Cheating the Hunger Games; Mechanisms Controlling Clonal Diversity of CD8 Effector and Memory Populations

Effector and memory CD8 T cells have an intrinsic difference in the way they must approach antigen; effector cells need to address the pathogen at hand and therefore favor outgrowth of only high-affinity clones. In contrast, the memory pool benefits from greater clonal diversity to recognize and eliminate pathogens with mutations in their immunogenic epitopes. Effector and memory fates are ultimately the result of the same three signals that control T cell activation; T cell receptor (TCR) engagement together with co-stimulation and cytokines. Great progress has been made in our understanding of the transcriptional programs that drive effector or memory differentiation. However, how these two different programs result from the same initial cues is still a matter of debate. An emerging image is that not only the classical three signals determine T cell differentiation, but also the ability of cells to access these signals relative to that of other activated clones. Inter-clonal competition is therefore not only a selective force, but also a mediator of CD8 T cell fate. How this is regulated on a transcriptional level, especially in the context of a selective “hunger game” based on antigen-affinity in which only cells of high-affinity are supposed to survive, is still poorly defined. In this review, we discuss recent literature that illustrates how antigen-affinity dependent inter-clonal competition shapes effector and memory populations in an environment of antigen affinity-driven selection. We argue that fine-tuning of TCR signal intensity presents an attractive target for regulating the scope of CD8 T cell vaccines

Cheating the Hunger Games; Mechanisms Controlling Clonal Diversity of CD8 Effector and Memory Populations

Effector and memory CD8 T cells have an intrinsic difference in the way they must approach antigen; effector cells need to address the pathogen at hand and therefore favor outgrowth of only high-affinity clones. In contrast, the memory pool benefits from greater clonal diversity to recognize and eliminate pathogens with mutations in their immunogenic epitopes. Effector and memory fates are ultimately the result of the same three signals that control T cell activation; T cell receptor (TCR) engagement together with co-stimulation and cytokines. Great progress has been made in our understanding of the transcriptional programs that drive effector or memory differentiation. However, how these two different programs result from the same initial cues is still a matter of debate. An emerging image is that not only the classical three signals determine T cell differentiation, but also the ability of cells to access these signals relative to that of other activated clones. Inter-clonal competition is therefore not only a selective force, but also a mediator of CD8 T cell fate. How this is regulated on a transcriptional level, especially in the context of a selective "hunger game" based on antigen-affinity in which only cells of high-affinity are supposed to survive, is still poorly defined. In this review, we discuss recent literature that illustrates how antigen-affinity dependent inter-clonal competition shapes effector and memory populations in an environment of antigen affinity-driven selection. We argue that fine-tuning of TCR signal intensity presents an attractive target for regulating the scope of CD8 T cell vaccines

The “Big Bang” in obese fat: Events initiatingobesity-induced adipose tissue inflammation

Obesity is associated with the accumulation of pro-inflammatory cells in visceral adiposetissue (VAT), which is an important underlying cause of insulin resistance and progres-sion to diabetes mellitus type 2 (DM2). Although the role of pro-inflammatory cytokinesin disease development is established, the initiating events leading to immune cell acti-vation remain elusive. Lean adipose tissue is predominantly populated with regulatorycells, such as eosinophils and type 2 innate lymphocytes. These cells maintain tissuehomeostasis through the excretion of type 2 cytokines, such as IL-4, IL-5, and IL-13,which keep adipose tissue macrophages (ATMs) in an anti-inflammatory, M2-like state.Diet-induced obesity is associated with the loss of tissue homeostasis and developmentof type 1 inflammatory responses in VAT, characterized by IFN-γ. A key event is a shiftof ATMs toward an M1 phenotype. Recent studies show that obesity-induced adipocytehypertrophy results in upregulated surface expression of stress markers. Adipose stressis detected by local sentinels, such as NK cells and CD8+T cells, which produce IFN-γ,driving M1 ATM polarization. A rapid accumulation of pro-inflammatory cells in VATfollows, leading to inflammation. In this review, we provide an overview of events lead-ing to adipose tissue inflammation, with a special focus on adipose homeostasis and theobesity-induced loss of homeostasis which marks the initiation of VAT inflammation

NK cell receptor NKG2D sets activation threshold for the NCR1 receptor early in NK cell development

The activation of natural killer (NK) cells depends on a change in the balance of signals from inhibitory and activating receptors. The activation threshold values of NK cells are thought to be set by engagement of inhibitory receptors during development. Here, we found that the activating receptor NKG2D specifically set the activation threshold for the activating receptor NCR1 through a process that required the adaptor DAP12. As a result, NKGD2-deficient (Klrk1-/-) mice controlled tumors and cytomegalovirus infection better than wild-type controls through the NCR1-induced production of the cytokine IFN-γ. Expression of NKG2D before the immature NK cell stage increased expression of the adaptor CD3ζ. Reduced expression of CD3ζ in Klrk1-/- mice was associated with enhanced signal transduction through NCR1, and CD3ζ deficiency resulted in hyper-responsiveness to stimulation via NCR1. Thus, an activating receptor developmentally set the activity of another activating receptor on NK cells and determined NK cell reactivity to cellular threats

Regulation of immune cell function and differentiation by the NKG2D receptor

NKG2D is one of the most intensively studied immune receptors of the past decade. Its unique binding and signaling properties, expression pattern, and functions have been attracting much interest within the field due to its potent antiviral and anti-tumor properties. As an activating receptor, NKG2D is expressed on cells of the innate and adaptive immune system. It recognizes stress-induced MHC class I-like ligands and acts as a molecular sensor for cells jeopardized by viral infections or DNA damage. Although the activating functions of NKG2D have been well documented, recent analysis of NKG2D-deficient mice suggests that this receptor may have a regulatory role during NK cell development. In this review, we will revisit known aspects of NKG2D functions and present new insights in the proposed influence of this molecule on hematopoietic differentiation

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Inflammageing mediated by cytotoxic lymphocytes is associated with diabetes duration

Aims: Inflammageing, the age-related systemic increase of proinflammatory factors, has been linked to the development of cardiovascular disease, chronic kidney disease and cancer in the elderly. Chronic inflammation is believed to be a causative factor in the development of diabetic complications. However, exactly how type 2 diabetes impacts the inflammatory state of the immune system is incompletely characterised. Methods: Blood collection and anthropometric measurements were performed in patients with type 2 diabetes (n=49) and control subjects (n=30). The phenotype, proliferation capacity and cytokine production by cytotoxic lymphocytes were analysed using multiparametric flow cytometry. Results: Type 2 diabetes did not impact the phenotype or proliferation of the investigated cells. However, we observed a significantly increased production of tumour necrosis factor-α by CD8+ T cells and Granzyme B by natural killer cells and γδ T cells compared to controls. Hyperresponsiveness of cytotoxic blood lymphocytes did not correlate with glycaemia or body mass index, but instead was associated with older age and longer diabetes duration. Conclusions: Type 2 diabetes is associated with an increased pro-inflammatory potential of cytotoxic blood lymphocytes correlating with age and diabetes duration. Further research is necessary to explore potential benefits of diabetes medications in reverting this effect

Type 2 diabetes and viral infection; cause and effect of disease

The recent pandemic of COVID-19 has made abundantly clear that Type 2 diabetes (T2D) increases the risk of more frequent and more severe viral infections. At the same time, pro-inflammatory cytokines of an anti-viral Type-I profile promote insulin resistance and form a risk factor for development of T2D. What this illustrates is that there is a reciprocal, detrimental interaction between the immune and endocrine system in the context of T2D. Why these two systems would interact at all long remained unclear. Recent findings indicate that transient changes in systemic metabolism are induced by the immune system as a strategy against viral infection. In people with T2D, this system fails, thereby negatively impacting the antiviral immune response. In addition, immune-mediated changes in systemic metabolism upon infection may aggravate glycemic control in T2D. In this review, we will discuss recent literature that sheds more light on how T2D impairs immune responses to viral infection and how virus-induced activation of the immune system increases risk of development of T2D