Intragraft Selection of the T Cell Receptor Repertoire by Class I MHC Sequences in Tolerant Recipients

Background: Allograft tolerance of ACI (RT1 a) recipients to WF (RT1 u) hearts can be induced by allochimeric class I MHC molecules containing donor-type (RT1A u) immunogenic epitopes displayed on recipient-type (RT1A a) sequences. Here, we sought the mechanisms by which allochimeric sequences may affect responding T cells through T cell receptor (TCA) repertoire restriction. Methodology/Principal Findings: The soluble [a1h u]-RT1.A a allochimeric molecule was delivered into ACI recipients of WF hearts in the presence of sub-therapeutic dose of cyclosporine (CsA). The TCR Vb spectrotyping of the splenocytes and cardiac allografts showed that the Vb gene families were differentially expressed within the TCR repertoire in allochimericor high-dose CsA-treated tolerant recipients at day +5 and +7 of post-transplantation. However, at day 30 of posttransplantation the allochimeric molecule-treated rats showed the restriction of TCR repertoire with altered dominant size peaks representing preferential clonal expansion of Vb7, Vb11, Vb13, Vb 14, and Vb15 genes. Moreover, we found a positive correlation between the alteration of Vb profile, restriction of TCR repertoire, and the establishment of allograft tolerance. Conclusions: Our findings indicate that presentation of allochimeric MHC class I sequences that partially mimic donor an

Down Regulation of Genes Involved in T Cell Polarity and Motility during the Induction of Heart Allograft Tolerance by Allochimeric MHC I

BACKGROUND:The allochimeric MHC class I molecule [alpha1h1/u]-RT1.Aa that contains donor-type (Wistar Furth, WF; RT1u) epitopes displayed on recipient-type (ACI, RT1a) administered in conjunction with sub-therapeutic dose of cyclosporine (CsA) induces indefinite survival of heterotopic cardiac allografts in rat model. In vascularized transplantation models, the spleen contributes to graft rejection by generating alloantigen reactive T cells. The immune response in allograft rejection involves a cascade of molecular events leading to the formation of immunological synapses between T cells and the antigen-presenting cells. METHODOLOGY/PRINCIPAL FINDINGS:To elucidate the molecular pathways involved in the immunosuppressive function of allochimeric molecule we performed microarray and quantitative RTPCR analyses of gene expression profile of splenic T cells from untreated, CsA treated, and allochimeric molecule + subtherapeutic dose of CsA treated animals at day 1, 3 and 7 of post transplantation. Allochimeric molecule treatment caused down regulation of genes involved in actin filament polymerization (RhoA and Rac1), cell adhesion (Catna1, Vcam and CD9), vacuolar transport (RhoB, Cln8 and ATP6v1b2), and MAPK pathway (Spred1 and Dusp6) involved in tubulin cytoskeleton reorganization and interaction between actin and microtubule cytoskeleton. All these genes are involved in T cell polarity and motility, i.e., their ability to move, scan and to form functional immunological synapse with antigen presenting cells (APCs). CONCLUSIONS:These results indicate that the immunosuppressive function of allochimeric molecule may depend on the impairment of T cells' movement and scanning ability, and possibly also the formation of immunological synapse. We believe that these novel findings may have important clinical implications for organ transplantation

Donor Morbidity After Living Donation for Liver Transplantation

Reports of complications among adult right hepatic lobe donors have been limited to single centers. The rate and severity of complications in living donors were investigated in the 9-center Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL)

Macrophage-, Dendritic-, Smooth Muscle-, Endothelium-, and Stem Cells-Derived Foam Cells in Atherosclerosis

International audienceAtherosclerosis is an inflammatory disease depending on the buildup, called plaque, of lipoproteins, cholesterol, extracellular matrix elements, and various types of immune and non-immune cells on the artery walls. Plaque development and growth lead to the narrowing of the blood vessel lumen, blocking blood flow, and eventually may lead to plaque burst and a blood clot. The prominent cellular components of atherosclerotic plaque are the foam cells, which, by trying to remove lipoprotein and cholesterol surplus, also participate in plaque development and rupture. Although the common knowledge is that the foam cells derive from macrophages, studies of the last decade clearly showed that macrophages are not the only cells able to form foam cells in atherosclerotic plaque. These findings give a new perspective on atherosclerotic plaque formation and composition and define new targets for anti-foam cell therapies for atherosclerosis prevention. This review gives a concise description of foam cells of different pedigrees and describes the main mechanisms participating in their formation and function

Natural genetic engineering: A programmed chromosome/DNA elimination

International audienceTypically, all cells of a given organism have the same set of chromosomes. However, there are exceptions to this rule, and in many organisms, the somatic cells and germ cells, various types of somatic cells or organs, or females and males, have different genomes. One of the sources of such differences is chromosome/DNA elimination/chromatin diminution that is a naturally programmed phenomenon. We describe chromosome/DNA elimination in various organisms and present the current hypotheses on its origin, mechanisms, significance, and consequences

How nicotine can inhibit cytokine storm in the lungs and prevent or lessen the severity of COVID-19 infection?

International audienceStatistical surveys of COVID-19 patients indicate, against all common logic, that people who smoke are less prone to the infection and/or exhibit less severe respiratory symptoms than non-smokers. This suggests that nicotine may have some preventive or modulatory effect on the inflammatory response in the lungs. Because it is known that the response to, and resolution of the SARS-CoV-2 infection depends mainly on the lung macrophages, we discuss the recent scientific findings, which may explain why and how nicotine may modulate lung macrophage response during COVID-19 infection

Memory Macrophages

International audienceImmunological memory is a crucial part of the immune defense that allows organisms to respond against previously encountered pathogens or other harmful factors. Immunological memory is based on the establishment of epigenetic modifications of the genome. The ability to memorize encounters with pathogens and other harmful factors and mount enhanced defense upon subsequent encounters is an evolutionarily ancient mechanism operating in all animals and plants. However, the term immunological memory is usually restricted to the organisms (invertebrates and vertebrates) possessing the immune system. The mammalian immune system, with innate and adaptive branches, is the most sophisticated among vertebrates. The concept of innate memory and memory macrophages is relatively new and thus understudied. We introduce the concept of immunological memory and describe types of memory in different species and their evolutionary status. We discuss why the traditional view of innate immune cells as the first-line defenders is too restrictive and how the innate immune cells can accumulate and retain immunologic memory. We describe how the initial priming leads to chromatin remodeling and epigenetic changes, which allow memory macrophage formation. We also summarize what is currently known about the mechanisms underlying development of memory macrophages; their molecular and metabolic signature and surface markers; and how they may contribute to immune defense, diseases, and organ transplantation

Invertebrate Immunity, Natural Transplantation Immunity, Somatic and Germ Cell Parasitism, and Transposon Defense

International audienceWhile the vertebrate immune system consists of innate and adaptive branches, invertebrates only have innate immunity. This feature makes them an ideal model system for studying the cellular and molecular mechanisms of innate immunity without reciprocal interferences from adaptive immunity. Although invertebrate immunity is evolutionarily older and a precursor of vertebrate immunity, it is far from simple. Despite lacking lymphocytes and functional immunoglobulin, the invertebrate immune system has many sophisticated mechanisms and features, such as long-term immune memory, which, for decades, have been exclusively attributed to adaptive immunity. In this review, we describe the cellular and molecular aspects of invertebrate immunity, including the epigenetic foundation of innate memory, the transgenerational inheritance of immunity, genetic immunity against invading transposons, the mechanisms of self-recognition, natural transplantation, and germ/somatic cell parasitism

Macrophages in diabetes mellitus (DM) and COVID-19: do they trigger DM?

International audienceDiabetes mellitus (DM) augments the risk of hospitalization and mortality resulting from viral, bacterial, or fungal pathogen infection. This has been also true for the past SARS and MERS, and current SARS-CoV-2 coronavirus epidemics. Clinical data indicate that SARS-CoV-2 infection triggers a severe course of COVID-19 more frequently in diabetic than non-diabetic patients. Here we overview the cellular and molecular mechanisms associated with this phenomenon. We focus on alterations in the immune cells, especially monocytes and macrophages, involved in innate immune response and inflammatory processes, which differ in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). We also describe the DM-related changes in the monocyte/macrophages functions, how they could lead to the severe outcome of SARS-CoV-2 infection, and importantly, if and how they could initiate DM in DM-susceptible patients

Memory Macrophages

Immunological memory is a crucial part of the immune defense that allows organisms to respond against previously encountered pathogens or other harmful factors. Immunological memory is based on the establishment of epigenetic modifications of the genome. The ability to memorize encounters with pathogens and other harmful factors and mount enhanced defense upon subsequent encounters is an evolutionarily ancient mechanism operating in all animals and plants. However, the term immunological memory is usually restricted to the organisms (invertebrates and vertebrates) possessing the immune system. The mammalian immune system, with innate and adaptive branches, is the most sophisticated among vertebrates. The concept of innate memory and memory macrophages is relatively new and thus understudied. We introduce the concept of immunological memory and describe types of memory in different species and their evolutionary status. We discuss why the traditional view of innate immune cells as the first-line defenders is too restrictive and how the innate immune cells can accumulate and retain immunologic memory. We describe how the initial priming leads to chromatin remodeling and epigenetic changes, which allow memory macrophage formation. We also summarize what is currently known about the mechanisms underlying development of memory macrophages; their molecular and metabolic signature and surface markers; and how they may contribute to immune defense, diseases, and organ transplantation