On correlation analysis, SOD activity was observed to be positively correlated (P < 0.05) with zinc and copper in both healthy and dermatophytosis affected dogs. In dermatophytosis affected dogs the MDA levels were negatively correlated (P < 0.05) with iron, β-carotene levels and the activities of antioxidant enzymes; SOD and catalase. Our results demonstrated that dermatophytosis in dogs is associated with significant alteration in oxidant/antioxidant balance and trace elements. It might be secondary

consequence of dermatophytosis infection or contributing factor in its pathogenesis. “
“The purpose of this study was to investigate the interaction between intravenous ampicillin-sulbactam treatment and (1,3)-beta-D-glucan

(BDG) assay. Fifteen patients with a median age of 60 (16–81) Roscovitine ic50 without known risk factors for invasive fungal infections who received a daily dose of 3 × 2 g ampicillin-sulbactam monotherapy from different batches were included in the study. Thirteen patients had soft tissue infections. The 5 of 13 patients who went under surgery had surgical dressings. Serum samples were obtained both before and after antibiotic infusion on the first, third, seventh and tenth days of an ampicillin-sulbactam treatment course. BDG was assayed using LEE011 order the Fungitell kit (Associates of Cape Cod, East Falmouth, MA, USA) according to manufacturers’ specifications. All serum samples were also tested for galactomannan (GM) antigenemia by Platelia Aspergillus ELISA (Bio-Rad Laboratories, Marnes-la-Coquette, France). A total of 37 of 117 serum samples were positive for BDG at a threshold of 80 pg ml−1. Seven of 37 BDG positive serum samples had a GM index ≥0.5. When a cutoff value of ≥0.5 was used for GM positivity, 16 (13.3%) serum samples were positive. For a cutoff value of ≥0.7, eight (6.6%) serum samples were positive. There were no statistically significant differences in the median BDG levels (P = 0.47) or median GM indices

(P = 0.28) of the various sampling times. None of the SAM vials tested positive for BDG or GM. After ruling out fungal infections and all known potential causes of false BDG Selleck Ponatinib positivity, environmental contamination remained possible cause of BDG reactivity. We did not observe any significant association of ampicillin-sulbactam administration and positive assays for BDG or GM. “
“Recent guideline recommendations on the management of candidaemia provide valuable treatment guidance for routine clinical practice, but need to be interpreted in the light of the actual situation of the patient and the local epidemiology of fungal infections. Echinocandins emerge as the generally preferred primary treatment. Treatment should be initiated immediately after notification of a Candida-positive blood culture in all patients.

The percent increase associated with fixed K562-CD161 was almost identical to that observed for unfixed K562-CD161 (data not shown). Our previous study demonstrated that LLT1 stimulation with a monoclonal antibody fails to alter natural cytotoxicity [11]. We performed cytotoxicity assays to determine whether interaction of LLT1 with CD161 plays any functional role in NK cell activation. NK92 cells were used as effectors against 51Cr-labelled K562 target cells stably transfected with CD161 or empty pCI-neo vector. In some reactions, K562 target cells were blocked

with DX12 anti-CD161 monoclonal antibody. K562-CD161 target cells were not associated with altered levels of killing compared to K562-pCI-neo targets, and blocking CD161 was not associated with any altered levels of killing (Fig. 6). These results suggest that LLT1 activation by CD161 does not regulate RAD001 NK cell cytotoxicity. Rapid production of IFN-γ is a critical role of NK cells responding to infection. LLT1 is a potent activator Carfilzomib price of IFN-γ production on human NK cells [10, 11]. To study the mechanisms of LLT1 signalling, we have developed a novel model of LLT1 ligation using NK92 and K562 cells stably transfected with the LLT1 natural ligand, CD161. Using LLT1:CD161 functional model, we have demonstrated that LLT1 stimulated IFN-γ

production is associated with the ERK signalling pathway and possibly the p38 pathway as well. Furthermore, IFN-γ secretion associated with LLT1 is detectable as little as six hours after ligation, and this IFN-γ production is not associated with

altered IFN-γ mRNA expression. We have demonstrated for the first time that LLT1 is expressed on the NK92 cell line, and that LLT1 is functional here in a manner identical to that observed on freshly isolated human NK cells and on the NK cell line YT. Our present data consistently demonstrated that LLT1 ligation on NK92 by its ligand CD161 strongly stimulates IFN-γ production. However, LLT1 ligation has never been associated with an increase or decrease in natural cytotoxicity [11]. These results illustrate the duality of NK activation Protein tyrosine phosphatase pathways. Activating NK receptors are known to exhibit multiple functions. KIR2DL4 ligation stimulates IFN-γ production in resting NK cells and stimulates both IFN-γ and cytotoxicity in activated cells [8]. CD16 and 2B4 are capable of stimulating cytotoxicity in resting NK cells, but not IFN-γ production [25]. However, 2B4 is capable of stimulating cytotoxicity and IFN-γ production in the activated NK cell line YT [26]. Inhibition of either the p38 or ERK pathways abrogates 2B4-associated cytotoxicity, whereas only the p38 pathway is associated with 2B4-induced IFN-γ production [9, 27].

To ensure age matching, we bred mice heterozygously and compared knockout and heterozygous littermates. Mice were used at 8–12 weeks of age unless otherwise stated. Thymic lymphocytes were isolated by removing the thymus and generating a single cell suspension by straining through a 70 μm wire mesh. Skin lymphocytes were

freshly isolated as previously described [23] with minor adjustments. Briefly, mouse ears were removed at the base, rinsed in 70% ethanol, air-dried, and split into dorsal and ventral halves. The ear halves were placed dermal side down on 0.8% trypsin in PBS (Sigma) and incubated for 30–45 min at 37°C. After enzymatic digestion, epidermis and dermis were separated using forceps. Epidermal www.selleckchem.com/products/Roscovitine.html sheets were transferred into complete IMDM medium, and dermal sheets were transferred into complete IMDM medium containing 2 mg/mL collagenase IV (Worthington). Skin sheets were shaken for 30 min at 37°C and filtered through a 100 μM cell strainer. Cell suspensions were washed twice with complete IMDM medium before enrichment of lymphocytes using a 40%/70% Percoll gradient. Cells were first blocked with FACS buffer (PBS with 0.5% BSA) containing 1μg/mL anti CD16/CD32 (clone 93, eBioscience).

The following antibodies were used for staining: CD3-PerCP Cy5.5 (145–2C11, eBioscience), TCR Vγ3-allophycocyanin (536, Biolegend), and TCRγ/δ-PE (GL3, BD Biosciences). Dead cells were excluded by propidium iodide staining (Sigma). FACS data were acquired on a Fortessa from BD, using the FACS Diva software. Further analysis was performed using FlowJo from Treestar. Statistics were calculated using GraphPad Prism, LBH589 chemical structure where the unpaired Student’s t-test was employed. Mouse ears were removed at the base and hairs were removed with Nair cream. Ears were then split into dorsal and ventral halves. The ear halves were placed dermal side down on 0.5M ammonium thiocyanate and incubated for 40 min at 37°C. Epidermis and dermis were separated using forceps. Epidermal sheets were mounted

on microscopic slides and incubated in 4% PFA for 5 min. After washing, cells were blocked for 30 min with Fc block in PBS containing 10% FCS and 0.1% saponin, followed by incubation with anti TCRγ/δ-PE (GL3, BD Biosciences) for 1 h. Slides were mounted by ProLong® Gold Antifade Reagent (Life Technologies). Mephenoxalone Supported in part by NIH grants R37 AI047822, R01 DK084647, R01 AI072618, and an award from the Department of Veterans Affairs to ECB. KL was supported by fellowships from the German Research Foundation (DFG), the Crohn’s and Colitis Foundation of America, and the ITI Young Investigator Award from Stanford. This work benefitted from data assembled by the Immgen Consortium. The authors declare no commercial or financial conflict of interest. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset.

To be more relevant to clinical conditions, we examined whether rapid and large-scale changes in environmental temperature affect micturition patterns in conscious rats (Fig. 2). The rat cystometry investigation system was quickly moved from the room (27 °C) into a refrigerator (4 °C). The sudden environmental change induced an increase in urinary frequency (Fig. 3, Phase 1), but the PARP inhibitor urinary frequency gradually settled down (Fig. 3, Phase 2).15 This observation indicated that the sudden cold stress induced an increase in urinary frequency, which settled down once the rats became acclimatized to the cold environment. When we moved these cystometry systems

back to normal room temperature (27 °C), the cystometric pattern returned to normal (Fig. 3). We also measured the urine volume by calculation of the infusion and micturition volumes; the results indicted that there was no increase in urinary output (unpublished data). This observation suggested that cold stress induces an increase in urinary frequency

without a concomitant increase in urinary output in rats. To determine the mechanism of the cold stress-induced increase in urinary frequency, we examined the parasympathetic pathway because we usually use anticholinergic https://www.selleckchem.com/products/Neratinib(HKI-272).html drugs for urinary frequency, especially in patients with bladder overactivity.16 We administered the non-selective anticholinergic drug atropine at a dose of 3 mg/kg (this dose was determined based on a pilot study) before cold stress during rat cystometry. However, we could not suppress the increase in urinary frequency associated with cold stress Amylase (Fig. 4a,b, unpublished data). A recent study showed that in tropical men acclimatized to the Antarctic environment, exposure to cold for long durations caused increased excretion of urinary epinephrine, norepinephrine, and salivary cortisol, all of which were associated with significant autonomic changes in heart rate and blood pressure.2 Based on these observations, we measured

blood pressure during cold stress. Sudden cold stress induced a significant elevation of blood pressure, but this elevation become non-significant after 30 min.17 This observation implied that cold stress induces elevation of blood pressure, which returns to normal once the rats become acclimatized to the cold environment. This phenomenon was very similar to the changes in urinary frequency pattern discussed previously.15 Clinically, we sometimes administer α1 adrenergic receptor (AR) blockers to patients with hypertension or those with benign prostatic hyperplasia.18 Chen et al.17 examined the changes in blood pressure associated with the administration of α1-AR blockers (silodosin: α1A selective AR blocker, naftopidil: α1D selective AR blocker, tamsulosin: α1A/D selective AR blocker), and these drugs were shown to prevent increases in blood pressure.

A football match of Italian versus German immunologists was thus unavoidable. With the precious help of Ms. Annanora Vanni, the perfect GSK126 in vitro organizer and leader of “Riccione Congressi”, and the participation of the Vice-Major of the city for the official kick-off, 44 outbred male immunologists of both countries and one heroic German female (p<0.00001, by squared Chi test) met for a beach soccer challenge at night (Fig. 3A–F). Needless to say, finding a suitable referee was an issue, and heavily debated until the two captains (the authors of this report) finally agreed on Josè Enrique O'Connor Blasco, a Spanish fellow scientist from the University

of Valencia, who was expected to lecture on “Cytomics and Immunology” the next day. At the end of the match, all players and the audience were impressed by him, and were very respectful even when he denied a couple of penalties – to both teams. As for BGJ398 the precise chronicle of the match – the first part of the first half was characterized by the physical and athletic dominance of the Germans, who scored two goals within a few minutes. But then the Italians were able to go even. In the second half of the match, Germany scored another two goals, but then Italy went even just

two minutes before the end, for a final result of 4-4, that was absolutely perfect, mainly because the organizers had bought only gold medals, and the victory of one team would have been a problem. To conclude this epic story, the title of best player was shared by Lorenzo Cosmi (Florence) and Benjamin Weisst (Berlin). The third day of science started with symposia on complement and soluble mediators, microRNAs (miRNAs), vaccines and infections, transplantation and tolerance and B cells. M. Kirschfink (Heidelberg) discussed the main mechanisms by which tumor cells acquire resistance to complement, and F. Tedesco (Trieste) reported on the non-canonical functions of C1q that can be secreted by trophoblasts in order to adhere and partially replace decidual endothelial cells. The session on miRNAs was attended by a huge crowd.

The miRNome of different human lymphocyte subsets was discussed by S. Abrignani (Milan), in particular the specific naïve CD4+ T-cell miRNA signature that inhibits GRB2, LNK, IFN-γ, IL-2Rβ, IL-10Rα and Blimp1. miRNA-regulated gene Adenosine expression in chronically activated effector memory Th cells was studied by M.-F. Mashreghi (Berlin) who described the regulation of clonal expansion of activated T cells by miR-182. miRNA-182, which is induced after activation of naïve T cells and regulated by IL-2/Stat5, downregulates the antiproliferative transcription factor Foxo1, which results in chronic T-cell proliferation. Another miRNA is specifically induced in chronically activated effector/memory Th1 cells, controlling survival of these cells by targeting Bim and Pten. G.

Several studies have shown that autoantibodies are heavily

mutated and back mutation of mutated human V genes to the germline sequences resulted in a loss of antigen binding [20–22]. However, other reports did not support these findings [23–25]. Some studies have shown a low rate of somatic mutation in autoantibodies of patients with SS [17, 26, 27]. In another study, an increased rate (19.6%) of unmutated clones was reported in the parotid gland specimen from a patient with SS [18]. In addition, VH gene analyses of non-Hodgkin lymphomas in patients with SS have shown that neoplastic B cell populations are often unmutated [14–28]. Our finding that B cells infiltrating inflammatory lesions of patients with SS possess less mutated VH genes is in line with these observations and supports the hypothesis check details that some germline or less mutated genes may play a role in the development of this autoimmune disease. Moreover, selleck autoantibodies encoded by such genes fail to be deleted in patients with SS. IgG4-related sclerosing sialadenitis is a chronic inflammatory disorder characterized by a dense infiltration of IgG4-positive plasma cells. As treatment with steroids is very effective, an autoimmune mechanism is highly implicated in the aetiology of IgG4-related sclerosing sialadenitis. In this study, we

showed that VH fragments of IgG4-related sclerosing sialadenitis and SS cases shared a common characteristics, a high rate of unmutated VH clones probably derived from the VH3 family. This finding suggests that an autoimmune mechanism similar to that of SS may also be responsible to the development of IgG4-related sclerosing sialadenitis. In conclusion, we studied VH usage and VH

somatic hypermutation in SS and IgG4-related sclerosing sialadenitis using sialolithiasis tissues as a control. The VH fragments, especially those of the VH3 family, were often unmutated when compared with those of the sialolithiasis cases. This finding will provide insight into the pathogenesis of SS and IgG4-related sclerosing sialadenitis. H. S., T. J., K. S, and H. I. designed research; H.S., F.O., and S.M. performed research; H.S., F. O., S. M., and H.I. analyzed data; and H. S. and H.I. wrote the paper. Authors thank Dr Hitoshi Miyachi, Aichi-Gakuin University School of Dentistry, for his valuable advice and Mr Takeo Vasopressin Receptor Sakakibara for his technical assistance. H. Sakuma and F. Okumura contributed equally to the study and should both be regarded as first authors. This study has no conflicts of interest. Data S1 Sequence analysis of Sjogren’s syndrome cases. Data S2 Sequence analysis of IgG4-related sclerosing sialadenitis cases. Data S3 Sequence analysis of sialolithiasis cases. Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

“
“Pathological heterogeneity of Aβ deposition in senile plaques (SP) and cerebral amyloid angiopathy (CAA) in Alzheimer’s disease (AD) has been long noted. The aim of this study was to classify cases of AD according to their pattern of Aβ deposition, and to seek factors which might click here predict, or predispose towards, this heterogeneity. The form, distribution

and severity of Aβ deposition (as SP and/or CAA) was assessed semiquantitatively in immunostained sections of frontal, temporal and occipital cortex from 134 pathologically confirmed cases of AD. Four patterns of Aβ deposition were defined. Type 1 describes cases predominantly with SP, with or without CAA within leptomeningeal vessels alone. Type 2 describes cases where, along with many SP, CAA is present in both leptomeningeal and deeper penetrating arteries. Type 3 describes cases where capillary CAA is 17-AAG purchase present along with SP and arterial CAA. Type 4 describes a

predominantly vascular phenotype, where Aβ deposition is much more prevalent in and around blood vessels, than as SP. As would be anticipated from the group definitions, there were significant differences in the distribution and degree of CAA across the phenotype groups, although Aβ deposition as SP did not vary. There were no significant differences between phenotype groups with regard to age of onset, age at death, disease duration and brain weight, or disease presentation. Women were over-represented in the type 1 phenotype and men in type 2. Genetically, type 3 (capillary subtype) cases were strongly associated with possession of the APOE ε4 allele. This study offers an alternative method of pathologically classifying cases of AD. Further studies may derive additional genetic, environmental

or clinical factors which associate with, or may be responsible for, these varying pathological presentations of AD. Classically, Alzheimer’s disease (AD) can be defined as a progressive neurodegenerative disorder Flucloronide which presents as a disturbance of memory and cognition and is characterized histopathologically by the presence of numerous senile plaques (SP) and neurofibrillary tangles (NFT) within neocortical and certain subcortical regions, accompanied in most cases by a deposition of amyloid β protein (Aβ) in the walls of leptomeningeal and intracortical (parenchymal) arteries, arterioles, capillaries and veins, and known as cerebral amyloid angiopathy (CAA). The same Aβ protein deposited in blood vessel walls is also present in the brain parenchyma within the SP, although this is mostly composed of the longer peptide, Aβx-42, whereas CAA Aβ protein is mostly composed of the shorter peptide, Aβx-40 [1]. Nonetheless, the origins of CAA are still poorly understood. Various mechanisms have been proposed, which include a derivation from blood and or cerebrospinal fluid [2], local production by smooth muscle cells and/or pericytes [3] or through secretion from neurones and perivascular drainage [4].

[16] CD4+ T cells labelled with CFSE were cultured with anti-CD3 antibody (0·5 μg/ml) Dasatinib mouse for 48 or 72 hr (Fig. 2f). At each time-point examined, SD-4+/+ and SD-4−/− T cells showed almost identical patterns of cell division (as reflected from diffusion of CFSE fluorescent intensity).

Similar results were also noted with lower concentrations (0·1 and 0·3 μg/ml) of anti-CD3 antibody (see Supplementary material, Fig. S2). We then examined the effect of SD-4 deletion on the intrinsic response triggered by concanavalin A, wihch activates T cells in a non-specific manner (Fig. 2g). Again, there was no significant change in T-cell proliferation. Hence, lack of SD-4 expression does not alter the intrinsic responsiveness of T cells to TCR-dependent or non-specific Staurosporine stimulation. These features distinguish SD-4 from PD-1 and BTLA, whose respective deletions augment T-cell responses to anti-CD3 stimulation.[20, 21] Using the mixed lymphocyte reaction, we examined the impact of SD-4 deletion on T-cell reactivity in response to allogeneic DC-HIL+ APC (Fig. 3a,b). CD4+ T cells

(varying numbers) isolated from WT or KO C57BL/6 mice were co-cultured with DC (constant number) prepared from BM cells of BALB/c mice. T-cell activation was measured by secreted IL-2 (Fig. 3a) or by proliferation (Fig. 3b). SD-4−/− T cells produced IL-2 at a four-fold greater level and proliferated at a two-fold higher level, respectively, than SD-4+/+ T cells. We next used a defined antigen model of gp100 (melanoma-associated antigen).[22] SD-4 gene deficiency was introduced into the pmel-1 TCR transgenic mice (in which all CD8+ T cells express the same TCR specific to a particular gp100 antigen peptide).[23] With respect to relative proportions of leucocyte sub-populations in lymphoid organs, there was no significant difference between SD-4+/+ and SD-4−/− pmel-1 mice (data not shown). We then assayed the reactivity of T cells to gp100 peptide-loaded APC. Spleen cells isolated from SD-4+/+ or SD-4−/− pmel-1 mice were

stimulated by increasing doses of antigen and measured for proliferation (Fig. 3c). SD-4+/+ pmel-1 spleen cells proliferated and produced IL-2 in response to gp100 antigen in a dose-dependent manner. Similarly, SD-4−/− pmel-1 spleen cells acetylcholine responded to antigen, but with significantly elevated levels (more than twofold greater responses by SD-4−/− pmel-1 T cells) at almost every single dose of antigen. To more rigorously examine the impact of SD-4 deletion, BMDC were prepared from WT mice and allowed to stimulate SD-4+/+ or SD-4−/− CD8+ T cells (Fig. 3d). SD-4−/− CD8+ T cells produced greater levels of IL-2 than SD-4+/+ CD8+ T cells (up to twofold), consistent with the previous data (Fig. 3c). As SD-4 is also expressed by DC (unpublished data), we examined the possibility that contaminant APC in the T-cell preparation from KO mice contributed to hyperactivation (Fig. 3a).

3). This observation is strengthened further by the intact capacity of Tregs

to phosphorylate STAT-5 in the presence of sotrastaurin (Fig. 2). Protein kinase C inhibition thus seems to have a differential effect on regulatory and effector T cell functions. The explanation for the observed Tregs ‘sparing result’ is not fully understood. In Tregs, IL-2 is required for the induction and maintenance of PARP activity FoxP3 expression to exert their suppressive function [18, 19]. Transcription of IL-2 is regulated via NF-κB, and as PKC activates the NF-κB transcription factor it might be expected that the PKC inhibitor sotrastaurin diminishes IL-2 production. Matz et al. indeed demonstrated a significant decrease in IL-2 expression in PMA/ionomycin-stimulated T cells treated with sotrastaurin [17]. The question arises as to how Tregs can escape from the inhibitory effect of sotrastaurin on their main buy PS-341 factor for expansion and function? Circulating Tregs already express FoxP3 protein and therefore sotrastaurin can no longer hamper these Tregs in their activities (Fig. 6), while the development of de novo FoxP3+ Tregs in patients on immunosuppressive drugs might be affected. Indeed, we found that

in neoral-treated patients the number of

circulating FoxP3+CD127low Tregs was lower at 3 months after transplantation (Fig. 4b). This was not found in sotrastaurin-treated patients, suggesting that the immune system bypassed the IL-2 blockade via activation of other intracellular signalling pathways, e.g. NFAT and p38. Both intracellular signalling molecules control the production of IL-2. However, in patients treated with the less selective immunosuppressive agent neoral, IL-2 production is inhibited via blockade of all major signalling pathways, i.e. NFAT, p38 and NF-κB1 [9, 20]. Another explanation for ‘Treg sparing’ might be the differential signalling Ribonucleotide reductase cascades downstream of the IL-2 receptor activation. Sewgobind et al. found that IL-2-induced STAT-5 phosphorylation had a different effect on Treg and Teff function [21]. Inhibition of IL-2-induced STAT-5 phosphorylation by the Janus kinase (JAK) inhibitor tofacitinib abrogated Teff function, while leaving the suppressive capacity of Tregs relatively intact. Molinero and Alegre have recently reviewed the role of NF-κB in alloreactivity and reported that development of thymic naive Tregs requires functional NF-κB, whereas the peripheral conversion into inducible Tregs may take place in the absence of NF-κB signalling [22].

It was taught that PF-01367338 ic50 NK cells belong to the innate immune system; however, this has recently been challenged as ‘adaptive’ memory-like NK cells have been reported [18, 19]. NK cells express some chemokine receptors such as CCR2, CCR5, CXCR3 and CX3CR1. Thus, they can respond to a variety of chemokines and migrate to distinct inflammatory sites. The trafficking patterns of NK cells are poorly understood; however, it appears that chemokines produced by different cells in a specific organ may direct NK cell migration to the target organ [20]. For instance, the CX3CL1 produced by neurons is necessary

and sufficient to conduct CX3CR1-bearing NK cells to inflamed brain [21]. This suggests that organ-intrinsic elements may be important in shaping NK cell homing and might be an appropriate target for approaching to treating the inflammatory CNS disorders. NK cell function is modulated by several activating and inhibitory receptors. NK cell receptors can be divided into functionally or structurally defined groups. In

mammals, there are two main classes of NK cell receptors, the immunoglobulin (Ig) superfamily receptors that include the killer cell Ig-like receptors (KIR), natural cytotoxicity receptors (NCR) NKp30, NKp44 and NKp46, and the structurally unrelated killer cell lectin-like receptors (KLR) that include the NKR-P1, CD94/NKG2 and NKG2D receptor families. NK https://www.selleckchem.com/Proteasome.html cell receptors can also functionally divided into various groups based on their ligands (Table 1). Majority of these receptors are encoded in the NK gene complex (NKC) and leucocyte receptor cluster (LCR) [13]. Several NK cell receptors are also expressed on other cells such as T cells [13, 15, 17]. The major characteristics of NK cell receptors are described in the Table 1. NK cells Nutlin-3 purchase have the potent inflammatory and destructive effects and are potentially dangerous. It is not clear how NK cells achieve tolerance. The engagement of self MHC-I molecules by inhibitory

NK cell receptors may be the principle mechanism by which killing of normal cells is prevented. The virally infected cells and tumour cells often downregulate MHC-I expression to evade CD8+ T cell recognition, but this makes them sensitive to NK cell-mediated killing. Several distinct models have been proposed, and the ‘missing self’ was the first hypothesis that suggested NK cells monitor cells for normal MHC-I expression by inhibitory NK cell receptors [22]. However, the NK cell tolerance mechanism is more complex as a subset of mouse NK cells lacking inhibitory MHC-I receptors have been shown to be functional or high-level expression of activating ligands may lead to NK cell activation even in the presence of inhibitory ligands [23].