29 In contrast to CD47−/− mice, these animals also showed a reduced level of total intestinal IgA. A defect in extravasation from blood vessels into the intestine and GALT, as suggested above for OVA-specific plasma cells, could be applied to all leucocytes and could explain the decreased number of total cells in CD47−/− mice. Maintained levels of total intestinal

IgA in CD47−/− mice could be the result of a homeostatic mechanism in place to ensure normal levels of IgA, possibly through generation of IgA-producing cells directly in the intestinal LP.30 We have previously shown that DC are required for activation of CD4+ T cells after antigen feeding.4 In this study, we show a significant reduction CT99021 cell line in the frequency of CD11b+ cells among CD103+ and CD103− DC in the MLN of CD47−/− mice. We additionally confirm that removal of MLN completely abrogates the capacity to induce oral tolerance.3 It is the CD103+ MLN DC that exclusively present orally administered antigen to T cells ex vivo,21 and this subset has been shown to be gut-derived.23 check details Furthermore, migration of DC from the gut to the MLN is crucial for the initiation of oral tolerance, as CCR7-deficient mice fail to generate this response.3 However, although CD47−/− mice have reduced cell numbers in their GALT, reduced DC frequencies in MLN, a reduced proportion of CD103+ CD11b+ DC in the LP and MLN, and decreased activation

of antigen-specific CD4+ T cells following antigen feeding, their capacity to induce oral tolerance is still maintained. Additionally, in preliminary experiments the capacity to generate OVA-specific FoxP3 regulatory T cells following feeding of OVA was not different between CD47−/− and Aurora Kinase WT mice (data not shown). These results indicate that the remaining CD11b+ and/or CD11b− DC are sufficient for the induction of oral tolerance in CD47−/− mice. Alternatively, DC are not completely necessary. We have recently

shown that feeding high doses of antigen can result in efficient proliferation of CD4+ T cells in DC-depleted mice.4 However, even when a 10-fold lower antigen dose was given orally, the CD47−/− mice were efficiently tolerized. Our study demonstrates reduced numbers of gut-derived CD11b+ CD172a+ DC and a blunted capacity to expand CD4+ T cells following oral immunization in CD47−/− mice. Importantly, these impairments do not influence the capacity to induce oral tolerance. This shows that decreased T cell proliferation does not necessarily equate to reduced T cell-mediated function. However, CD47−/− mice have a gut-specific defect in total immune cell numbers, and following oral immunization they show reduced levels of antigen-specific intestinal IgA but normal systemic IgA and IgG. Replacing the haematopoietic compartment with CD47-expressing cells does not restore cellularity or the capacity to produce intestinal IgA.

Future studies to investigate LPS-induced CGRP synthesis in monocytes/macrophages of RAMP1 over-expressing

transgenic mice20 and knockout mice37 should verify this hypothesis. In the present study, we have used exogenous CGRP, peptide CGRP receptor antagonist CGRP8-37 and non-peptide CGRP receptor antagonist BIBN4096BS, selleck screening library to establish the possible role of CGRP receptor signalling in basal and LPS-induced pro-inflammatory and anti-inflammatory chemokines and cytokines in the RAW 264.7 macrophage cell line. The affinities of αCGRP, CGRP8-37 and BIBN4096BS to bind human CGRP receptors have been well established, with the affinities BIBN4096BS (Ki = 14·4 ± 6·3 pm) > αCGRP (Ki = 31·7 ± 1·6 pm) > CGRP8-37 (Ki = 3·6 ± 0·7 nm), respectively.25 Hence, the physiological concentrations for BTK inhibitor both CGRP and BIBN4096BS are within nm range25 whereas for CGRP8-37, it is within the μm range.38 We used the physiological range of concentrations of the antagonists in the current study. The mechanisms underlying the blocking activities of both antagonists on CGRP receptors are rather different. Since CGRP8-37 peptide includes all but the first seven amino acids at the C-terminal

of CGRP, it works as a competitive antagonist to block the binding of full-length CGRP to its receptor. In contrast, the specific affinities of BIBN4096BS depend on its interaction with the RAMP1 subunit of CGRP receptor.39 From the literature, the role of CGRP in the induction of pro-inflammatory and anti-inflammatory chemokines and cytokines is controversial.21–23 In these studies, depending on the cell type and concentration, CGRP exhibits either stimulating or suppressing effect on the production of MCP-1, IL-1β, TNFα, IL-6 and IL-10. Consistently, CGRP receptor signalling in the current study also demonstrates positive or negative effects on basal and LPS-induced release of these inflammatory mediators depending on the concentration of CGRP and CGRP receptor antagonists. Generally speaking, a lower concentration of CGRP seems to facilitate the basal Bcl-w release of MCP-1, TNFα and IL-6 but had no effect on the basal release of IL-1β and IL-10. The facilitating effects were

blocked by a lower concentration of CGRP8-37 (10 nm), suggesting that CGRP receptor mediates the effect. In contrast, a higher concentration of CGRP suppressed basal TNFα release but had no effect on others. Contrary to the effect of CGRP, a higher concentration of the peptide antagonist CGRP8-37 significantly increased the basal release of all chemokines and cytokines examined, but the lower concentration had no effect at all. Non-peptide antagonist BIBN4096BS also manifested the same tendency. However, at higher concentration, it only significantly increased the basal release of MCP-1, IL-6 and IL-10 but had no effect on IL-1β and TNFα. Similar to CGRP8-37, a lower concentration of BIBN4096BS had no effect on the basal release of chemokines and cytokines.

For the original untreated negative control iDCs, after

cell transfer to a new 24-well plate, one well still remained untreated whereas Stem Cells inhibitor the other well was treated with LPS. After another 24 hr (Day 2), contents of each well were collected for either cell or cytokine assays. After DC treatment with chemokines (Day 1) and subsequent LPS stimulus (Day 2), cell viability was also determined using Trypan blue exclusion. All treatments and controls exhibited at least 90% viable cells (data not shown). Hereafter, any combination of CCL3 and CCL19 at a specific ratio will adhere to the nomenclature: CCL3 + 19 (ratio). To measure the endocytic capacity of DCs upon chemokine or subsequent LPS treatment, DCs were incubated with fluorescently labelled OVA 24 hr after chemokine treatment (Day 1) or 24 hr after subsequent LPS treatment (Day 2) and the amount of OVA

internalized by DCs was determined using flow cytometry. Immature DCs treated with individual chemokines or chemokine combinations exhibited endocytic capacity comparable to untreated iDCs (Fig. 2a). As expected, upon subsequent LPS maturation, iDCs treated only with LPS reduced their www.selleckchem.com/products/ink128.html endocytic capacity significantly compared with untreated iDCs. However, iDCs pre-treated for 24 hr (Day 1) with individual chemokines or an equal Obatoclax Mesylate (GX15-070) combination of CCL3 + 19 (5 : 5), then subsequently treated with LPS exhibited an endocytic capacity similar to untreated iDCs. Surprisingly, even after subsequent

LPS treatment, iDCs pre-treated with CCL3 + 19 (7 : 3) showed an endocytic capacity 36% higher than untreated iDCs, whereas iDCs pre-treated with CCL3 + 19 (3 : 7) exhibited a 30% lower endocytic capacity than untreated iDCs (Fig. 2a,b). When endocytic capacity (MFIs by flow cytometry) was recalculated, now normalized to the value of endocytic capacity for untreated iDCs on Day 1, iDCs pre-treated with CCL3 + 19 (7 : 3) retained 57% of their endocytic capacity, even after subsequent LPS treatment. Conversely, the normalized endocytic capacity of untreated iDCs or iDCs treated with only LPS was reduced to 44% or 15%, respectively (Fig. 2c). Even though there is no direct evidence explaining why the endocytic capacity of untreated iDCs decreased over time, this natural decrease was presumably attributed to effects of the GM-CSF in the culture media[41-43] and of the cell transfer (Fig. 1)[41] on minimal maturation of these DCs during the 3-day culture in this study.

For the 0.1-μg dose, lymphocyte and eosinophil numbers were significantly higher in 20- compared with 1-week-old mice (* in Fig. 3A, B). For the 10-μg dose, this was opposite; the cell numbers decreased with age (Fig. 3A, B). In a separate study, mice were sensitized by i.n. instillation of OVA in Al(OH)3 and challenged i.n. with OVA. The main and interaction effects are reported above the figures. When a significant effect of age or a significant sex and age interaction

was found, the result of the post hoc test is given on the figure. Fig. 4A shows the OVA-specific IgE response in 1-, 6- and 20-week-old female and male mice. Significant main effects of both sex and age were found. Sensitized females produced higher levels of OVA-specific IgE compared with males (Fig. 4A). selleck products Further, the IgE response increased with age as 20-week-old mice had significantly higher levels than 1-week-old mice. The same pattern was observed for OVA-specific IgG1 production; females had significantly higher antibody production than males, and the response in both sexes increased with age (Fig. 4B). Cells from both SLNs and MLNs were stimulated with OVA ex

vivo. In MLNs, IL-4 was undetectable. Only IL-10 secretion was influenced by the sex of the mice, with females releasing significantly more IL-10 than males (Fig. 5A). IL-5 and IL-13 secretion was higher in 1-week-old mice compared with NSC 683864 older mice (Fig. 5B, C). INFγ was affected by age in the same manner as IL-17A secretion (Fig. 5D, E); 6-week-old mice had significantly lower IFNγ and IL-17A secretion than Afatinib 20-week-old mice and for IFNγ also significantly

lower than the 1-week-old mice. A significant age and sex interaction was found for the total number of cells in MLNs (Fig. 5F). The post hoc test revealed that only in the oldest age group did females have significantly higher number of cells compared with males (bracket in Fig. 5F). In SLNs, IL-4, -5, -10, -13 and IFNγ were undetectable and IL-17A produced at very low levels (data not shown and Fig. 5G). IL-17A production increased with age but was not affected by sex. The total number of cells in SLNs was unaffected by both sex and age (Fig. 5H). Control groups of mice were immunized i.n. with OVA alone. When comparing the OVA and OVA + Al(OH)3 treatments, MLN cell numbers, but not SLN cell numbers, were highly increased after using the adjuvant for sensitization, and this was observed for all age groups (data not shown). In contrast to the control groups (data not shown), a pronounced airway inflammatory cell influx dominated by macrophages, lymphocytes, some epithelial cell shedding and in particular by eosinophils was found in BALF of the mice. However, only lymphocytes, epithelial cells and eosinophils were significantly affected by the investigated experimental factors. The number of lymphocytes, eosinophils and epithelial cells in BALF was significantly higher in female mice compared with male mice (Fig. 6A, B, C).

One of these, the L1007insC frameshift mutation (31% prevalence), results in a truncated NOD2 protein lacking part of the last LRR. Homozygous carriers of this mutation exhibit a much more severe disease phenotype and have a higher Nutlin-3 in vivo risk for ileal stenosis and surgical intervention

42. A different subset of CARD15 mutations cause a distinct and highly penetrant autosomal dominant systemic disorder called Blau syndrome (BS) 43. BS mutations almost exclusively target the NBD of the protein and produce a broader distribution of affected tissues than CD. Three-dimensional structure analysis predicted that the NLRP3 R260W mutation and the BS-associated R334W mutation of NOD2 encode a substitution at a homologous, structurally conserved amino acid residue 44. Therefore, as is the case for NLRP3 in CAPS, NBD mutations in BS may produce a protein that is constitutively active, a hypothesis MG132 supported by the finding that R334W NOD2 leads to increased basal NF-κB activation 45. As LRRs are implicated in sensing microbial components, CD-associated mutations in NOD2 may alter the threshold of mycobacterial N-glycolyl muramyl dipeptide recognition and its downstream signalling rather than lead to a constitutively active form as in BS. However, the consensus mechanism by which mutations in NOD2 predispose

to CD remains controversial. Indeed, Segal and colleagues have reported that CD patients, irrespective of their genotype, share a dampened inflammatory phenotype in response to injury or bacterial challenge 46. Enhanced lysosomal degradation

was proposed to be at the basis of the cytokine secretion defect in CD. This raises the question of whether CD is a systemic immune deficiency disease with manifestations in the intestinal tract due to the uniquely high bacterial content of this organ. Only recently did a study reveal the surprising discovery that, unlike its WT counterpart, L1007insC mutant NOD2 actively suppresses the constitutive transcription of human IL-10 many in a peptidoglycan- and NF-κB-independent manner by inhibiting the activity of hnRNP-A1 in monocytes 47. This phenomenon was not found with the mouse orthologues and cautions on the necessity of human functional immunological studies. In this context, it is not surprising that enhanced IL-10 production, which can occur after treatment with certain probiotic bacteria, helps to calm inflammation in CD 48. Such data suggest a complex interaction between NOD2 and a number of other loci controlling innate and adaptive immune function (e.g. IL-23R 49) to confer susceptibility to CD. Nonetheless, these studies provide initial evidence in support of a long-held theory that conjectures that NOD2 normally functions as an innate signal that tolerizes the host’s adaptive immune system to the commensal intestinal flora. Although there are limitations inherent to GWAS design (e.g.

Bacterial counts are reported as colony-forming units per gram. Mice were sacrificed 2 weeks post-Cr infection. Lymphocyte suspensions

were prepared from the mesenteric lymph nodes (MLN) and spleen as described previously (Shi et al., 2000; Chen et al., 2005). Cells (5 × 106 cells mL−1) were cultured on 48-well plates in the presence or absence of Cr antigen (50 μg mL−1) or plate-bound anti-CD3 MAb (10 μg mL−1). Culture supernatants were collected after 72 h and stored at −20 °C until assayed for cytokine production. ELISA capture antibodies [R4-6A2, interferon gamma (IFN-γ); JESS-2A5, IL-10] and biotinylated secondary antibodies (XMG1.2, IFN-γ; SXC-1, IL-10) were purchased from PharMingen (San Diego, CA), whereas TNF-α ELISA capture C59 wnt antibodies (MP6-XT22) and biotinylated secondary antibodies (C1150-14) were purchased from BD Pharmingen, San Jose, CA. The biotinylated secondary antibodies were used as a second layer, and reactions were visualized with mTOR inhibitor O-phenylenediamine at 492 nm (OPD; Zymed Labs, South San Francisco,

CA). Standard curves were obtained using recombinant murine IFN-γ (Genzyme, Cambridge, MA), IL-10 (R&D Systems, Minneapolis, MN), and TNF-α (BD Pharmingen). Optical density values were converted to pg mL−1 for each cytokine by linear regression with Delta Soft II (Biometallics, Princeton, NJ). At necropsy, colonic tissues were isolated and small fragments were then frozen in Tissue-Tek® O.C.T. Compound (Miles Inc. Elkhart, IN) and stored at −80 °C. Some colonic fragments were snap-frozen in liquid nitrogen and

then stored at −80 °C for detection of colonic cytokine gene expression. Seven-micrometer sections were cut on a 2800 Frigocut cryostat (Reichert-Jung, Germany) and stained with hematoxylin and eosin. Sections were analyzed without prior knowledge of treatment. Colonic pathology was scored using a modified histology scoring system based on previously published methods (Chen et al., 2005). The scoring ASK1 system consists of two parts. Part 1 is the determination of the infiltration of inflammatory cells in the colon, with scores ranging from 0 to 4 (0, normal cell pattern; 1, scattered inflammatory cells in the lamina propria; 2, increased numbers of inflammatory cells in the lamina propria; 3, confluence of inflammatory cells extending into the submucosa; and 4, transmural extension of the infiltrative inflammatory cells). Part 2 is the evaluation of colon tissue damage, with scores that also range from 0 to 4 (0, normal tissue pattern; 1, minimal inflammation and colonic crypt hyperplasia; 2, mild colonic crypt hyperplasia with or without focal invasion of epithelium; 3, obvious colonic crypt hyperplasia, invasion of epithelium, and goblet cell depletion; and 4, extensive mucosal damage and extension through deeper structures of the bowel wall). The total colon pathology score equals the inflammatory cell score plus the tissue damage score (Fig. 3g).

Various other end-points evaluating the efficacy of IgG therapy in patients with PI have been explored. Pulmonary click here function has been studied [15–20],

but the lack of sensitivity of the available methods has prevented the wide use of this measure. The Chest CT in ADS Group (http://www.chest-ct-group.eu/), an international group of immunologists, pulmonologists and radiologists, has developed a methodology for improving the diagnosis of disease in patients with antibody deficiency syndrome. This group uses high-resolution chest computed tomography (CT) scanning along with a battery of lung function tests which are used to give a CT score to track the progression of lung disease. The potential

use of C-reactive protein (CRP) as an indicator of IgG therapy efficacy was discussed. CRP is an acute-phase protein produced in response to various stimuli involving tissue damage such as inflammation and infection. Serum CRP has been used extensively as a marker of bacterial infection [21]. However, due to its low specificity, its true diagnostic value in clinical practice has been questioned [22,23]. A retrospective, single-centre study was carried out to examine the association between CRP levels and clinical outcomes in patients with CVID on immunoglobulin replacement. The cohort consisted of 112 CVID patients Olaparib supplier and was divided into three groups based on median CRP values (0–5, 5–10 and > 10 mg/l). There were 10 patients in the > 10 mg/l group. There were a large number of patients in both 0–5 and 5–10 mg/l groups and 12 patients were selected randomly from each group for the analysis. Five outcome parameters

were investigated: number of infections, number of serious Guanylate cyclase 2C infections, number of antibiotic courses, days off sick and days in hospital. These parameters are also part of the quality of life data set in the ESID database [14]. The working hypothesis was that these outcome parameters would correlate positively with serum CRP levels. However, when considering CRP on a continuous scale, no strong evidence of an association between CRP and any of the parameters examined was found (Table 1). Only weak evidence of an association between CRP and the number of serious infections was observed, but this was not statistically significant (P = 0·08). The Spearman’s rank correlation coefficient between the two variables was positive, suggesting that the number of serious infections increased with increasing serum CRP level. When the CRP measurements were divided into three categories (0–5, 5–10 and > 10 mg/l), the Kruskal–Wallis analysis suggested that there was not enough evidence that any of the outcome parameters varied between CRP categories (Table 1).

C57BL/6J, BALB/cJ, C57BL/6-Tg(TcraTcrb)1100Mjb/J (here: OT-I), and C57BL/6.SJL-Ptprca (CD45.1) mice were obtained from Charles River (Germany).

Mice were bred and housed under specific pathogen free (SPF) conditions in the central animal facility of Hannover Medical School (Germany) and used at 6–12 wk of age. All experiments were approved by the Local Institutional Animal Care and Research Advisory committee and authorized by the local government. This study was conducted www.selleckchem.com/products/BKM-120.html in accordance with the German Animal Welfare Law and with the European Communities Council Directive 86/609/EEC for the protection of animals used for experimental purposes. Anti-CD4-PacificOrange (RmCD4-2), buy Navitoclax anti-CD4-PacificBlue (GK1.5), anti-CD4-Cy5 (RmCD4-2), anti-CD8β-PacificOrange, anti-CD8β-biotin (RmCD8), and anti-CD62L-PacificOrange (MEL-14) were purified from hybridoma supernatants and conjugated in house. Anti-CD44-PacificBlue (IM7), anti-TCRβ-allophycocyanin-Alexa750 (H57-597), anti-Thy1.2-PE (MMT1), and anti-CD62L-allophycocyanin-AlexaFluor780 (MEL-14) were obtained from eBioscience. Anti-CD25-PerCP-Cy5.5 (PC61), anti-BrdU-Alexa647 (mglG1k), anti-Thy1.1-biotin

(HIS51), anti-CD45.1-Alexa405 (A20), anti-CD103-PE (M290), anti CD8α-allophycocyanin-Cy7 (53-6.7), anti-Vα2-PE (B20.1), anti-Vβ3-PE (KJ25), anti-Vβ4-PE (KT4), anti-Vβ5-biotin (MR9-4), anti-Vβ6-PE (RR4-7), anti-Vβ7-PE (TR310), anti-Vβ8-PE (F23.1), anti-Vβ11-PE (RR3-15), and Streptavidin coupled to PE-Cy7 or PerCP were purchased from BD Bioscience. aminophylline CCR9 staining with rat anti-mouse CCR9 (7E7-1-1) was performed as described 56. Human rIL-2 (Roche) was obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH. Lymph nodes and spleens were mashed through a 100-μM nylon gauze and washed with PBS/3% FCS (PAA). Spleen and blood samples were treated with erythrocyte-lysis buffer. For isolation of LPL, gut content and Peyer’s patches were removed before intestines were opened longitudinally, washed twice

in cold PBS/3% FCS, and incubated 3×15 min in HBSS (Gibco) with 10% FCS and 2 nM EDTA at 37°C. After each incubation step, tubes were shaken for 10 s and the supernatant was discarded. Intestines were washed once in PBS, incubated 2×45 min in RPMI 1640 (Gibco) containing 10% FCS, 0.24 mg/mL collagenase A (Roche), and 40 U/mL DNase I (Roche) at 37°C, then tubes were shaken for 10 s, and cell suspensions pooled, resuspended in 40% Percoll (Amersham) in RPMI 1640/PBS, overlaid onto 70% Percoll in RPMI 1640/PBS, and centrifuged at 2000 rpm for 20 min at room temperature. LPL were recovered from the interphase and washed with PBS/3% FCS. To assess BrdU incorporation, mice received 2 mg BrdU in PBS i.p. and were sacrificed after 20 h. Before staining, cell suspensions were incubated at 4°C for 5 min with Fc block (mAb 2.4G2).

AML cells at presentation of disease show a number of abnormalities suggestive of immune pressure to select variants that evade immune surveillance. click here AML can express the ligand for the glucocorticoid-induced tumour necrosis factor-related protein (GITRL), which can block NK function through triggering GITR on the NK cell directly or through soluble GITRL [32]. AML blasts often weakly express co-stimulatory molecules which may favour their escape from T cell-mediated

killing, and the probability of remaining in remission is greatest in patients who express both CD80 and CD86 [4]. AML cells can shed ligands for co-stimulatory molecules such as the 4-1BB ligand, which may allow the leukaemia to block T cell attack by the binding of soluble ligand to the T cell [33]. The class II-associated invariant chain

self-peptide (CLIP) is expressed variably in AML. CLIP down-regulation can increase antigenicity of AML cells (by unblocking MHC class II loading with self-antigen) and increase CD4 responses. Patients whose AML blasts have less CLIP bound to HLA-DR molecules have prolonged remissions [34]. AML cells secrete soluble factors which may be responsible for a variety of defects observed in T cell and NK cell function [35,36]. Through their myeloid-lineage affinity, AML cells can generate leukaemic dendritic cells (DC) in vitro and in vivo which function as antigen-presenting PIK3C2G cells (APC). However, AML DC are distinctly abnormal [37]. see more They can inhibit the induction of CTL, inducing T cell anergy [38–40] and favouring the generation of regulatory T cells [41] which are increased

in AML [42]. Probably as a consequence of the leukaemia, T cells in AML show several abnormalities: recent thymic emigrants are reduced, suggesting defective thymic function [43]. In a detailed study of T cells in AML Le Dieu and colleagues found T cells with abnormal phenotypes and genotypes that formed defective immune synapses with AML blasts [44]. Finally, the AML microenvironment may favour AML survival – mesenchymal stromal cells in leukaemias can provide an immunosuppressive milieu [45] and the protective endosteal region of the marrow favours the survival of leukaemic stem cells [46]. Whether the goal of immunotherapy in AML is to boost the patient’s immune system or to confer immunity with T cells, NK cells or monoclonal antibodies, immune treatment is usually planned as a means of sustaining remission once the disease has been bulk-reduced with chemotherapy. Animal models of AML have proved useful in providing the basis for adoptive T cell and NK cell therapy [47], exploring the combination of immunotherapy with chemotherapy [48] and defining the role of regulatory T cells in preventing full efficacy of leukaemia-specific cytotoxic T cells in a mouse AML model [49].

Natural killer (NK) cells are a specialized subset of lymphocytes that navigate through the circulatory and lymphatic systems and provide a first line

of defence against pathogen-infected and neoplastic cells. In humans, NK cells are phenotypically characterized as CD3− CD56dim/bright cells that account for up to 15% of peripheral blood lymphocytes.1,2 NK cells, discovered in 1975,3–5 are components of the innate PCI-32765 in vitro immune system that protect host organisms against viral, bacterial and parasitic infections.6 They are also capable of directly killing tumour cells.2,7 NK cells exert their function through two major effector mechanisms: direct killing of target cells, and production of inflammatory and regulatory cytokines.8 As cytotoxic effectors, NK cells are unique because they can kill certain target cells in vitro without

Selleckchem CHIR 99021 previous sensitization.9 Unlike T cells, NK cells are not capable of antigen-specific receptor somatic recombination. Therefore, in vivo, NK cells rely on the surface recognition of MHC class I, class I-like molecules, and other ligands, by germline-encoded activating and inhibitory NK cell receptors (NKRs) to induce or arrest their cytotoxic activity against target cells.10–12 Additionally, NK cells are capable of secreting a wide variety of cytokines and chemokines, which not only enhance innate immunity, but also shape downstream adaptive immune responses.12–14 Human circulatory NK cells are phenotypically characterized in two subsets: cytolytic CD56dim CD16+ NK cells (≥ 90%), and cytokine-producing CD56bright CD16−/dim NK cells (≤ 10%).7 Cytolytic CD56dim CD16+ NK cells express

high levels of killer cell IMP dehydrogenase immunoglobulin-like receptors (KIRs) and are capable of mediating potent antibody-dependent cellular cytotoxicity (ADCC). On the other hand, cytokine-producing CD56bright NK cells express low levels of KIRs and mediate low ADCC and cytotoxic responses.2 Rhesus macaques (Macaca mulatta) are an important and reliable animal model for the study of retrovirus-induced human diseases. In fact, pre-clinical vaccine trials using macaque simian immunodeficiency virus (SIV) and simian/human immunodeficiency virus (SHIV) platforms are becoming gatekeepers for the advancement of candidate human immunodeficiency virus (HIV) vaccines into human trials.15 Even though the direct role played by NK cells during HIV infection remains undefined, there is strong evidence that these cells can provide some measure of protection against both initial infection and disease progression. Certain NKR phenotypes are associated with protection against HIV infection,16 and non-progressive HIV infections are associated with higher levels of NK cell cytotoxicity.17 Furthermore, vaccine-elicited non-neutralizing anti-envelope antibodies have been shown to contribute to protection against HIV, SIV and SHIV89.