Immunological memory in the bone marrow in old age

Die Immunfunktion nimmt im Alter ab. Dieser als Immunoseneszenz bezeichnete Prozess führt zu häufigeren und schwerer verlaufenden Infektionskrankheiten und verringert die Schutzwirkung von Impfungen im Alter. Aufgrund der Rückbildung des Thymus nimmt im Alter insbesondere die Anzahl naiver T-Zellen ab. Deshalb müssen neue Strategien gefunden werden, um diesem Problem entgegenzuwirken. Besonders wichtig ist die Erhaltung von Gedächtniszellen, die im Laufe des Lebens gebildet werden. Gedächtnis T-Zellen und langlebige Plasmazellen können in Knochenmarksnischen lange überleben. Diese Nischen produzieren für den Erhalt von Plasmazellen CXCL-12 und APRIL , für den von Gedächtnis- und Effektor T-Zellen IL-7 und IL-15. Eine persistierende Infektion mit dem Zytomegalievirus (CMV) beschleunigt die Entwicklung der Immunoseneszenz. Je nach geografischer Lage sind 60 bis 100 Prozent der erwachsenen Bevölkerung mit dem Virus infiziert. Eine Infektion führt zu einer markanten T-Zell Antwort, die mehr als 20% des gesamten CD8+ T-Zell Pools beansprucht. Im ersten Teil unserer Studie wurde der Einfluss des Alterns auf die Produktion von Überlebensfaktoren für Effektor-/Gedächtniszellen und langlebige Plasmazellen im menschlichen Knochenmark untersucht. Wir zeigen, dass sich die Expression von IL-7, einem Zytokin, welches das Überleben von Gedächtnis T-Zellen fördert, im Alter verringert, während IL-15, das auch hoch differenzierte Effektor T-Zellen schützt, vermehrt produziert wird. IL-6 ist im Alter ebenfalls überexprimiert und kann synergistisch mit IL-15 wirken. Im Gegensatz dazu wird das für das Überleben von Plasmazellen wichtige Protein APRIL (a proliferation-inducing ligand) vermindert produziert. Ferner zeigen wir, dass subklinische Entzündungsprozesse im Knochenmark die Produktion von IL-15 und IL-6 induzieren, im Speziellen durch die Entstehung von reaktiven Sauerstoffspezies (ROS). Im zweiten Teil des Projektes wurde der Einfluss einer latenten CMV-Infektion auf den Phänotyp von Effektor-/Gedächtnis CD8+ T-Zellen und auf die Expression von Nischenproteinen im Knochenmark untersucht. Seneszente CD8+ Effektor T-Zellen mit einer hohen Expression von CD45RA, einer hohen Bindungsfähigkeit von IL-15 und einer niederen von IL-7 sind im Knochenmark von CMV+ Personen häufig. Ferner führt die CMV-Infektion zu einer erhöhten Produktion von IL-15 im Knochenmark. Die höchsten IL-15 Spiegel wurden bei alten CMV+ Personen nachgewiesen. Zusammenfassend zeigen unsere Ergebnisse, dass die für die Erhaltung des immunologischen Gedächtnisses wichtigen Knochenmarksnischen im Alter und bei Personen mit latenter CMV-Infektion verändert sind. Mit hohem Alter und CMV assoziierte Entzündungsprozesse im Knochenmark führen zu einer vermehrten Produktion von IL-15 und IL-6 und fördern das Überleben hoch differenzierter/seneszenter CD8+ Effektor T-Zellen, die große Mengen an IFN- und TNF produzieren. Diese Zellen brauchen Platz, der sonst für Gedächtnis T-Zellen und Plasmazellen zur Verfügung steht.Aging leads to a decline of immune function, a process known as immunosenescence, which contributes to a higher incidence and severity of infectious diseases and decreased efficacy of vaccines in the elderly. In particular, due to the involution of the thymus, the numbers of naïve T cells are low in old age. It is therefore important to find new strategies to counteract this problem, in particular through the maintenance of memory cells generated during life. Memory T cells and long-lived plasma cells survive in the bone marrow (BM) niches for long periods of time. Plasma cells home to CXCL-12+ APRIL+ cells while effector/memory T cells are in close proximity to IL-7+ and IL-15+ BM cells. Cytomegalovirus (CMV) has been considered one of the most important propagators of immunosenescence. Depending on the geographical area, the virus infects 60 to 100% of the adult population. CMV infection leads to a very prominent T cell response, which occupies >20% of the total CD8+ T cell pool. It has been suggested that CMV-driven effector/memory T cell expansions significantly accelerate the age-associated loss of naïve T cells, decreasing de novo immune responses. In the first part of our study, the impact of aging on the production of survival factors for effector/memory T cells and long-lived plasma cells in the human BM has been investigated. We show that the expression of IL-7, a cytokine involved in the maintenance of memory T cells, decreases while the levels of IL-15, important for the survival of memory and highly differentiated T cells, increase in old age. IL-6, which may synergize with IL-15 but can also support the survival of long-lived plasma cells, is also overexpressed in the elderly. In contrast, the plasma cell survival factor a proliferation-inducing ligand (APRIL), is reduced. A BM pro-inflammatory environment was found to induce IL-15 and IL-6 expression, in particular through the production of reactive oxygen species (ROS). In the second part of the project, the impact of CMV on the phenotype of effector/memory CD8+ T cells and on the production of survival factors for these cells in the BM has been studied. Senescent CD8+ effector memory RA T (TEMRA) cells with a bright expression of CD45RA, high responsiveness to IL-15 and reduced levels of IL-7R accumulate in the BM of CMV+ persons. Increased IL-15 mRNA expression was observed with CMV, and the highest levels were found in old seropositive donors.In summary, our results show that the BM environment involved in the maintenance of immunological memory is impaired in old age and in persons with CMV. Age-related inflammation (“inflammaging”) in the BM leads to an increased expression of IL-15 and IL-6 and promotes the persistence of highly differentiated/senescent CD8+ CD28- T cells, which produce high levels of IFN- and TNF, thus contributing to a vicious circle of inflammation. In addition, CMV seropositivity leads to the accumulation of senescent T cells in the BM, which may occupy space otherwise available for “healthy” memory T cells.submitted by Luca Pangrazzi, M.Sc.Kumulative Dissertation aus vier ArtikelnZusammenfassung in deutscher SpracheIm Titel ist das + hochgestelltMedical University of Innsbruck, Dissertation, 2017OeBB(VLID)214711

Oxidative Stress and Immune System Dysfunction in Autism Spectrum Disorders

Autism Spectrum Disorders (ASDs) represent a group of neurodevelopmental disorders associated with social and behavioral impairments. Although dysfunctions in several signaling pathways have been associated with ASDs, very few molecules have been identified as potentially effective drug targets in the clinic. Classically, research in the ASD field has focused on the characterization of pathways involved in neural development and synaptic plasticity, which support the pathogenesis of this group of diseases. More recently, immune system dysfunctions have been observed in ASD. In addition, high levels of reactive oxygen species (ROS), which cause oxidative stress, are present in ASD patients. In this review, we will describe the major alterations in the expression of genes coding for enzymes involved in the ROS scavenging system, in both ASD patients and ASD mouse models. In addition, we will discuss, in the context of the most recent literature, the possibility that oxidative stress, inflammation and immune system dysfunction may be connected to, and altogether support, the pathogenesis and/or severity of ASD. Finally, we will discuss the possibility of novel treatments aimed at counteracting the interplay between ROS and inflammation in people with ASD

Antioxidants N-Acetylcysteine and Vitamin C Improve T Cell Commitment to Memory and Long-Term Maintenance of Immunological Memory in Old Mice

Aging is characterized by reduced immune responses, a process known as immunosenescence. Shortly after their generation, antigen-experienced adaptive immune cells, such as CD8+ and CD4+ T cells, migrate into the bone marrow (BM), in which they can be maintained for long periods of time within survival niches. Interestingly, we recently observed how oxidative stress may negatively support the maintenance of immunological memory in the BM in old age. To assess whether the generation and maintenance of immunological memory could be improved by scavenging oxygen radicals, we vaccinated 18-months (old) and 3-weeks (young) mice with alum-OVA, in the presence/absence of antioxidants vitamin C (Vc) and/or N-acetylcysteine (NAC). To monitor the phenotype of the immune cell population, blood was withdrawn at several time-points, and BM and spleen were harvested 91 days after the first alum-OVA dose. Only in old mice, memory T cell commitment was boosted with some antioxidant treatments. In addition, oxidative stress and the expression of pro-inflammatory molecules decreased in old mice. Finally, changes in the phenotype of dendritic cells, important regulators of T cell activation, were additionally observed. Taken together, our data show that the generation and maintenance of memory T cells in old age may be improved by targeting oxidative stress

Increased IL-15 Production and Accumulation of Highly Differentiated CD8+ Effector/Memory T Cells in the Bone Marrow of Persons with Cytomegalovirus

Cytomegalovirus (CMV) has been described as a contributor to immunosenescence, thus exacerbating age-related diseases. In persons with latent CMV infection, the CD8+ T cell compartment is irreversibly changed, leading to the accumulation of highly differentiated virus-specific CD8+ T cells in the peripheral blood. The bone marrow (BM) has been shown to play a major role in the long-term survival of antigen-experienced T cells. Effector CD8+ T cells are preferentially maintained by the cytokine IL-15, the expression of which increases in old age. However, the impact of CMV on the phenotype of effector CD8+ T cells and on the production of T cell survival molecules in the BM is not yet known. We now show, using BM samples obtained from persons who underwent hip replacement surgery because of osteoarthrosis, that senescent CD8+ TEMRA cells with a bright expression of CD45RA and a high responsiveness to IL-15 accumulate in the BM of CMV-infected persons. A negative correlation was found between CMV antibody (Ab) titers in the serum and the expression of CD28 and IL-7Rα in CD8+TEMRAbright cells. Increased IL-15 mRNA levels were observed in the BM of CMV+ compared to CMV− persons, being particularly high in old seropositive individuals. In summary, our results indicate that a BM environment rich in IL-15 may play an important role in the maintenance of highly differentiated CD8+ T cells generated after CMV infection

Fcμ receptor as a Costimulatory Molecule for T Cells

Summary: Fc receptor for IgM (FcμR)-deficient mice display dysregulated function of neutrophils, dendritic cells, and B cells. The relevance of FcμR to human T cells is still unknown. We show that FcμR is mostly stored inside the cell and that surface expression is tightly regulated. Decreased surface expression on T cells from elderly individuals is associated with alterations in the methylation pattern of the FCMR gene. Binding and internalization of IgM stimulate transport of FcμR to the cell surface to ensure sustained IgM uptake. Concurrently, IgM accumulates within the cell, and the surface expression of other receptors increases, among them the T cell receptor (TCR) and costimulatory molecules. This leads to enhanced TCR signaling, proliferation, and cytokine release, in response to low, but not high, doses of antigen. Our findings indicate that FcμR is an important regulator of T cell function and reveal an additional mode of interaction between B and T cells. : Meryk et al. demonstrate that uptake of IgM mediated by FcμR expressed on T cells increases the surface expression of TCR and costimulatory molecules to facilitate T cell activation, particularly when antigen concentrations are low. Consequently, FcμR increases TCR signaling, proliferation, and cytokine release. Keywords: FcμR, IgM, T cells, TCR activatio

CD8+HLADR+ Regulatory T Cells Change With Aging: They Increase in Number, but Lose Checkpoint Inhibitory Molecules and Suppressive Function

CD4+ regulatory T cells have been intensively studied during aging, but little is still known about age-related changes of other regulatory T cell subsets. It was, therefore, the goal of the present study to analyze CD8+human leukocyte antigen–antigen D related (HLADR)+ T cells in old age, a cell population reported to have suppressive activity and to be connected to specific genetic variants. We demonstrate a strong increase in the number of CD8+HLADR+ T cells with age in a cohort of female Sardinians as well as in elderly male and female persons from Austria. We also show that CD8+HLADR+ T cells lack classical activation molecules, such as CD69 and CD25, but contain increased numbers of checkpoint inhibitory molecules, such as cytotoxic T lymphocyte-associated antigen 4, T cell immunoglobulin and mucin protein-3, LAG-3, and PD-1, when compared with their HLADR− counterparts. They also have the capacity to inhibit the proliferation of autologous peripheral blood mononuclear cells. This suppressive activity is, however, decreased when CD8+HLADR+ T cells from elderly persons are analyzed. In accordance with this finding, CD8+HLADR+ T cells from persons of old age contain lower percentages of checkpoint inhibitory molecules than young controls. We conclude that in spite of high abundance of a CD8+ regulatory T cell subset in old age its expression of checkpoint inhibitory molecules and its suppressive function on a per cell basis are reduced. Reduction of suppressive capacity may support uncontrolled subclinical inflammatory processes referred to as “inflamm-aging.