capable of presenting exogenous antigens to either CD8+ or CD4+ T cells via cross-presentation or major histocompatibility complex (MHC) class II-mediated presentation, respectively. Antigen presentation by these stromal nonprofessional APCs differentially affect T cell function, depending on the type of cells that present the antigen, as well as the local (inflammatory) micro-environment. It has been recently appreciated that nonprofessional APCs can, as such, orchestrate immunity against pathogens, tumor survival, or rejection, and aid in the progression of various auto-immune pathologies. Therefore, the interest for these nonprofessional APCs is growing as they might be an important target for enhancing various immunotherapies. In this review, the different nonprofessional APCs are discussed, as well as their functional consequences on the T cell response, with a focus on immuno-oncology.
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Upon recognition of peptide displayed on MHC molecules, Th1 and Th2 cells form distinct immunological synapse structures. Th1 cells have a bull’s eye synapse structure with TCR/ MHC-peptide interactions occurring central to a ring of adhesion molecules, while Th2 cells have a multifocal synapse with small clusters of TCR/MHC interactions throughout the area of T cell/antigen-presenting cell interaction. In this study, we investigated whether this structural difference in the immunological synapse affects delivery of T cell help. The immunological synapse is thought to ensure antigen-specific delivery of cytolytic granules and killing of target cells by NK cells and cytolytic T cells. In helper T cells, it has been proposed that the immunological synapse may direct delivery of other effector molecules including cytokines. CD40 ligand (CD40L) is a membrane-bound cytokine essential for antigen-specific T cell help for B cells in the antibody response. We incubated Th1 and Th2 cells overnight with a mixture of antigen-presenting and bystander B cells, and the delivery of CD40L to B cells and subsequent B cell responses were compared. Despite distinct immunological synapse structures, Th1 and Th2 cell do not differ in their ability to deliver CD40L and T cell help in an antigen-specific fashion, or in their susceptibility to inhibition of help by a blocking anti-CD40L antibody.
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Antigen exposure via airway epithelia is often associated with a failure to prime or with the preferential priming of Th2 cells. We previously reported that the intranasal delivery of a Th1-inducing antigen promoted Th2-dominated responses, rather than the expected Th1 responses. Thus, we proposed that when pulmonary T cell priming is induced, the lung microenvironment might intrinsically favor the generation of Th2 types of responses. To establish a potential mechanism for such preferential priming, we examined the initial interactions between antigens and resident antigen-presenting cells (APCs) within the lung. We show that intranasally delivered antigens are preferentially taken up and can be presented to antigen-specific T cells by a resident population of CD11cbright APCs. Most of these antigen-loaded APCs remained within lung tissues, and migration into secondary lymphoid organs was not crucial for T cell priming to occur within the pulmonary tract. Furthermore, these pulmonary APCs demonstrated a marked expression of IL-6 and IL-10 within hours of antigen uptake, suggesting that resident tissue APCs have the capacity to promote Th2 T cell differentiation in situ.
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T cells are critical for co-ordinating the immune response. T cells are activated when their surface T cell receptors (TCRs) engage cognate antigens in the form of peptide-major histocompatibility complexes (pMHC) presented on the surface of antigen presenting cells (APCs). Large changes in the contact interface between T cells and APCs occur over the course of tens of minutes from the initial contact to the formation of a large-scale junction between the two cells. The mature junction between a T cell and APC is known as the immunological synapse (IS), and this specialised plasma membrane structure is the major platform for TCR signalling. It has long been known that the complex organisation of signalling molecules at the IS is critical for appropriate activation of T cells, but within the last decade advances in microscopy have opened up investigation into the dynamics of T cell surface topology in the IS. From mechanisms mediating the initial contact between T cells and APCs to roles in the organisation of molecules in the mature IS, these studies have made it increasing clear that local membrane topology has a large impact on signalling processes. This review focuses on the functional consequences of the T cells’ highly dynamic and heterogeneous membrane, and in particular how membrane topology leads to the reorganisation of membrane proteins on the T cell surface.
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Dendritic cells are specialized cells of the innate immune system, with high capacity to present antigens in the context of the Major Histocompatibility Complex II (MHC-II) to T lymphocytes (CD4+); these cells are up to 100 times stronger than any other antigen presenting cell. The ability of the antigen presentation by dendritic cells has been documented in animal models and clinical studies conducted in humans. Based on the above, different techniques and methods have been developed to use dendritic cells in cancer-aimed immunotherapies. The dendritic cell vaccines refer to biological therapies, prepared by different strategies (ex vivo and in vivo), which aim to enhance the presentation of tumor antigens and develop a more targeted and sustained immune response on these. They are obtained from precursor cells that mature with specific stimuli that direct them to the desired therapy. Different applications for these therapies have been described in numerous types of cancers, which will be described.
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Successful priming of adaptive immune responses is crucially dependent on innate activation signals that convert resting antigen-presenting cells (APCs) into immunogenic ones. APCs expressing the relevant innate pattern recognition receptors can be directly activated by pathogen-associated molecular patterns (PAMPs) to become competent to prime T-cell responses. Alternatively, it has been suggested that APCs could be activated indirectly by proinflammatory mediators synthesized by PAMP-exposed cells. However, data obtained with CD4 + T cells suggest that inflammatory signals often cannot substitute for direct pattern recognition in APC activation for the priming of T helper responses. To test whether the same is true for CD8 + T cells, we studied cytotoxic T lymphocyte development in vitro and in mixed chimeric mice in which coexisting APCs can either present a preprocessed model antigen or directly recognize a given PAMP, but not both. We show that indirectly activated APCs promote antigen-specific proliferation of naïve CD8 + T cells but fail to support their survival and cytotoxic T lymphocyte differentiation. Furthermore, CD8 + T cells primed by indirectly activated APCs are unable to reject tumors. Thus, inflammation cannot substitute for direct recognition of single PAMPs in CD8 + T-cell priming. These findings have important practical implications for vaccine design, indicating that adjuvants must be judiciously chosen to trigger the relevant pattern recognition receptors in APCs.
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