Stoyan Dimitrov

Stoyan Dimitrov
University of Tuebingen | EKU Tübingen · Institute of Medical Psychology and Behavioral Neurobiology

Ph.D.

About

63
Publications
12,410
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Introduction
My research is in the area of neuroimmunology: effect of sleep, circadian rhythm and Galpha(s)-coupled receptor signaling on immune system. My primary interest is the regulation of integrin activation on antigen-specific T cells by Galpha(s)-coupled receptor stimulation. I have a vast experience (20+) in flow cytometry and evaluation of T-cell immune response. Recently we have published a ms in PNAS describing a method for assessment and isolation of antigen-specific T cells detecting activated integrins by multimeric ICAM-1. My hope for the next few years is to further advance the ICAM-1 assay in order to be implemented broadly for the measurement and isolation of functional antigen-specific T cells in basic research and in the clinical setting.

Publications

Publications (63)
Article
Full-text available
Conformational change of the β2 integrin lymphocyte function‐associated antigen 1 (LFA‐1) is an early marker of T cell activation. A protocol using the monoclonal antibody (mAb) clone m24 recognizing the active, extended high‐affinity conformation has been previously described for the assessment of functional CD4+ and CD8+ T cells in response to MH...
Article
Full-text available
We have previously shown that conformational change in the β2-integrin is a very early activation marker that can be detected with fluorescent multimers of its ligand intercellular adhesion molecule (ICAM)-1 for rapid assessment of antigen-specific CD8+ T cells. In this study, we describe a modified protocol of this assay for sensitive detection of...
Article
Full-text available
Dietary obesity compromises brain function, but the effects of high-fat food on synaptic transmission in hypothalamic networks, as well as their potential reversibility, are yet to be fully characterized. We investigated the impact of high-fat feeding on a hallmark of synaptic plasticity, i.e., the expression of glutamatergic α-amino-3-hydroxy-5-me...
Preprint
Full-text available
We have previously shown that beta 2 -integrin conformational change is a very early activation marker that can be detected with fluorescent multimers of its ligand ICAM-1 for a rapid assessment of antigen-specific CD8 ⁺ T cells. Here, we describe a modified protocol of this assay for sensitive detection of functional antigen-specific CD4 ⁺ T cells...
Article
Full-text available
Monitoring T cells is of major importance for the development of immunotherapies. Recent sophisticated assays can address particular aspects of the anti-tumor T-cell repertoire or support very large-scale immune screening for biomarker discovery. Robust methods for the routine assessment of the quantity and quality of antigen-specific T cells remai...
Article
Full-text available
Background: Obesity and depression are complex conditions with stronger comorbid relationships among women than men. Inflammation and cardiometabolic dysfunction are likely mechanistic candidates for increased depression risk, and their prevalence differs by sex. Whether these relationships extend to depressive symptoms is poorly understood. There...
Article
Full-text available
Although the CNS is immune privileged, continuous search for pathogens and tumours by immune cells within the CNS is indispensable. Thus, distinct immune-cell populations also cross the blood-brain barrier independently of inflammation/under homeostatic conditions. It was previously shown that effector memory T cells populate healthy CNS parenchyma...
Article
Full-text available
Efficient T cell responses require the firm adhesion of T cells to their targets, e.g., virus-infected cells, which depends on T cell receptor (TCR)–mediated activation of β 2 -integrins. Gα s -coupled receptor agonists are known to have immunosuppressive effects, but their impact on TCR-mediated integrin activation is unknown. Using multimers of p...
Data
Graphical summary to the article "Activated integrins identify functional antigen-specific CD8 + T cells within minutes after antigen stimulation": Following T-cell receptor-mediated stimulation, integrin activation occurs within seconds through a process known as "inside-out" signaling that leads to an affinity increase and clustering of membran...
Data
Supplementary information to the article "Activated integrins identify functional antigen-specific CD8 + T cells within minutes after antigen stimulation"
Article
Full-text available
Immediate β2-integrin activation upon T cell receptor stimulation is critical for effective interaction between T cells and their targets and may therefore be used for the rapid identification and isolation of functional T cells. We present a simple and sensitive flow cytometry-based assay to assess antigen-specific T cells using fluorescent interc...
Article
Full-text available
Sleep is essential for health. Slow wave sleep (SWS), the deepest sleep stage hallmarked by electroencephalographic slow oscillations (SOs), appears of particular relevance here. SWS is associated with a unique endocrine milieu comprising minimum cortisol and high aldosterone, growth hormone (GH), and prolactin levels, thereby presumably fostering...
Article
Regular exercise is shown to exert anti-inflammatory effects, yet the effects of acute exercise on cellular inflammatory responses and its mechanisms remain unclear. We tested the hypothesis that sympathoadrenergic activation during a single bout of exercise has a suppressive effect on monocytic cytokine production mediated by β2 adrenergic recepto...
Article
In humans, the numbers of cytotoxic T lymphocytes (CTLs) in blood display a strong circadian rhythm with a steep decrease from night to daytime. However, CTLs are composed of various subsets and exert antigen-specific responses which are highly adapted to the specific pathogen. We therefore investigated whether CTL subpopulations of distinct antige...
Article
An efficient immune response requires a selective and strong interaction of T cells with endothelium or target cells. These interactions are strengthened by the rapid induction of beta2-integrin-mediated adhesion upon chemokine receptor or T-cell receptor (TCR) stimulation, respectively. We and others have shown that an increase in G-alpha-s-protei...
Article
Pathophysiology of hypertension includes hyperactive sympathoadrenal system and elevated inflammation, but the link between the two and its clinical risk remain unclear. Subclinically elevated blood pressure (BP), pre-hypertension (PHT), is related to future cardiovascular disease (CVD) and greater mortality. In 177 adults with PHT (125 < SBP < 140...
Article
In humans numbers of circulating T cells show a circadian rhythm with peak counts during the night and a steep decline in the morning. Sleep per se appears to counter this rhythm by acutely reducing the number of total T cells. The T-cell population, however, is rather heterogeneous comprising various subpopulations with different features and func...
Article
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is observed in various conditions, including depression and obesity, which are also often related. Glucocorticoid (GC) resistance and desensitization of peripheral GC receptors (GRs) are often the case in HPA dysregulation seen in depression, and GC plays a critical role in regulation o...
Article
Circulating T cells show circadian rhythms, the direction and extent of which depend on the specific subset. Naïve and memory T cells peak during nocturnal sleep, whereas cytotoxic effector T cells show an opposite rhythm with highest numbers during daytime. In the current study, we were interested in how sleep affects these different circadian rhy...
Article
We have previously reported that low-grade systemic inflammation is associated with compromised immunocompetence in obese individuals. We then showed that an extended recombinant human-TNF treatment of monocytes results in decreased immune response, indicating contribution of chronic inflammation in compromised immunity in obesity. In this study we...
Article
Overwhelming data indicate that individuals with even mildly elevated blood pressure (BP) are at great risk for developing clinical hypertension and future cardiovascular disease (CVD). There remains a lack of consensus regarding treatment strategies for mildly elevated BP, termed prehypertension, and the knowledge of pathophysiology and mechanisms...
Article
Tumor necrosis factor (TNF) is considered a key molecule in the regulation of sleep in health and disease. Conversely, sleep compared to sleep deprivation can modulate TNF release, but overall results are conflicting. In this study we focused on the influence of sleep on spontaneous, i.e., unstimulated TNF production, which might be involved in sle...
Article
Full-text available
Glucocorticoids are well-known to affect T-cell migration, leading to a redistribution of the cells from blood to the bone marrow, accompanied by a concurrent suppression of lymph node homing. Despite numerous studies in this context with most of them employing synthetic glucocorticoids in rather non-physiological doses, the mechanisms of this redi...
Article
Evidence shows that both poor physical fitness and obesity are linked to low-grade inflammation and inflammatory diseases. However, their relative roles on inflammation and underlying mechanisms remain unclear. Given the inhibitory effect of catecholamines on inflammatory cytokine production, we speculated that compromised responsiveness of immune...
Article
Obesity is a state of chronic inflammation and also characterized by compromised immunocompetence. Little knowledge is available in cellular mechanism linking chronic inflammation and impaired immunity. We investigated systemic inflammation and antigen-stimulated intracellular cytokine levels in 96 asymptomatic individuals and effects of in vitro r...
Article
Elevated blood pressure (BP) and infiltration of the vasculature by monocytes contribute to vascular pathology; but, monocyte migratory characteristics based on differing inflammatory potential under adrenergic activation remains unclear. We compared nonclassical (CD14(+)CD16(++); HLA-DR(+)), intermediate (CD14(++)CD16(+); HLA-DR(++)), and classica...
Article
Elevated blood pressure (BP) and infiltration of the vasculature by monocytes contribute to vascular pathology; but, monocyte migratory characteristics based on differing inflammatory potential under adrenergic activation remains unclear. We compared “non-classical” (CD16++CD14+), “intermediate” (CD16+CD14++), and “classical” (CD16-CD14++) monocyte...
Article
Immunosenescence is phenotypically characterized by increased cytokine-producing, effector immune cells. Elevated inflammation is associated with the pathophysiology of cardiovascular diseases, including heart failure (HF). Depression rates are greatly elevated in patients with HF, which is prognostic for adverse outcomes and related to disease sev...
Article
Elevated blood pressure (BP) has been associated with an increased inflammatory state; conversely, healthy lifestyle, leading to higher cardiovascular fitness and lower adiposity, is promoted to reduce inflammation. We examined relationships among cardiovascular fitness, adiposity, and circulating levels of TNF-alpha in 57 men and women with normal...
Article
Full-text available
Sleep regulates immune functions. We asked whether sleep can influence immunological memory formation. Twenty-seven healthy men were vaccinated against hepatitis A three times, at weeks 0, 8, and 16 with conditions of sleep versus wakefulness in the following night. Sleep was recorded polysomnographically, and hormone levels were assessed throughou...
Article
Many immune parameters show systematic fluctuations over the 24-h day in human blood. Circulating naive T-cells and production of proinflammatory cytokines, like interleukin-12 (IL-12), peak during nighttime, whereas cytotoxic effector leukocytes and production of the anti-inflammatory cytokine IL-10 peak during daytime. These temporal changes orig...
Article
Full-text available
It is well-known that acute stress, presumably as a first defense against pathogens, enhances PBMC counts by mobilizing these beta2-adrenoceptor positive cells from the marginal pool. Yet, only select leukocyte subsets participate in this phenomenon of adrenergic leukocytosis and underlying mechanisms are obscure. In this study, we analyzed in huma...
Article
Full-text available
Behavioral scientists have increasingly included inflammatory biology as mechanisms in their investigation of psychosocial dynamics on the pathobiology of disease. However, a lack of standardization of inclusion and exclusion criteria and assessment of relevant control variables impacts the interpretation of these studies. The present paper reviews...
Article
Full-text available
Pronounced circadian rhythms in numbers of circulating T cells reflect a systemic control of adaptive immunity whose mechanisms are obscure. Here, we show that circadian variations in T cell subpopulations in human blood are differentially regulated via release of cortisol and catecholamines. Within the CD4(+) and CD8(+) T cell subsets, naive cells...
Article
A number of immunological functions are dependent on circadian rhythms and regular sleep. This has impact on the type and magnitude of immune responses following antigenic challenge, for example in vaccination. Little is known about the underlying mechanisms. One possibility may be the circadian and sleep-dependent modulation of CD4(+)CD25(-) T cel...
Article
Growing evidence points towards a beneficial effect of sleep on immune function. Human studies indicate that the T cell mediated adaptive immune function including formation of antigen specific antibodies is facilitated by sleep. Along this line, here we aimed to dissociate the effect of sleep and circadian rhythm on circulating interleukin-7 (IL-7...
Article
Full-text available
There is evidence that sleep facilitates the adaptive immune response to infectious agents and, thereby, supports immunologic memory. The effect might be attained by sleep-induced changes in the number and function of dendritic cells (DCs), which play a key role in the initiation of the immune response. This study aimed to dissociate effects of sle...
Article
Full-text available
Sleep is commonly considered to support immune defense. The underlying sleep-immune interaction appears to rely critically on cytokines, like interleukin-6 (IL-6), that combine effects on immune and neuronal functions. The IL-6 signal is conveyed in two ways: it stimulates a restricted group of (mostly immune) cells via membrane-bound IL-6 receptor...
Article
Full-text available
Sleep is considered to strengthen immune defense. We hypothesized that sleep achieves this effect by shifting the balance between types 1 and 2 cytokine activity toward increased type 1 activity, thereby supporting adaptive cellular immune responses. We analyzed monocyte-derived type 1 (interleukin 12 [IL-12]) and type 2 (IL-10) cytokines by means...
Article
Slow wave sleep (SWS) is characterized by maximum release of growth hormone (GH) and minimum release of cortisol. We hypothesized that this hormonal pattern during SWS leads, in addition to generally increased T cell cytokine production, to a shift towards type1 cytokines. To test this hypothesis, blood was sampled from 8 humans during SWS, and who...
Article
While the acute phase reaction to infection is associated with hyperglycemia, during progressing infection hypoglycemia can develop. The cytokines regulating the dynamics of host defense may concurrently contribute to blood glucose regulation. To examine this hypothesis, changes in blood glucose concentrations in healthy men were compared following...
Article
Recent human studies suggested a supportive influence of regular nocturnal sleep on immune responses to experimental infection (vaccination). We hypothesized here that sleep could ease such responses by shifting the balance between T helper 1 (Th1) and T helper 2 (Th2) cytokine activity towards Th1 dominance thereby favoring cellular over humoral r...
Article
The release of the pituitary hormones, prolactin and growth hormone (GH), and of adrenal corticosteroids is subject to a profound regulation by sleep. In addition these hormones are known to be involved in the regulation of the immune response. Here, we examined their role for in vitro production of T-cell cytokines. Specifically, we hypothesized t...
Article
The release of the pituitary hormones, prolactin and growth hormone (GH), and of adrenal corticosteroids is subject to a profound regulation by sleep. In addition these hormones are known to be involved in the regulation of the immune response. Here, we examined their role for in vitro production of T-cell cytokines. Specifically, we hypothesized t...
Article
Recent human studies suggested a supportive influence of regular nocturnal sleep on immune responses to experimental infection (vaccination). We hypothesized here that sleep could ease such responses by shifting the balance between T helper 1 (Th1) and T helper 2 (Th2) cytokine activity towards Th1 dominance thereby favoring cellular over humoral r...

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Project (1)
Project
The goal of this project is to advance multimeric ICAM-1 and clone m24 Ab for detection of activated integrins and implement the method for the measurement and isolation of functional antigen-specific T cells for basic research and in the clinical setting.