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Summary: The in‐depth understanding of skin resident memory CD8+ T lymphocytes (TRM) may help to uncover strategies for their manipulation during disease. We investigated isolated TRM from healthy human skin, which expressed the residence marker CD69, and compared them to circulating CD8+ T cell populations from the same donors. There were significantly increased proportions of CD8+CD45RA–CD27– T cells in the skin that expressed low levels of killer cell lectin‐like receptor G1 (KLRG1), CD57, perforin and granzyme B. The CD8+ TRM in skin were therefore phenotypically distinct from circulating CD8+CD45RA–CD27– T cells that expressed high levels of all these molecules. Nevertheless, the activation of CD8+ TRM with T cell receptor (TCR)/CD28 or interleukin (IL)‐2 or IL‐15 in vitro induced the expression of granzyme B. Blocking signalling through the inhibitory receptor programmed cell death 1 (PD)‐1 further boosted granzyme B expression. A unique feature of some CD8+ TRM cells was their ability to secrete high levels of tumour necrosis factor (TNF)‐α and IL‐2, a cytokine combination that was not seen frequently in circulating CD8+ T cells. The cutaneous CD8+ TRM are therefore diverse, and appear to be phenotypically and functionally distinct from circulating cells. Indeed, the surface receptors used to distinguish differentiation stages of blood T cells cannot be applied to T cells in the skin. Furthermore, the function of cutaneous TRM appears to be stringently controlled by environmental signals in situ. [ABSTRACT FROM AUTHOR]

Two studies with the same goal, but different instruments, investigated the correlation between basic personality traits and electrodermal reactivity to aversive visual stimuli. Study 1 focused on the Five Factor Model traits, while in Study 2, we investigated the HEXACO model, and an additional trait, Disintegration. In Study 1, emotional reactivity was expressed using Polyscore, a composite polygraph measure in which electrodermal response (EDR) had the largest weight, and it was measured with respect to stimuli with positive, neutral, and negative valences. In Study 2, we employed several measures of EDR to stimuli with negative valence. In both experiments, Conscientiousness correlated positively with EDR to aversive stimuli. Additionally, in Study 2, there was a negative correlation between Disintegration and EDR to aversive stimuli. Other traits were not related to EDR to aversive stimuli, and, in Study 1, we found no relationship between personality traits and reactivity to stimuli with positive or neutral valence.

Background/Aim. Systemic sclerosis (SSc) is a chronic systemic disease of the connective tissue. It is characterized by diffuse microangiopathy, increased activity and creating deposits of collagen in the skin and internal organs. Involvement of the lung function disturbances in SSc is a bad prognostic sign. The aim of our study was to investigate the association between smoking habits and lung function disorder in the SSc patients. Methods. The testing was conducted at the Clinic for Rheumatology and Immunology of the Military Medical Academy in 2016. In this study, we included 42 patients with the newly diagnosed SSc and the patients whose disease had been diagnosed earlier. Results. The patients were classified according to the smoking habits, 14 (33.3%) patients were nonsmokers, while 28 (66.7%) patients were current (23 patients) or ex-smokers (5 patients). We found no significant differences in examined parameters among smokers and nonsmokers. In addition, distribution of the patients with the obstructive pulmonary pattern revealed by spirometry was uniform between smokers and nonsmokers. The concentrations of C reactive protein (CRP) were significantly higher in the SSc patients with the obstructive pulmonary pattern. The patients with the obstructive pattern on spirometry had significantly lower values of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1/FVC ratio, diffusing lung capacity for carbon monoxide (DLCO) and FVC/DLCO ratio. Conclusion. In our study, we concluded that in the SSc patients with the obstructive pulmonary pattern revealed by spirometry, there were no significant differences between smokers and nonsmokers. CRP is a significant predictor of the lung involvement existence in the SSc patients.

Background: Systemic sclerosis (SSc) is an autoimmune connective tissue disease which affects various tissues and organs, including skin, lungs, kidneys, gastrointestinal tract and cardiovascular system. Cardiac involvement is the most commonly recognized problem and a significant cause of morbidity. The brain natriuretic peptide (BNP) is a previously known marker of elevated cardiovascular risk in SSc, but the levels of BNP in various forms of SSc have not been investigated so far. Aim: The aim of our study was to evaluate the influence of SSc on the function of the right ventricle and the right atrium using the echocardiographic parameters. Moreover, we examined the levels of BNP in different forms of SSc as well as the association of disease severity with the plasma concentrations of BNP Methods: We included 42 patients with newly diagnosed SSc and patients whose disease had been diagnosed earlier. SSc patients and non-SSc control patients were examined by using echocardiography and the concentrations of BNP were determined. Results: We analyzed differences in the parameters of right ventricle (RV) function and right atrium (RA) function between SSc patients and healthy controls. The two groups had similar distribution of gender, but SSc patients were significantly older than controls. RV wall thickness was increased in SSc patients (p< 0.001), while right ventricular end-systolic area (RVesa; p= 0.408) and right ventricular end-diastolic area (RVEDa; p= 0.368) did not differ among the examines. In contrast, RA minor-axis dimension (p=0.001) and the tricuspid annular plane systolic excursion (TAPSE) (p= 0.001) were significantly higher in SSc patients. Also, we analyzed differences in brain natriuretic peptide (BNP) concentrations between diffuse cutaneous systemic sclerosis (DSSc) and limited cutaneous systemic sclerosis (LSSc) patients. DSSc patients had significantly higher concentrations of BNP. We found that levels of BNP were in significant positive correlations with age (p= 0.007), disease duration (p= 0.023), C reactive protein (CRP) (p= 0.032), right ventricle fractional area change (FAC) (p= 0.022), pulmonary vascular resistance (PVR) and Rodnan score (p= 0.019). Conclusions: Given the obtained results, the laboratory determination of BNP could be useful in differentiating different forms of systemic sclerosis as well as in predicting the severity of the disease and future cardiovascular complications.

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Introduction/Objective. Increasing incidence of spinal cord injuries presents a very important issue. These patients are usually very young, treatment is very tough, long, expensive and, in general, of little success rate. The aim of this study was to evaluate the angiogenic potential of the omental graft in spinal cord revascularization after the injury. Methods. The study included 19 patients, who underwent recurrent surgical procedure for pain syndrome or surgical complication, and one patient in whom angiography revealed no flow in distal part of omental graft. Results. Our study confirmed angiogenic capabilities of omental graft placed in the course of omentomyelopexy for the injured spinal cord revascularization, macroscopically and histopathologically. Study results are limited due to inclusion of patients, only when the postoperative period was complicated. Conclusion. Our study provides some insight into the angiogenic capabilities. Although, further (likely less invasive) studies are needed to provide more insight into omental angiogenesis and to include patients in whom the procedure went well.

Background/Aim. Sarcoidosis is a multisystem infmammatory disease of unknown etiology, with the lungs and intrathoracic lymph nodes the most commonly involved. The aim of this study was to assess the contribution of conventional transbronchial needle aspiration (TBNA) cytology in the diagnosis of sarcoidosis presenting as mediastinal/hilar lymphadenopathy. Methods. In this retrospective study, 58 patients with suspicion of stage I and II sarcoidosis underwent first flexibile, and then, a rigid bronhoscopy, during which TBNA of mediastinal or hilar lumph node with a 19 gauge (G) needle was done. Material from the needle was put on glass slide and prepared for the cytological and histopathological examination. Results. Out of 58 patients submitted to TBNA of mediastinal or hilar lymph nodes, adequate material for cytological diagnostics was obtained in 53 (91.37%). Out of 53 adequate cytological samples, in 38 (71.69%) noncaseous granulomatous inflammation (NGI) was found, while in corresponding histopathological samples, NGI was found in 48 (90.56%), which was significantly higher (p < 0.05). Of cytological smears, out of the cell types typical for granulomatous inflammation, in 26 (63.15%) patients the clusters of the epitheloid cells were found, in 8 (21.05%) there were both, clusters of epitheloid cells and giant multinuclear hystiocytes, and in 6 (15.76%) only single scattered epitheloid cells or small clusters of several epitheloid cells were found. The sensitivity of TBNA cytology in our group of patients with sarcoidosis was 76%, specificity 100% and accuracy 77.34%. Conclusion. TBNA is an efficient and safe procedure in the diagnosis of sarcoidosis, minimally invasive and with a little risk of complications. Using 19 G needle enables obtaining material for histological and cytological analyses, as well which contribute to the sensitivity of diagnosting sarcoidosis. The value of this type of diagnostics depends on qualification and experience both of bronchoscopist and cytologist/pathologist, as well, of the interpreter of such a material.

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The isatin derivatives, Schiff bases, were synthesized by the reaction of isatin and various substituted primary amines and characterized by several spectroscopic methods. Investigation of the antimicrobial activity of the synthesized compounds was performed by the agar dilution method, against different strains of bacteria and one fungi. The antioxidative activity of the synthesized compounds was also determined. Some of the compounds have shown the significant activity against the selected strains of microorganisms and the antioxidative activity. [Projekat Ministarstva nauke Republike Srbije, br. 172013 i III 46010]

Individual protection of the respiratory tract is a key factor in preventing/stopping a potential epidemic/pandemic caused naturally or during biological agents application in war or terrorist activities. Improving the existing or introducing new appropriate personal protective equipment to the military environment would be invaluable. In order to acquire a confirmation of reliability and physiological suitability for use in the protection of military personnel in case of a declared epidemic/pandemic, the protection effectiveness and physiological suitability of three models of epidemiological masks were tested in accordance with BS EN 149: 2007 under the conditions of simulated biological air contamination. The test results and their statistical processing have shown that an epidemiological mask possesses high efficiency and physiological suitability as a protective device in the case of air contamination with aerosols of biological agents. It is recommended for use in peacetime together with the existing standard military masks.

Introduction. Natural course of aneurysms that occur on blood vessels of the brain singles out the need for understanding the mechanism of the occurrence of aneurysm wall rupture and identification of anatomic characteristics as predictive factors for hemorrhage to occur. Objective. In this study we comparatively present results of our researches and experimental models on animals. Methods. We made a comparative analysis of anatomical characteristics of blood vessels of the brain and aneurysms obtained on the basis of digital subtraction angiography and intraoperative finding. In this article we review recent research in the anatomic characteristics of intracranial aneurysms and parent blood vessels. We present a series of 185 aneurysms (ruptured and unruptured) dissected at the Neurosurgical Clinic of Clinical Center of Serbia in Belgrade. Results. Inclination angle may be considered as the vital predesposing factor for intracranial aneurysm rupture. In aneurysms that ruptured it was 139.748±27.242°, while in unruptured aneurysms it was considerably smaller and amounted to 100.882±22.001° (p

Background/Aim. During exposure to low-level doses (LLD) of ionizing radiation (IR), the most of harmful effects are produced indirectly, through radiolysis of water and formation of reactive oxygen species (ROS). The antioxidant enzymes - superoxide dismutase (SOD): manganese SOD (MnSOD) and copper-zinc SOD (CuZnSOD), as well as glutathione (GSH), are the most important intracellular antioxidants in the metabolism of ROS. Overproduction of ROS challenges antioxidant enzymes. The aim of this study was to examine if previous exposure to low doses of IR induces adaptive response by means of stimulation of intracellular antioxidant defense system. Methods. We investigated a group of medical workers occupationally exposed to IR (n = 44), 29 male and 15 female. The controls (n = 33) consisted of medical workers not exposed to IR, 23 male and 10 female. The examinees from both groups worked in the same environment and matched in crucial characteristics. All measurements were performed by a calibrated thermoluminiscent dosimeter type CaF2:Mn. SOD activity and GSH content were measured spectrophotometrically in the plasma of both groups of medical workers. Half of each blood sample was irradiated by 2Gy of γ radiation, dose-rate 0.45 Gy/min, and the distance from the source of 74 cm. Results. The dosimetry results indicate that occupational doses were very low. Our results confirmed significantly higher SOD activity in the exposed vs. unexposed workers (p < 0.00006). SOD activity after irradiation of blood samples failed to show a significant difference between the exposed workers and the controls (p = 0.905), even the difference in each group before and after the irradiation was significant. In blood samples of the exposed workers expression of enzymes after the irradiation, was not as high as in the controls, or even in the case of the exposed in nuclear medicine personnel, SOD activity was decreased. There were no significant differences in the content of GSH between the groups. Conclusion. Our results pointed out that occupational exposure to low doses of IR compromised mitochondrial function. During occupational exposure, the activity of antioxidant enzymes was increased as a protection against the increased production of ROS. After high-dose irradiation dysfunction of mitochondrial system was noticed, suggesting the break-down of antioxidant defense and failure of an adaptive response. Therefore, the "chronic oxidative stress" might reduce antioxidant defense in the case of accidental exposure to high doses of IR. It could indirectly increase the incidence of some other "free radicals' diseases" in occupationally exposed personnel. .

Introduction: The size of meningioma and its relation with neurovascular structures in petroclival region stipulate the degree of surgical radicalism and determine an operation risk. In spite of progress of surgical technology, the rate of surgical morbidity in view of cranial nerves deficit is 30%-50%. Objective: The objective of our study was to present the results of treatment of patients with petroclival meningiomas and to point to correlation of preoperative radiological findings and intraoperative results as well as neurological status of patients before and after surgical treatment. Method: Retrospective analysis of 35 operated petroclival meningiomas at the Institute of Neurosurgery, CCS, in the period from 1995 to 2004 was presented. The following parameters were analyzed: size of tumor, relation with bone and neurovascular structures, preoperative condition, degree of surgical radicalism and postoperative outcome. Results: The size of tumor was classified in four groups. There were 20 tumors at the right, and 15 at the left side. At the time of diagnostic procedures (based on CT and MRI), 20 tumors were in contact with brainstem, 9 compressed the brainstem, and 6 obstructed the IV ventricle. Preoperative patient condition was evaluated by Karnofsky index. Mean value for group I was 90, II - 80, III - 70 and IV - 50. In 9 cases, liquor drainage was performed preoperatively. In 3 cases, external liquor drainage was carried out postoperatively, and in one case it was replaced by permanent liquor drainage. Radical operation was performed in 44%, and significant reduction was done in other cases. In the postoperative period, 11% patients died, 28% had cranial nerves deficit, and pyramid deficit was recorded in 14% of the patients. The tumor size (III-IV) and brainstem compression were found to be statistically significant (p

Background. Traumatic delayed epidural hematoma (DEH) can be defined as insignificant or not seen on the initial CT scan performed after a trauma but seen on the subsequent CT scan as a “massive” epidural bleeding. Case report. We presented two cases of traumatic DEH after mild head injury. Both patients were conscious and without neurological deficit on the admission. Initial CT scan did not reveal intracranial hematoma. Repeated CT scan, that was performed after neurological deterioration, revealed epidural hematoma in both cases. The patients were operated with a favorable surgical outcome. Conclusion. Traumatic DEH could occur in the patients with head injuries who were conscious on the admission with a normal initial CT scan finding. Early detection of DEH and an urgent surgical evacuation were essential for a good outcome.

INTRODUCTION Hydrocephalus is one of the most significant complications of spontaneous subarachnoidal haemorrhaging that can be treated surgically. OBJECTIVE We analyzed risk factors that caused spontaneous subarachnoidal haemorrhaging. Patients were divided into two groups: shunt-dependent and shunt-independent. METHOD We retrospectively analyzed 174 patients (63 men and 111 women), surgically treated at the Institute of Neurosurgery of Clinical Center of Serbia in the period from January 2002 to January 2004. RESULTS The prevalence of hydrocephalus in patients with a shunt (shunt-dependent) was most significant in women (18%:9.5%), but not statistically significant (p>0.05). Concerning the significance of age (years), we found that hydrocephalus in patients with a shunt was most significant in older patients (p0.05%). In patients with intraventricular haemorrhaging (29.3%:10.5%) and vasospasms (34.6%:6.5%), the prevalence of shunt-dependent hydrocephalus was statistically very significant (p0.05). The prevalence of shunt-dependent hydrocephalus with aneurysms in the a. basillaris basin was 47.4%, with multiple aneurysms 17.2%, and with aneurysms of the anterior segment 9.5%, which represents a statistically significant difference (p

Radiation cataract is one of ensuing effects of ionizing radiation, since its threshold dose under which it does not occur, and above which it shows dose dependency, has been observed. Clinical course of radiation cataract is identical for all the types of ionizing radiation and is very typical. Minimal dose for progressive cataract formation is determined by the type of radiation, i.e., its relative biological efficacy, dose, and the duration of the exposure period. Theoretically, threshold dose existence does not exclude the incidence of cataract formation under significantly smaller doses, as well. The aim of this study was to analyze the incidence of cataract formation among the medical staff professionally exposed to ionizing radiation. Neither of the diagnosed cataracts had typical morphology, nor was the correlation established between the dose, exposure time, and the cataract formation. All the diagnosed cataracts were described as premature, and therefore ionizing radiation was considered as a co-factor in premature cataract formation in the examined groups.

Cataract surgery is most common in human surgery and comprises 80% of eye surgery programs. Owing to sophisticated technologies, it has become a routine surgery with lowered complications rate; hence, the functional outcome is more conditioned by operative trauma. The aim of this study was to demonstrate the significance of specular microscopy in the evaluation of operative trauma during extra-capsular cataract extraction (ECCE) and phacoemulsification (P), in a controlled environment. The study included 100 consecutive patients who met the established criteria, and groups were formed according to the type of surgery by the assignment of successive numbers from a random number table. Examination and photographs of the corneal endothelium, as well as pachymetry were performed on Keeler-Konan Poclington Specular Microscope (KSP). The obtained results revealed significant dissimilarity in endothelial cell reduction (9.17% in group E, and 4.72% in group P), which generated statistically significant correlation of pre-operative and post-operative pachymetry in the group E (p=0.0004). On the basis of the results obtained by specular microscopy, it was concluded that under the same conditions phacoemulsification caused reduced operative trauma of the corneal endothelium.

BACKGROUND: Chronic exposure to low-dose radiation doses could be much more harmful than high, short-term doses because of lipid peroxidation initiated by free radicals. The cell membranes and cellular organelles are the main targets for free radicals attack. Peroxidation of cell membrane increases with decreasing dose rate (Petkau effect). The aim of this study was to establish if chronic occupational exposure to low-dose ionizing radiation could induce cell membrane damage. METHODS: Our investigation comprised 77 medical workers: 44 occupationally exposed to ionizing radiation (E), divided in two subgroups-exposed to x-rays (Ex) or gamma rays (En), and 33 controls (C). Informed consent and questionnaire containing dietary, habits, medical factors and exposure history were taken. Groups were matched in gender, age, dietary habits, alcohol consumption, smoking habit, and specific exposure time. Radiation dose accumulated by occupationally exposed over years was calculated on the basis of individual TL-dose records. Besides regular biochemical and cytogenetic tests, lipid peroxidation index, expressed as malondyaldehyde production was performed. RESULTS: Significantly higher lipid peroxidation index was found in workers occupationally exposed to low-dose of ionizing radiation (p>0.000028), which is correlated with age, smoking habit, and significantly correlated with doses. After blood samples in vitro irradiation by 2 Gy of gamma-radiation malondyaldehyde production significantly increased in each group, but were not significantly different between groups. CONCLUSION: Lipid peroxidation index could be considered as triage parameter for further cytogenetic studies in workers chronically exposed to low-dose radiation.

When B cells engage in an immune response, metabolic reprogramming is key to meeting cellular energetic and biosynthetic demands. Epstein-Barr virus (EBV) is a highly prevalent gamma-herpesvirus, latently infecting B cells for the human host's lifetime. By hijacking signaling pathways of T cell-dependent humoral immunity, EBV activates B cells in a T cell-independent manner, forcing lymphoblastoid transformation. Interlinked with this coercion of signaling pathways, EBV has also evolved strategies to manipulate B cell metabolism. In this opinion article we integrate recent findings from studies of B cell metabolic reprogramming after EBV infection and during antigen-specific activation, respectively. We hypothesize that defining EBV host-cell metabolic vulnerabilities that differ from pathways required for B cell immunity might uncover novel therapeutic targets against EBV-related diseases., Competing Interests: Declaration of interests C.H., B.M-D., and G.R.B. are inventors on a patent relating to a study referenced in this manuscript filed by the University of Basel (EP 21161105.8) which is being developed in a start-up company (Hornet Therapeutics Ltd; Scientific Founder: C.H.). C.H. is a board member of Hornet Therapeutics. The authors declare that they have no other competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

After infection of B cells, Epstein-Barr virus (EBV) engages host pathways that mediate cell proliferation and transformation, contributing to the propensity of the virus to drive immune dysregulation and lymphomagenesis. We found that the EBV protein EBNA2 initiates nicotinamide adenine dinucleotide (NAD) de novo biosynthesis by driving expression of the metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in infected B cells. Virus-enforced NAD production sustained mitochondrial complex I activity, to match adenosine triphosphate (ATP) production with bioenergetic requirements of proliferation and transformation. In transplant patients, IDO1 expression in EBV-infected B cells, and a serum signature of increased IDO1 activity, preceded development of lymphoma. In humanized mice infected with EBV, IDO1 inhibition reduced both viremia and lymphomagenesis. Virus-orchestrated NAD biosynthesis is therefore a druggable metabolic vulnerability of EBV-driven B cell transformation, opening therapeutic possibilities for EBV-related diseases.

Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.

Latent Epstein-Barr virus (EBV) infection can clinically reactivate in immunosuppressed individuals causing lymphoproliferative disease and rarely hepatitis. In this study, we provide in vivo and in vitro evidence that Treponema pallidum infection can cause EBV reactivation with hepatitis in an immunocompetent patient. We report the diagnostic challenges and immunological findings of coinciding syphilis and EBV-associated hepatitis. Using an in vitro EBV-reactivation assay, we demonstrate that T pallidum reactivates latent EBV in a Toll-like receptor (TLR)2/B-cell receptor signaling-dependent manner. Epstein-Barr virus-associated reactivation or lymphoproliferation should be considered in infections with pathogens that activate TLR2., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Natural killer cells lacking expression of CD56 (CD56 neg NK cells) have been described in chronic HIV and hepatitis C virus infection. Features and functions of CD56 neg NK cells in the context of latent infection with CMV and / or EBV with age are not known. In a cohort of healthy donors >60 years of age, we found that co-infection with CMV and EBV drives expansion of CD56 neg NK cells. Functionally, CD56 neg NK cells displayed reduced cytotoxic capacity and IFN-γ production, a feature that was enhanced with CMV / EBV co-infection. Further, the frequency of CD56 neg NK cells correlated with accumulation of end-stage-differentiated T cells and a reduced CD4 / CD8 T cell ratio, reflecting an immune risk profile. CD56 neg NK cells had a mature phenotype characterized by low CD57 and KIR expression and lacked characteristics of cell senescence. No changes in their activating NK cell receptor expression, and no upregulation of the negative co-stimulation receptors PD-1 or TIM-3 were observed. In all, our data identify expansion of dysfunctional CD56 neg NK cells in CMV + EBV + elderly individuals suggesting that these cells may function as shape-shifters of cellular immunity and argue for a previously unrecognized role of EBV in mediating immune risk in the elderly.

Mitogen-activated protein kinases (MAPKs) including Erk, Jnk and p38 regulate diverse cellular functions and are thought to be controlled by independent upstream activation cascades. Here we show that the sestrins bind to and coordinate simultaneous Erk, Jnk and p38 MAPK activation in T lymphocytes within a new immune-inhibitory complex (sestrin-MAPK activation complex (sMAC)). Whereas sestrin ablation resulted in broad reconstitution of immune function in stressed T cells, inhibition of individual MAPKs allowed only partial functional recovery. T cells from old humans (>65 years old) or mice (16-20 months old) were more likely to form the sMAC, and disruption of this complex restored antigen-specific functional responses in these cells. Correspondingly, sestrin deficiency or simultaneous inhibition of all three MAPKs enhanced vaccine responsiveness in old mice. Thus, disruption of sMAC provides a foundation for rejuvenating immunity during aging.

NK cells are the first line of defense against infected and transformed cells. Defective NK cell activity was shown to increase susceptibility for viral infections and reduce tumor immune-surveillance. With age, the incidence of infectious diseases and malignancy rises dramatically, suggesting that impaired NK cell function might contribute to disease in these individuals. We found an increased frequency of NK cells with high expression of the inhibitory killer cell lectin-like receptor G1 (KLRG1) in individuals >70 y. The role of KLRG1 in ageing is not known, and the mechanism of KLRG1-induced inhibition of NK cell function is not fully understood. We report that NK cells with high KLRG1 expression spontaneously activate the metabolic sensor AMP-activated protein kinase (AMPK) and that activation of AMPK negatively regulates NK cell function. Pre-existing AMPK activity is further amplified by ligation of KLRG1 in these cells, which leads to internalization of the receptor and allows interaction with AMPK. We show that KLRG1 activates AMPK by preventing its inhibitory dephosphorylation by protein phosphatase-2C rather than inducing de novo kinase activation. Finally, inhibition of KLRG1 or AMPK prevented KLRG1-induced activation of AMPK and reductions in NK cell cytotoxicity, cytokine secretion, proliferation, and telomerase expression. This novel signaling pathway links metabolic sensing, effector function, and cell differentiation with inhibitory receptor signaling that may be exploited to enhance NK cell activity during ageing., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Antigen-experienced memory T cells acquire effector function with innate-like kinetics; however, the metabolic requirements of these cells are unknown. Here we show that rapid interferon-γ (IFN-γ) production of effector memory (EM) CD8(+) T cells, activated through stimulation mediated by the T cell antigen receptor (TCR) and the costimulatory receptor CD28 or through cognate interactions, was linked to increased glycolytic flux. EM CD8(+) T cells exhibited more glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity at early time points, before proliferation commenced, than did naive cells activated under similar conditions. CD28 signaling via the serine-threonine kinase Akt and the metabolic-checkpoint kinase mTORC2 was needed to sustain TCR-mediated immediate-early glycolysis. Unlike glycolysis in proliferating cells, immediate-early glycolysis in memory CD8(+) T cells was rapamycin insensitive. Thus, CD8(+) memory T cells have an Akt-dependent 'imprinted' glycolytic potential that is required for efficient immediate-early IFN-γ recall responses.

Epstein-Barr virus (EBV) infects ≈ 95% of the adult population. The factors that confer protection in the remaining ≈ 5% remain unknown. In an exploratory study, we assessed immunogenetic factors and tonsillectomy in a cohort of 17 EBV-negative and 39 EBV-positive healthy individuals aged >60 years. Analyses of HLA genotypes revealed an association between EBV negativity and the presence of HLA-C-35T/T and/or HLA-Bw4 alleles. In addition, EBV-negative donors presented with a history of tonsillectomy more often than EBV-positive donors.

T cells exit secondary lymphoid organs along a sphingosine1-phosphate (S1P) gradient and, accordingly, are reduced in blood upon fingolimod-mediated S1P-receptor (S1PR)-blockade. Serving as a model of adaptive immunity, we characterized cellular and humoral immune responses to influenza vaccine in fingolimod-treated patients with multiple sclerosis (MS) and in untreated healthy controls. Although the mode of action of fingolimod might predict reduced immunity, vaccine-triggered T cells accumulated normally in blood despite efficient S1PR-blockade. Concentrations of anti-influenza A/B immunoglobulin (Ig)M and IgG also increased similarly in both groups. These results indicate that fingolimod-treated individuals can mount vaccine-specific adaptive immune responses comparable to healthy controls., (Copyright © 2011 American Neurological Association.)

In a prospective influenza-vaccination trial we show that HIV-infected individuals with CD4 T-cell counts less than 350 microl were distinct from HIV-infected individuals with more than 350 CD4 T-cell counts/microl, and from HIV-negative individuals, in that an influenza-specific immunoglobulin M-response was absent and expansion of interferon-gamma-secreting CD4 T cells was impaired. By contrast, immunoglobulin G-responses were induced in all study groups. These data suggest that establishing broad influenza-specific (immunoglobulin G) B-cell memory prior to severe immunodeficiency is important.

This study exploited alloreactivity of natural killer (NK) cells for augmenting the recognition of human acute myeloid leukemia (AML). To circumvent the inhibitory effect of killer immunoglobulin receptor (KIR) signaling, we generated NK-cell lines with single KIR specificities for major human leukocyte antigen (HLA) class I allotypes. We demonstrated efficient cytolysis of KIR-HLA class I-mismatched primary AML blasts even at low effector-to-target ratios. To define the impact of tumor-associated activating NKG2D-ligands (NKG2D-L), 66 AML patients at diagnosis were analyzed. NKG2D-L were selectively expressed on monoblastic cells in AML M4 and M5 yet absent or weakly expressed on myeloblastic cells in all AML subtypes. Paucity of cell-surface NKG2D-L was not the result of shedding because levels of soluble ULBP1 ligand measured in AML plasma were in the normal range. Notably, purified NKG2D-L(+) monoblastic cells were more susceptible to NK-mediated killing than NKG2D-L(-) myeloblastic cells. Accordingly, induction of cell-surface NKG2D-L by treatment with the histone deacetylase inhibitor, valproic acid, rendered cells more sensitive to NK cytolysis. These data suggest that adoptive transfer of selected populations of alloreactive HLA class I-mismatched NK cells in combination with pharmacologic induction of NKG2D-L merits clinical evaluation as novel approaches to immunotherapy of human AML.