The results revealed that IL-13 significantly enhanced C/EBP-α/CO

The results revealed that IL-13 significantly enhanced C/EBP-α/COX-2 expression and PGE2 production in LPS-treated microglial cells. Paradoxically, IL-13 abolished C/EBP-β/PPAR-γ/HO-1

expression. IL-13 also enhanced ER stress-evoked calpain activation by promoting the association of C/EBP-β and PPAR-γ. SiRNA-C/EBP-α effectively reversed the combined LPS-activated caspase-12 activation and IL-13-induced apoptosis. In contrast, siRNA-C/EBP-β partially increased microglial PI3K inhibitor cell apoptosis. By NeuN immunochemistry and CD11b staining, there was improvement in the loss of CA3 neuronal cells after intrahippocampal injection of IL-13. This suggests that IL-13-enhanced PLA2 activity regulates COX-2/PGE2 expression through C/EBP-α activation. In parallel, ER stress-related calpain downregulates the PPAR-γ/HO-1 pathway via C/EBP-β and leads to aggravated

death of activated microglia via IL-13, thereby preventing cerebral inflammation and neuronal injury. Microglial cell Selleck Navitoclax activation is exquisitely sensitive to brain injury and diseases that contribute to neuronal cell death (e.g. repeated infection, traumatic brain damage, and stroke). Such activation likely plays a crucial role in inflammatory neuronal injury and chronic neurodegenerative diseases [1]. Anti-inflammatory medications may be protective against brain damage. Emerging evidence indicates that endoplasmic reticulum

(ER) stress plays a pivotal role in the pathogenesis of neurodegeneration [2]. The ER activates the unfolded protein response, a signaling pathway for adaptive response, which initially exerts a protective effect by upregulating specific ER stress-regulated genes and inhibiting general protein translation [3, 4]. However, severe or prolonged ER stress results in cell death via apoptotic signaling, ultimately leading to neurodegeneration. A previous study has shown that IL-13 downregulates peroxisome aminophylline proliferator-activated receptor gamma/heme oxygenase 1 (PPAR-γ/HO-1) via ER stress-stimulated calpain activation. Thus, IL-13 may reduce chronic brain inflammation [5]. This finding is consistent with the findings of Yang et al. [6] showing that IL-13 enhances cyclooxygenase-2 (COX-2) expression in activated rat brain microglia, thereby reducing brain inflammation. Recently, Kawahara et al. [7] suggested that intracerebral microinjection of IL-4/IL-13 reduces β-amyloid accumulation on the ipsilateral side and improves cognitive deficits in young amyloid precursor protein 23 mice. However, the mechanisms underlying how IL-13 regulates activated microglia and its relationship with the dampening of neuronal death have not been well elucidated. Studies on the relationship between glial activation and neurotoxicity have identified several molecular targets for transcription factor research.

92 Moreover, polymorphisms in not only STAT3, but also in IL23R

92 Moreover, polymorphisms in not only STAT3, but also in IL23R

and JAK2 loci, correlate with Crohn’s disease.93–95 Therefore, appropriate activation of the STAT proteins is clearly required for the development of a healthy immune response. Interestingly, several studies show abnormal expression of SOCS proteins in autoimmune diseases. In particular, SOCS1 mRNA is elevated in patients who present with systemic lupus erythematosus96 and rheumatoid arthritis,97 and single nucleotide polymorphisms in SOCS1 are associated with multiple sclerosis98 and coeliac disease.99 All of these autoimmune pathologies are characterized by increased IL-17 secretion, which would be consistent with the fact that SOCS1 promotes the development of Th17 cells. Compellingly, Trametinib mouse the correlation between SOCS3 expression and the severity of atopy is also apparent in patients. Markedly High Content Screening elevated SOCS3 expression is observed in skin samples from patients suffering from severe atopic dermatitis (AD) when compared with individuals with normal skin or with the Th1-mediated condition psoriasis.100 Furthermore, specific haplotypes of the SOCS3 gene have been linked with AD in two independent Swedish childhood cohorts

and SOCS3 mRNA is more highly expressed in AD skin.101 The detection of elevated SOCS3 expression in peripheral T cells and in AD skin may be of particular relevance because the SOCS3 gene is located on chromosome 17q25, one of the established AD genetic loci.102 Similarly, SOCS3 expression in T cells positively correlates with the severity of asthma and AD,33 whereas elevated SOCS3 mRNA levels and polymorphisms within Avelestat (AZD9668) the SOCS3 locus are found in patients with AD.101 Asthmatics also present with polymorphisms within the SOCS1 promoter, consistent with the fact that SOCS3 and SOCS1 regulate Th2 differentiation.103

The correlation between elevated SOCS1 expression and asthma severity in patients suggests that SOCS1 may inhibit IFN-γ-dependent Th1 differentiation, thereby enhancing Th2-mediated pathology.104 Of note, disruption of SOCS2 expression increases murine susceptibility to atopy but whether this is of relevance in patients has yet to be determined.59 Taken together, these different studies confirm the importance of SOCS proteins in the regulation of human pathogenic immune responses. Clearly, both STATs and SOCS are key regulators of lineage commitment and collaborate to tightly regulate CD4+ T-cell polarization. As with STATs, SOCS often exert opposing effects and may cross-regulate one another,59,61,105,106 and although murine null models exemplify this cross-compensation, this may well reflect reality because SOCS proteins are differentially expressed in individual CD4+ lineages.

The correlation between CD28null/CD8+ T cells and FEV1 suggests t

The correlation between CD28null/CD8+ T cells and FEV1 suggests that enumeration of this subset may further simplify monitoring of potential BOS development in patients. However, one must also be cautious in drawing definite conclusions selleck products from this small cross-sectional study, particularly the exact role that CD4/CD28null and CD8/CD28null play in the development of BOS, and further longitudinal patient studies are required to confirm these findings. In

conclusion, BOS is associated with down-regulation of CD28 and up-regulation of alternate co-stimulatory molecules on steroid-resistant CD4+ and CD8+ T cells. Early therapeutic targeting of alternate T cell co-stimulatory molecule expression following transplant

and monitoring response using these assays may elucidate the exact role played by alternate co-stimulatory molecules in lung transplant rejection and may possibly help to manage patients with BOS, where current treatments are ineffective and following progress is limited to lung function. This study was funded by a National Health and Medical Research Council grant. The authors have no conflicts of interest. “
“We have previously described a protein termed selleck chemicals Shigella enterotoxin 2 (ShET-2), which induces rises in short-circuit current in rabbit ileum mounted in the Ussing chamber. Published reports have postulated that ShET-2 may be secreted by the Shigella type III secretion system (T3SS). In this study, we show that ShET-2 secretion into the extracellular space requires the T3SS in Shigella flexneri 2a strain 2457T and a ShET-2–TEM fusion was translocated into epithelial cells in a T3SS-dependent manner. The ShET-2 gene, sen, is encoded downstream of the ospC1 gene of S. flexneri, and we show

that sen is cotranscribed with this T3SS-secreted product. Considering that T3SS effectors have diverse roles selleck in Shigella infection and that vaccine constructs lacking ShET-2 are attenuated in volunteers, we asked whether ShET-2 has a function other than its enterotoxic activity. We constructed a ShET-2 mutant in 2457T and tested its effect on epithelial cell invasion, plaque formation, guinea pig keratoconjunctivitis and interleukin 8 (IL-8) secretion from infected monolayers. Although other phenotypes were not different compared with the wild-type parent, we found that HEp-2 and T84 cells infected with the ShET-2 mutant exhibited significantly reduced IL-8 secretion into the basolateral compartment, suggesting that ShET-2 might participate in the Shigella-induced inflammation of epithelial cells. Shigella spp. are important enteric pathogens, producing an estimated 164.7 million infections worldwide per year (Kotloff et al., 1999). Shigella infections are characterized by invasion of the colonic mucosa, followed by epithelial cell inflammation and ultimately destruction.

The harvested BMDC were divided into groups and further cultured

The harvested BMDC were divided into groups and further cultured for 18 hr in medium alone as control or in the presence of rHp-CPI, LPS, CpG, LPS plus rHp-CPI or CpG plus rHp-CPI. The BMDC were stained and analysed for the expression of co-stimulatory and

MHC-II molecules. The results show that treatment of the immature DC with rHp-CPI alone reduced the expression of the MHC-II molecule but did not alter the frequencies of CD11c+ DC that express CD40, CD80 and CD86 and the expression levels of these molecules compared with medium control group (Fig. 5a,b). The immature DC stimulated with LPS showed significantly increased expression of CD40 and CD80 (both the frequencies of positive cells KU-57788 order and the MFI) compared with medium control, and rHp-CPI treatment reduced the increased CD80 expression in response to LPS stimulation, but had no effect on CD40 expression (Fig. 5a,b). CpG stimulation of the immature BMDC also induced enhanced expression of CD40 and CD80. The rHp-CPI inhibited the increased expression of CD40 and CD80 induced by CpG (Fig. 5a,b). We further examined the cytokine production by BMDC and observed that the differentiated immature

BMDC with or without rHp-CPI treatment produced minimal levels of IL-6, IL-12p40 and TNF-α. Stimulation of the immature BMDC with LPS and CpG induced increased production R428 ic50 of these pro-inflammatory cytokines. The rHp-CPI treatment reduced the IL-6 production induced by both LPS and CpG, and TNF-α production induced by CpG (Fig. 5c). These results show that although treatment of rHp-CPI alone did not alter immature BMDC co-stimulatory molecule expression and cytokine production, it modulates these activation responses of DC induced by LPS and CpG. To determine whether the T-cell activation function of DC is altered by rHp-CPI, DC and CD4+

a T-cell co-culture assay was performed. Bone marrow cells were cultured in the AZD9291 solubility dmso medium containing GM-CSF as described above. The immature BMDC were harvested on day 7, re-plated and cultured for 24 hr to obtain matured DC. Mature BMDC were incubated either in medium alone or with rHp-CPI for 2 hr and then pulsed with OVA antigen. The two groups of DC were then co-cultured with OVA-specific CD4+ T at the ratio of 1 : 2. As shown in Fig. 6(a), BMDC treated with rHp-CPI before OVA antigen pulsing induced a lower level CD4+ T-cell proliferation response than the BMDC that were pulsed with OVA only. CD4+ T cells co-cultured with BMDC that were treated with rHp-CPI and pulsed with OVA produced significantly less interferon-γ than the CD4+ T cells co-cultured with BMDC pulsed with OVA only (Fig. 6b). In this DC and CD4 T-cell co-culture, no significant levels of IL-4, IL-10 and IL-13 were detected. Adoptive transfer of BMDC was performed to further assess the effect of rHp-CPI on the function of DC. Mice were transferred with enriched BMDC that were pulsed with OVA with or without pre-treatment of rHp-CPI and boosted 4 weeks later with OVA antigen.

To date, our results provide the only evidence showing the existe

To date, our results provide the only evidence showing the existence of FEZ1 in striatum and substantia nigra of adult rat brain, an elevation of FEZ1 gene and protein levels

after 6-OHDA injection, and the cellular localization of FEZ1 in striatum and substantia nigra of both 6-OHDA-lesioned and sham-lesioned rats. Navitoclax Additionally, our data showed that FEZ1 mRNA and protein expression in striatum and substantia nigra gradually increased after injury, peaked, and then decreased. It has been previously described that FEZ1 is associated with dopaminergic neurone differentiation [30], and furthermore, another study has shown that FEZ1-deficient mice often present with abnormal behaviours resulting from altered dopamine release in the mesolimbic pathway [32]. Colocalization of FEZ1 within GFAP-positive click here or TH-positive cells demonstrated that FEZ1 was predominantly expressed by TH-positive neurones in sham-operated rats. In contrast, FEZ1 colocalized with GFAP-positive cells in PD rats, demonstrating the exclusive expression of FEZ1 in reactive astrocytes. Altogether, the preservation of FEZ1 mRNA levels in PD rats likely reflects a dynamic shift of expression from dopaminergic neurones to astrocytes during disease-associated

tissue remodelling. Sakae et al. indicated that a FEZ1 deficiency in GABAergic neurones may alter dopaminergic transmission, resulting in abnormal behaviours. They suggested that FEZ1 in GABAergic neurones might be neuroprotective [32]. In our observations,

FEZ1 levels in astrocytes increased in substantia nigra of PD rats, suggesting that astrocytic FEZ1 also plays an important role in neuroprotection. In cultured hippocampal neurones, the silencing of FEZ1 by FEZ1 siRNA inhibits axonal elongation [24]. Therefore, the loss of FEZ1 in TH-positive neurones may lead to the degeneration of dopamine Coproporphyrinogen III oxidase neurones. We supposed that injury to DA neurones might increase astrocytic FEZ1 levels in substantia nigra, knowing that the participation of reactive astrocytes in PD pathogenesis was generally assumed. Thus, we hypothesized that FEZ1 might be critical for astrocyte activation after injury. Our triple immunostaining detection of TH, GFAP and FEZ1 further confirmed our hypothesis. In addition, Western blot analysis showed that in striatum and substantia nigra after injury, there was a remarkable increase in GFAP expression levels. It is therefore possible that a direct link between FEZ1 expression and reactive astrocytes exists after injury. We examined the cortex and did not find changes in FEZ1 in neurones or astrocytes (data not shown). We believe that relocalization of FEZ1 into astrocytes might be caused by the damage to DA neurones, which induces an upregulation of FEZ1 in astrocytes. Taken together, these data indicate that a relationship exists between FEZ1 expression and reactive gliosis following 6-OHDA-induced injury.

In humans, Bregs were first identified mainly as CD5+B1a cells, C

In humans, Bregs were first identified mainly as CD5+B1a cells, CD21+CD23–

marginal zone cells or CD1d+CD21+CD23+ T2-marginal zone precursor B cells [33]. Mauri and colleagues AZD1152-HQPA nmr narrowed down the core phenotype of at least one Breg population to CD19+CD24+/intermediateCD38+/intermediate which produces IL-10 [23, 32]. Even though IL-10 production appears to define all suppressive B cells identified thus far, including the B220+CD19+CD11c– population we reported [31], IL-10-producing B cells are not necessarily regulatory [49]. In fact, IL-10 expression may be transient as Bregs seem to transition through an IL-10-expressing phase to finally rest as immunoglobulin-secreting cells that might not rely on IL-10 for suppressive ability [50]. In our clinical trial [31], we discovered that the suppressive B cell population whose frequency was increased in cDC and iDC recipients did not rely on IL-10 for suppression in vitro [31]. Those reported B cells represent a heterogeneous population. Herein, we confirm that the bulk of suppressive activity inside those B cells is concentrated selleck screening library inside the already characterized CD19+CD24+CD38+ B cell population [32] which constitutes about 20% of the CD19+B220+CD11c– IL-10+ population, on average, in a small sample of normal individuals.

We also discovered that CD19+CD24+ cells are as suppressive as the Bregs reported by Mauri and colleagues [32, 40]. These cells could represent either a novel and distinct suppressive cell type, a less-differentiated population from which the CD19+CD24+/intermediateCD38+/intermediate B cells emerge under currently unknown conditions, or a phenotypically metastable population that modulates between CD27+/CD38+ and CD27–/CD38– states without any functional difference. Whether the increase

in frequency of the suppressive CD19+B220+CD11c– IL-10+ B cells in tolerogenic DC recipients as reported in [31] represents an effect of DC on B cells to induce the differentiation of suppressor precursors to become CD19+CD24+ suppressive cells, or to specifically induce the proliferation of pre-existing suppressive CD19+CD24+ cells with a plasticity in CD27 and CD38 expression, is currently unknown. Nevertheless, in view of our data, if RA is one of the mediators of DC effects on the generation of Bregs, both proliferation of existing Bregs and differentiation of precursors could be operational. DC generated from PBMC progenitors in the presence of GM-CSF/IL-4 are known to be tolerogenic [51, 52] and produce RA [53]. Mechanistically, evidence suggests that RA alone, as well as DC producing RA, maintain the balance of T cells in favour of immunosuppressive forkhead box protein 3 (FoxP3)+ Tregs at the expense of proinflammatory T helper 17 (Th17) T cells [54, 55].


TAN LI PING, MOHAN YASHINI, LIM SOO KUN, NG KOK PENG, KENG TEE CHAU, KONG WAI YEW, WONG CHEW MING, WA HAFIZ, WONG MUN HOE, LIM LI HAN, JALALONMUHALI MAISARAH University of Malaya Medical Center Introduction: Cardiovascular disease is a leading cause of death among kidney patients. Screening for cardiovascular disease is therefore thought to be an essential step in the evaluation of the kidney transplant recipient. However, controversy exists

regarding the optimal assessment technique. The American Heart Association and the American College of Cardiology advise no preoperative cardiac evaluation if the patient has a good functional status. The American Society of Nephrology on the other hand, recommends myocardial perfusion imaging as part of the evaluation. Selleck NVP-LDE225 CCI-779 ic50 In Malaysia, there is currently no consensus addressing this issue. We conducted a retrospective review of cardiac assessment modalities among potential kidney transplant recipients in our hospital. Methods: All living donor kidney transplant recipients who underwent a kidney transplant

evaluation in our center from 2001 to 2013 were eligible for inclusion. Basic demographic data was collected. Key variables of interest were history of ischemic heart disease, presence of heart failure, stroke, diabetes mellitus. Information regarding methods of cardiac evaluation and results were obtained. Data was analyzed with SPSS v16.0. Results: 180 C1GALT1 patients

were identified, however due to missing data only 68 patients were included in the study. 66.2% were male. Mean age was 35.8 yrs (S.D 9.69). 11.8% had diabetes mellitus and 7.4% had a history of ischemic heart disease. All patients had a screening ECG done of which 85.3% were normal while the remaining had mild abnormalities. 66 (97.1%) patients had a stress ECG which was read as normal in 86.8%. The remainder had inconclusive results. 13 patients underwent coronary angiogram of which 23% (n = 3) had significant coronary stenosis requiring PCI. All of those who required PCI had history of ischemic heart disease. Conclusion: In our single center cohort of potential kidney transplant recipients, only 0.04% required PCI for cardiac optimaization, all of whom were among patients with preexisting ischemic heart disease. Due to cost constraints, more advanced techniques for cardiac evaluation like myocardial perfusion imaging of dobutamine stress echocardiograms were not done. But in our limited sample of mostly non diabetic patients; basic cardiac evaluation including screening ECG and stress ECG appeared to be sufficient. Further follow up of post operative outcomes would be important to support this. AN GUN-HEE, YU JI HYUN, HWANG SEUN DEUK, CHUNG BYUNG HA, PARK CHEOL WHEE, YANG CHUN WOO, KIM YONG-SOO, CHOI BUM SOON Transplant Research Center, Division of Nephrology, Department of Internal Medicine, Seoul St.

3D), whereas in CRIg-Fc-treated EAU mouse retina, only mild foci

3D), whereas in CRIg-Fc-treated EAU mouse retina, only mild foci of infiltration were seen, and retinal structure was largely preserved NVP-BGJ398 clinical trial (Fig. 3E). On average, there was a 54% reduction in the inflammatory cell infiltration score and a 58% reduction in the structural damage score in CRIg-Fc-treated mice as compared with PBS-treated EAU mice (p<0.05) (Fig. 3A–F). When CRIg-Fc was injected after T-cell priming and the initiation of EAU (i.e. from day 18 to day 24 p.i.), retinal inflammation was also significantly reduced (Fig. 3G). However, when CRIg-Fc was injected only at the T-cell priming stage, i.e.

from day 1 to day 10 p.i. no significant reduction in EAU severity was observed (Fig. 3H). In addition to reduced retinal inflammation (Fig. 3G), complement C3d deposition in the photoreceptor/RPE layer (Fig. 4A and B), the ganglion cell layer (Fig.

4C and D), and the ciliary body (Fig. RG7420 mw 4E and F) was also markedly reduced by CRIg-Fc treatment, indicating decreased AP-mediated complement activation. Furthermore, quantitative real-time PCR (qRT-PCR) analysis revealed that the 59-fold increase in CFB expression in isotype-IgG1 EAU mice was restored to the essentially normal values by treatment with CRIg-Fc (Fig. 4H). There was also a 50% reduction in CFB gene expression in RPE/choroid/sclera tissue of CRIg-Fc-treated mice as compared with that of isotype IgG1-treated EAU mice, although the reduction did not reach statistical significance (Fig. 4H). To further understand the mechanism of CRIg-Fc-mediated inhibition of retinal inflammation, the proliferation of T cells from EAU mice treated with or without CRIg-Fc was evaluated. Without in vitro IRBP stimulation, splenocytes from PBS-treated EAU mice showed low levels of spontaneous Rolziracetam proliferation (500 CPM on 3H incorporation, Fig. 5A). Cells from CRIg-Fc treated (days 1–22 p.i.) EAU mice had the same levels of 3H incorporation as the cells of nonimmunized

normal mice (around 200 CPM, Fig. 5A), indicating the lack of proliferation. After IRBP peptide (25 μg/mL) stimulation, splenocytes from PBS-treated EAU mice proliferated massively as compared with cells from nonimmunized normal mice (Fig. 5A). However, the level of cell proliferation in CRIg-Fc-treated EAU mice was significantly lower than that of PBS-treated EAU mice (Fig. 5A). Splenocytes from day 18 to day 24 p.i. CRIg-Fc-treated EAU mice showed similar results (data not shown). When splenocytes from PBS-treated EAU (day 25 p.i.) mice were activated in vitro with retinal antigen (i.e. human interphotoreceptor retinoid-binding protein peptide (pIRBP), 25 μg/mL) or nonspecifically with Con A (2.5 μg/mL) in the presence of different concentrations of CRIg-Fc, CRIg-Fc dose-dependently suppressed cell proliferation (Fig. 5B). Splenocytes from day 25 p.i.

The questions yet unanswered by all the studies are: best source

The questions yet unanswered by all the studies are: best source of MSC, the timing of infusion, dose of infusion, site of infusion and efficacy in terms of recovery Selleckchem INK128 and/or minimization of immunosuppression. Trivedi et al. have probably answered most of the queries haunting transplanters for the last 50 years. We have shown that

combined adipose tissue-derived MSC and HSC have been useful in reaching the Utopian dream of tolerance. In one of our studies of 606 living donor RT we have addressed several questions haunting transplanters. We have deleted rejecting T and B cells by non-myeloablative conditioning of total lymphoid irradiation (200 cGY × 4 or 5 days) and/or Bortezomib, 1.5 mg/kgBW in four divided doses, every third day, Cyclophosphamide, 20 mg/kg body weight and rabbit antithymocyte globulin, 1.5 mg/kg body weight. We infuse combined adipose tissue-derived MSC and HSC in portal and thymic circulation, since liver is the most tolerogenic organ due to its microanatomy and various functional aspects.[31, 32] Cells entering thymus undergo both positive and negative selection, resulting in T cells with a broad range of reactivity to foreign antigens but with a lack of reactivity to self-antigens. It is also a source of a subset

of regulatory T cells that inhibit auto-reactivity of T-cell Copanlisib order clones that may escape negative selection. Hence, thymus is 4��8C believed to be essential for induction of tolerance. We have also observed that stem cells when infused before solid organ transplantation help in blocking direct and indirect pathways of rejection. Furthermore, although there is no definite evidence of their grafting we have seen maintenance

of T-regulatory cells recruited by MSC, which help in sustaining tolerance. In addition, with better HLA matching, the weaning off immunosuppression becomes safer. We have observed in our pilot study of two patients that post-transplant infusion of MSC can lead to acute rejection (unpublished data) hence the best timing of MSC infusion is before organ transplantation and preferably 10 days before transplantation as depicted in Figure 1. Infections remain a major challenge for all transplantations especially in developing countries where social, economic and environmental conditions are far from health-promoting. Therefore the major cause of death is infections with 15% developing tuberculosis, 30% cytomegalovirus, and nearly 50% bacterial infections in developing countries.[33] The prevalence of post-transplant tuberculosis in India is reported to be the highest (12 to 20%) in the world, and the mortality among those afflicted is high at 20 to 25%.

The authors declare to have no competing interests JSH conceived

The authors declare to have no competing interests. JSH conceived and designed the study, collected and analysed the data and drafted the manuscript. UCN, TA and HR contributed to the data collection and critically revised the manuscript. ML obtained funding for the study, discussed experiments and critically revised the manuscript. “
“Natural killer (NK) cells are affected by infection with human cytomegalovirus (HCMV) manifested by increased expression of the HLA-E binding activating receptor NKG2C. We here show that HCMV seropositivity

was associated with a profound expansion of NKG2C+CD56dim NK cells in patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Trichostatin A order Multi-color flow cytometry revealed that the expanded NKG2C+CD56dim NK

cells displayed a highly differentiated phenotype, expressed high amounts of granzyme B and exhibited polyfunctional responses (CD107a, IFN-γ, and TNF-α) to stimulation with antibody-coated as well as HLA-E expressing target cells but not when stimulated with IL-12/IL-18. More importantly, NKG2C+CD56dim NK cells had a clonal expression pattern of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self-HLA class I molecules, with predominant usage of KIR2DL2/3. KIR engagement dampened NKG2C-mediated activation suggesting that such biased expression of self-specific KIRs may preserve self-tolerance and limit immune-pathology find more during viral infection. Together, these findings shed new light on how the human NK-cell compartment adjusts to HCMV infection resulting in clonal expansion and differentiation of educated

and polyfunctional NK cells. Natural killer (NK) cells have the ability to kill targets without prior sensitization and their involvement in antiviral and antitumor immunity is well established 1, 2. Recent studies have demonstrated a high degree of functional heterogeneity in the NK-cell compartment attributable to a vast network of inhibitory or activating receptors that allow these cells to recognize target cells 3, 4. Killer cell immunoglobulin-like receptors (KIR) and CD94/NKG2 heterodimers are two major types of HLA class I binding Hydroxychloroquine cell line receptors that regulate NK cell function 5, 6. Both these receptor-families exist in activating and inhibitory forms and contribute to the functional education of human NK cells by interactions with their cognate ligands 7, whereas KIR are expressed in a stochastic manner with a variegated distribution in the NK cell population 8, 9, NKG2A is expressed on all CD56bright NK cells and disappears gradually during differentiation of CD56dim NK cells 10, 11. NKG2C and NKG2A are covalently associated with CD94 12.