Racial disparities in HIV prevalence are profound, both between regions and within regions. These disparities are not often discussed, perhaps because it is assumed that they are driven by stigmatizing socio-behavioural factors such as sexual concurrency or promiscuity, partner violence and so on. While such factors may be important in some contexts, the purpose of this review has been

to emphasize that biological factors such as endemic co-infections and immunology also play a key role. To develop better prevention tools, it is critical Selleckchem Erismodegib that communities, researchers and policy makers come together to discuss and investigate these tremendous disparities in an open and non-judgmental fashion. This work was supported by grants from

the Canadian Institutes of Health Research (RK, HET-85518; LRM and DC, salary support). Study sponsors played no role in the writing of the manuscript or decision to submit for selleck chemicals llc publication. No author has any financial or personal relationship posing a conflict of interest in relation to this study. Study concept and initial draft: RK; manuscript revisions: CRC, TJY, DC, WT, LRM, OA, JK, RR. “
“Class switching and plasma cell differentiation occur at a high level within all mucosa-associated lymphoid tissues. The different classes of membrane immunoglobulin heavy chains are associated with the Igα/Igβ heterodimer within the B-cell receptor (BCR). Whether BCR isotypes convey specific signals adapted to the corresponding differentiation stages remains debated but IgG and IgA membranes have been suggested to promote plasma cell differentiation. We investigated the impact of blocking expression of the IgA-class BCR through a ‘αΔtail’ targeted mutation, deleting the Cα immunoglobulin

second gene membrane exon. This allowed us to evaluate to what extent class switching and plasma cell differentiation can be concurrent processes, allowing some αΔtail+/+ B cells with an IgM BCR to directly differentiate into IgA plasma cells and yield serum secreted IgA in spite of the absence of membrane IgA+ B lymphocytes. By contrast, in secretions the secretory IgA was very low, indicating that J-chain-positive plasma cells producing secretory IgA overwhelmingly differentiate from previously class-switched membrane IgA+ memory B cells. In addition, although mucosa-associated lymphoid tissues are a major site for plasma cell accumulation, αΔtail+/+ mice showed that the gut B-cell lineage homeostasis is not polarized toward plasma cell differentiation through a specific influence of the membrane IgA BCR. Immunoglobulin A is considered a major actor in specific mucosal immunity.

In the murine-Langerin-DTR models, developed originally to target only LCs, it was realized subsequently that both CD207/Langerin+ DDCs and LCs were ablated by diphtheria toxin treatment. Because the two DC

subsets reconstituted ABT 199 with different kinetics, interpretation of the effect on T cell responses was complex [63-65]. Finally, depletion of CD205+ DCs in CD205-DTR mice dramatically reduced CD4+ and CD8+ T cell responses to bacterial and viral infections [48]. However, given that the steady-state frequency and distribution of Tregs, Th1 and Th17 cells was grossly altered by diphtheria toxin treatment, it was difficult to attribute the effect solely to CD205+ DCs, without considering the effect of the altered immune environment [48]. CD11c-cre and Langerin-cre mice have also been used to generate targeted knock-outs of multiple immune signalling molecules, including recombination signal binding protein for immunoglobulin kappa J (RBPJ) [66], signal transducer and activator of transcription 3 (STAT3) [67], tumour necrosis factor, alpha-induced protein 3 (TNFAIP3) (A20) [68] and myeloid differentiation primary response gene 88 (Myd88) [69]. These applications suffer from the same subset specificity issues as the DTR models, due to model-dependent artefacts

and the complex expression patterns of Langerin and the CD11c transgene [70, 71]. Administration of horse cytochrome c is an alternate strategy used to ablate cross-presenting DCs via specific induction of the apoptosis pathway in

cells possessing cross-presentation machinery [72]. Experiments using this treatment have suggested that cross-presentation is selleck chemicals limited to a subset of splenic CD8+ cDCs, although the Inositol monophosphatase 1 model was complicated by the partial depletion of CD11b+(CD4+) cDCs, which are usually considered to be incapable of cross-presentation [73]. In addition to inducible ablation, transcription factor knock-out mice have been used to define in-vivo DC subset function, as they show complete or partial deficiencies in well-defined DC subsets (reviewed in [1, 74]). For example, the comparison of interferon regulatory factor 4 (IRF4–/–) mice (lacking CD11b+ DCs) with Id2–/– or IRF8–/– mice (both lacking CD8+ DCs) has supported the paradigm that CD11b+ DCs promote Th2 cytokine production, while CD8+ cDCs promote Th1 cytokine production [75, 76]. Similarly, basic leucine zipper transcription factor, ATF-like 3 (BATF3–/–) mice have been used to demonstrate that cross-presentation is confined to the CD8+ cDC and CD103+ mDC subsets, which are selectively deficient in these mice [77]. Interestingly, while both CD205-DTR [48] and BATF3-deficient mice [77] lack CD8+ cDCs, only in the CD205-DTR model were splenic CD4+ T cell responses affected. An additional complexity in transcription-factor knock-out mice is that the targeted transcription factors are expressed, albeit at lower levels, in the remaining DC subsets [74, 78].

3; for methods see supplementary information). Thus, Venetoclax mutations in genes that lead to mutator phenotypes in P. aeruginosa can enhance microcolony initiation and growth during biofilm culture. This different architecture of

the biofilm formed by mutator strains has an impact on the tolerance of the biofilms to antibiotics. We found that the PAO1 ∆mutT had increased tolerance to piperacillin/tazobactam compared with the wild-type (Fig. 4). It has been shown in planktonic growth that under piperacillin/tazobactam selective pressure PAO1 ∆mutT developed a larger resistant subpopulation compared with PAO1 and that the mechanism of resistance was related to increased beta-lactamase production (Mandsberg et al., 2009). Selection of such a resistant subpopulation during treatment of the biofilm might explain the increased tolerance to piperacillin/tazobactam MLN0128 of PAO1 ∆mutT compared with PAO1. It has been shown recently that theoretically optimized PK/PD parameters failed to suppress resistance development in biofilm-grown bacteria. The antibiotic concentration that prevents the selection of resistant mutants (mutant preventive concentration) is increased in biofilms compared with planktonic growth due to the particular physiology and architecture of biofilms favouring gradual mutational

resistance development, especially in mutator strains (Macia et al., 2011). The increased tolerance to piperacillin/tazobactam of PAO1 ∆mutT might also be due to a more efficient SOS response in mutators. We have recently shown in another mutant that is unable to repair DNA oxidative

lesions that such unrepaired lesions trigger an oxidative stress response in P. aeruginosa (Mandsberg et al., 2011) that could trigger an SOS response and better survival in the presence of antibiotics. Hyperproduction of beta-lactamase (Ciofu et al., 1994; Bagge et al., 2002) and overexpresison of efflux-pumps (Jalal et al., 2000; Islam et al., 2009) are the most common mechanisms of resistance encountered in CF P. aeruginosa isolates. Due to the selective pressure exerted by maintenance antibiotic treatment, occurrence of resistant P. aeruginosa strains during chronic airway infection in CF is common, and the Farnesyltransferase most important mechanism of resistance to beta-lactam antibiotics is overproduction of the chromosomally encoded beta-lactamase (Giwercman et al., 1990; Ciofu, 2003). In biofilms of P. aeruginosa that overproduce beta-lactamase, the presence in the biofilm matrix of beta-lactamases will lead to hydrolysis of the beta-lactam antibiotics before they reach the bacterial cells. Nichols et al. (1989) predicted from mathematical models that bacteria expressing high levels of chromosomal beta-lactamase growing in biofilms would be exposed to reduced concentrations of beta-lactam antibiotics due to accumulation of the enzyme in the polysaccharide matrix.

Activation was arrested by fixing the cells with warm Cytofix Buffer (BD Biosciences) at 37° for 10 min.

Cells were then permeabilized with ice-cold Perm Buffer III (BD Biosciences) at 4° for 30 min and incubated with PE mouse anti-Akt (pS473) (BD Biosciences) for 30 min at room temperature. Cells were washed in stain buffer (BD Pharmingen) and acquired Adriamycin ic50 on a BD FACS Calibur 2 flow-cytometer (BD Biosciences) and analysed using FlowJo software (TreeStar). Statistical analysis was performed using GraphPad Prism version 4.00 (GraphPad Software, San Diego, CA) and P < 0·05 was considered significant. Multiple linear regression was performed using PaswStatistics 18.0 (IBM-SPSS, Chicago, IL). Age and CMV infection have been shown to profoundly affect the overall composition

of the CD8+ T-cell compartment.12 We found that the frequency of CD45RA+ CD27+ (naive) CD4+ T cells significantly decreased with age (Fig. 1a,b; P = 0·0003) whereas the frequencies of all the primed/memory subsets significantly increased with age: CD45RA− CD27+ (P = 0·0033), CD45RA− CD27− (P = 0·0321), CD45RA+ CD27− (P = 0·0315). However, this analysis does not take into account the individual contribution of ageing and CMV infection in shaping the CD4+ T-cell compartment. An earlier study showed that CMV infection is associated Crizotinib mw with the accumulation of highly differentiated CD4+ T cells.16 Here we extend these observations by further discriminating between highly

differentiated CD4+ T cells in the basis of CD45RA re-expression. We analysed the results in two ways. First, we divided the subjects into young (< 40 years) and old (> 60 years) groups and further subdivided these individuals on the basis of their CMV seropositive or negative status (Fig. 1c). Second, we performed multiple linear regression analysis to examine more closely the impact of aging and CMV in determining the T-cell subset composition during ageing. The percentage of CD45RA+ CD27+ (naive) CD4+ T cells decreased with age; this decrease was significant in CMV-positive Verteporfin mw (P = 0·003) but not in CMV-negative donors as assessed by the Mann–Whitney U-test. However, when we analysed the data using multiple linear regression analysis (see Supplementary Information, Table S1) we found that age and CMV both induce a significant decrease of the CD45RA+ CD27+ CD4+ T-cell compartment (P < 0·001 and P < 0·045, respectively) but age alone seems to be the main factor modulating the increased CD45RA− CD27+ subset. The frequencies of CD45RA− CD27− and CD45RA+ CD27− subsets were significantly higher in CMV-infected donors in both young and old age groups (Fig. 1c). Furthermore, old CMV-positive donors had significantly higher proportions of these cells compared with young seropositive subjects as assessed by the Mann–Whitney U-test (Fig. 1c, lower panels).

Three members of the mammalian Pellino family were initially characterised as scaffold proteins that regulate TLR-mediated activation of NF-κB and MAPKs 10, 11. More recently, Pellinos have been shown to function as E3 ubiquitin ligases, catalysing K63-linked polyubiquitination of IRAK-1 14–16. Indeed there exists a bidirectional communication in the IRAK–Pellino associations, in that IRAK-1 and IRAK-4 can phosphorylate Pellino proteins on various serine and threonine residues, thus enhancing the E3 ubiquitin ligase activity of the Pellinos. The latter can then catalyse polyubiquitination of

IRAK-1 16, 17. The C-terminal regions of the Pellino proteins contain a conserved RING-like domain that confers E3 ubiquitin ligase activity.

Furthermore, the recent resolution of the x-ray structure of a N-terminal fragment (amino acids 15–275) of Pellino2 that lacks the RING-like domain, revealed a cryptic forkhead-associated (FHA) https://www.selleckchem.com/products/Adriamycin.html domain that was not apparent from the primary structure 18. The FHA domain is a phosphothreonine-binding module and underlies the ability of Pellino proteins to interact with phosphorylated IRAK-1. The FHA domain in the Pellino family differs from the classical FHA domain present in other proteins by containing Crizotinib an additional appendage or “wing” that is formed by two inserts in the FHA region 18. Although the importance of this appendage region for IRAK binding remains to be experimentally addressed, it is worth noting that multiple IRAK phosphorylation sites reside in the “wing” region 17. Intriguingly, a viral form of Pellino has been previously identified as an open reading frame (ORF) from the genome of Melanoplus sanguinipes entomopoxvirus (MsEPV) 19, 20. The genomic location of this ORF near the right-hand side inverted terminal repeat indicates that viral Pellino could possess an immunomodulatory function 19. The conceptual translation of the viral Pellino ORF has been shown to display sequence similarity to human, insect and nematode Pellino proteins 19, 20, suggesting

this website that viral Pellino is a homolog of genes encoding receptor proximal intracellular signalling proteins in the Toll and TLR pathways. This prompted us to perform a functional characterisation of the regulatory effects of viral Pellino in these pathways. We demonstrate that viral Pellino can down-regulate Toll-mediated activation of the Drosophila antimicrobial response and inhibit human TLR signalling to NF-κB, underscoring the importance of Pellinos within this signalling axis in the innate immune system. The amino acid sequence and the two available structures of Pellino2 (PDB: 3EGA at 1.8 Å and 3EGB at 3.3 Å) 18 were used as templates for comparative modelling of viral Pellino. An initial alignment between the full amino acid sequence of Pellino2 and the viral Pellino resulted in a poor overall sequence identity of 15.6% (http://www.ebi.ac.uk/). This sequence identity rises to 16.5% (26.

Although several studies have been performed with the aim of developing an efficacious vaccine against T. gondii, there are currently no notable immunoprophylactic treatments for human toxoplasmosis. However, there are live attenuated vaccines for veterinary use that are expensive, are limited in use, cause unpleasant side effects RG 7204 and have a short shelf life [7, 8]. Therefore, identifying and characterizing potential

protective antigens that induce appropriate immune responses for vaccine development would be an effective route to control toxoplasmosis [9]. Several T. gondii antigens, such as AMA1 have exhibited strong specific immune responses and provide effective protection against oral infection by the T. gondii Beverley strain in BALB/c mice [10]; IMP1, MIC3 and ADF, have been shown to elicit high specific humoral ABT-263 concentration and cellular immune responses

and have significant protection efficiency (longer survival time of animals, lower number of brain cysts) after an intraperitoneal challenge by T. gondii RH strain tachyzoites in BALB/c mice.[11-13]. Cyclophilin (CyP) belongs to a highly conserved and multifunctional protein family found in both prokaryotic and eukaryotic organisms. Large numbers of cyclosporine binding proteins that belong to this family are believed to be mediators of intra- and intercellular communications. CyP exhibits peptidyl-prolyl cis-trans isomerase (PPIase) activity in several protozoan parasites (including Plasmodium falciparum and Leishmania donovani) and plays a vital role in protein folding [14]. PPIases can alter the activity of key regulatory enzymes.

Several studies have focused on the protein phosphatase calcineurin, which may be critical in modulating the immunosuppressive effects of cyclosporin A (CsA). Furthermore, the CsA-cyclophilin complex can strongly influence a Ca2+-dependent signalling pathway in T lymphocyte Molecular motor suppression [15]. The amino acid sequence of T. gondii CyP-20 exhibits homology with the B subunit of mammalian calcineurin. Therefore, the microbial PPIases can interact with host cell proteins [16]. T. gondii CyP (TgCyP) can trigger the cysteine-cysteine chemokine receptor CCR5 in pro- and anti-inflammatory host cells and consequently induce the production of IL-12. Previously, the production of IL-12 dependent IFN-γ was found to be up-regulated, which is important to maintain host survival during acute toxoplasmosis [17]. Neospora cyclophilin (NcCyP), which exhibits high similarity to TgCyP, is believed to be a efficacious vaccine candidate against Neospora infection, and this antigen can stimulate IFN-γ production in bovine peripheral blood mononuclear cells and N. caninum-specific CD4+ T cells [18, 19]. The TgCyP antigen may be a potent vaccine candidate that would be useful in protection against toxoplasmosis. In this study, a humoral response that was specific for the immune modulation of TgCyP was elicited in immunized BALB/c mice.

Of the seven species that affect the poultry industry, E. maxima is considered as the most immunogenic (56). Early studies therefore concentrated on the E. maxima model and much work was focused on better understanding the basis of immunity and the lifecycle stages that are predominantly involved in immune responses (56–58). In addition, E. maxima was selected as the model species for initial work on development Fostamatinib in vivo of a subunit vaccine as its gametocytes are very large in size and relatively easily visualized and purified (59). The induction

of immunity using the E. maxima model was first demonstrated by Rose (56), who showed that a single low dose of E. maxima oocysts could protect chickens against a challenge with high doses of oocysts of the homologous strain, and that one

cycle of infection was enough to stimulate this protective immunity. It was further demonstrated that sera taken 14 days post-infection with E. maxima can give passive protection learn more to naive chickens against a challenge (57,58). However, it was first thought that the asexual stages of the lifecycle of Eimeria were predominantly responsible for the immune response invoked in chickens. Analysis of convalescent sera taken 14–20 days after an E. maxima infection, which was shown to passively protect naive birds, demonstrated that the early stages of development have a strong immunogenic effect, and the Rebamipide later sexual stages were poorly immunogenic in E. maxima,

E. necatrix and E. tenella (58,60). Kouwenhoven and Kuil (61) also reported that sera taken from chickens infected with E. tenella showed no reaction with sexual stages or first generation schizonts, indicating that gametocytes had poor immunizing capabilities in chickens. Later studies, however, contradicted these earlier findings (62,63). The antigenicity of sexual stages of Eimeria was first demonstrated when a monoclonal antibody to an E. tenella gametocyte antigen was shown to inhibit fertilization in vitro (64). In 1989, Pugatsch et al. (62) developed a method to isolate and purify gametocytes by enzymatic digestion of the infected mucosa with hyaluronidase, followed by size separation. They showed that whole gametocytes were highly antigenic both in the course of an infection and when injected into rabbits/mice. During the same year, convalescent sera from E. maxima immune chickens were found to recognize two immunodominant macrogametocyte antigens of 56 and 82 kDa in size (63). When these two proteins were administered to a variety of hosts in the form of a crude extract, they were found to be highly immunogenic (63). Following this discovery, it was hypothesized that these macrogametocyte antigens may play a role in conferring protective immunity to the host (63).

Many immune activities are attributed to NKT cells, although they are associated most often with providing effective immunity against cancer, infections and autoimmune diseases [2-4]. Given these varied roles [5, 6], it is surprising (and an issue of conjecture [7, 8]) that usually only the CD4+ and CD4− subsets of mature human NKT cells are assayed when clinically assessing the human NKT cell pool [9]. CD4+ NKT cells produce cytokines associated with T helper PI3K inhibitor type 0 (Th0) responses,

and CD4− NKT cells are associated with Th1 responses [10, 11]. The extent to which additional functionally distinct human NKT cell subsets exist is not known, but others have been defined in mice, and human NKT cells express differentially several cell surface antigens used to define conventional T cell subsets [8, 10-13]. A recent study showed MAPK inhibitor that both the CD4+

and CD4− NKT cell subsets were highly heterogeneous in their expression of cell surface antigens and cytokine production, which suggested that unidentified functionally distinct subsets may exist within both these subsets [14]. This was an important finding, however, similar to earlier reports that examined the significance of CD8 expression by human NKT cells [15, 16], the study used expanded NKT cell lines to obtain sufficient cell numbers and it is uncertain whether or not the phenotype of the expanded cells accurately reflected the in situ (i.e. non-expanded) human NKT cell pool. Like many other NKT cell studies, the analysis was conducted using only NKT cells sourced from peripheral blood. This is an important issue to consider because, although analysis of blood is the dominant source of cells for assessing patient immunity, NKT cell tissue location is an important determinant of their function in mice [17]. Mouse studies have also shown that the profile of blood NKT cells often does not reflect NKT cells from other tissue

sites [18]. It is not known whether this also applies to human NKT cells, although NKT cells from human thymus are functionally unresponsive compared to blood-derived NKT cells Clomifene [19] and liver NKT cells are distinct from blood NKT cells in their expression of cell surface proteins [20]. In this study, we characterize the heterogeneity of the human NKT cell pool by analysing cell surface antigen and cytokine expression of the overall NKT cell pool and of the CD4+ and CD4− subsets from different tissues, with an emphasis on testing freshly isolated, rather than in-vitro-expanded, NKT cells. We detail significant heterogeneity within the established CD4+ and CD4− NKT cell subsets from peripheral blood, thymus, spleen and cord blood and identify several candidate antigens where differential expression correlates with distinct patterns of cytokine production by blood-derived NKT cells. Our findings provide a platform for an improved understanding of the complex organization of the normal human NKT cell pool.

Although the binding activity of Ezh2 at the Il17a promoter was higher than at the Ifng promoter, we recognized some binding activity of Ezh2 at the Ifng and Tbx21 promoters. Therefore, a dual activity of Ezh2 as transcriptional activator of Il17a and repressor of the alternative cytokine genes, is feasible,

albeit we have not observed derepression of the opposing cytokine genes Ifng and Il4 following Selleck PARP inhibitor the knockdown of Ezh2. It is possible that a more severe silencing of PcG expression is necessary to reveal their repressive activities. With regard to Tbx21, in some experiments we did find upregulation of its expression following Ezh2 knockdown, but this finding was not consistent, and currently we cannot draw any conclusions in that aspect. Published results using reporter mouse PS 341 strain mapping the fate of cells that have activated IL-17A demonstrated that IL-17A expressing Th cells have distinct extent of plasticity in different inflammatory setting in vivo: they can either acquire the Th1 effector functions instead or in addition to their Th17 phenotype 41. However, the Th17 cells can also shut off their Th17 transcriptional profile without turning on other lineage-specific programs 41. Probably, the mode of the reprogramming process is affected by the external cytokine milieu. Intrinsic factors, which can be modulated during differentiation, may also influence the stability

of the Th17 phenotype, and can underlie some conflicting estimations as to the extent of the plasticity of the Th17 lineage in vivo 36, 40, 41, 45. In our in vitro experiments, we found that the differentiation of Th17 cells in the presence of TGF-β and IL-6 but in the absence of IL-23 resulted in a more stable expression pattern of Rorc mRNA 18 h following cytokine-free restimulation (data not shown); namely, the expression of Rorc mRNA was not reduced 18 h following Ribonucleotide reductase restimulation in the absence of TGF-β, if the cells were differentiated with TGF-β and IL-6 but in the absence of IL-23 (although the expression of Rora and

of both Il17a and Il17f mRNAs did decrease). These results suggest that even though the changes in the expression of Rorc in cells differentiated with or without IL-23 are initially invisible, the presence of IL-23 during differentiation may potentiate a subsequent more flexible Rorc repression pattern. Indeed the involvement of IL-23 in promoting Th17 plasticity is starting to emerge. In vivo models of genetic ablation of Il23 revealed that IL-23 drives the Th1-IFN-γ inflammatory axis 77, and in its absence the differentiation of T cells into both Th1 and Th17 cells is severely impaired 78. Moreover, the IL17A+IFN-γ+ double positive CD4+ T-cell population was significantly reduced in Il23r−/− mice 18, and experiments in IL-17A fate mapping mouse strain confirmed that IL-23 enhance the emergence of this double positive population 41.

Furthermore,

a Cbl-b-MyD88 regulatory axis is not required for TLR inhibition in macrophages. Instead, Itgb2−/- macrophages presented with enhanced IκBα degradation, leading to changes in NF-κB recruitment to target promoters and elevated cytokine, chemokine, and anti-apoptotic gene transcription. Thus, β2 integrins limit TLR signaling by inhibiting NF-κB pathway activation and promoting p38 MAPK activation, thereby fine-tuning TLR-induced inflammatory responses. Innate immune cell activation depends on the activity of Toll-like receptors (TLRs) that bind conserved molecular features expressed on invading pathogens [1]. Upon encountering microbes, macrophages and dendritic cells (DCs) respond to TLR stimulation by inducing antimicrobial and antiviral programs that result in the rapid synthesis and secretion selleck compound of inflammatory cytokines and type I interferons. In turn, this potent response must be restrained to spare host tissues from the deleterious effects of exaggerated inflammation. This is accomplished by a variety of inhibitory mechanisms, including cytoplasmic effectors that block TLR signaling directly as well as secreted negative regulators, which work together to limit the severity of the immune response [2]. Although originally considered as an archetypal cell activation pathway, signals through immunoreceptor tyrosine-based

activation motifs (ITAMs) display functional heterogeneity and have been PLX4032 cost recently appreciated to cross-inhibit TLR responses [3, 4]. ITAM signaling in myeloid cells is mediated by the ITAM-containing molecules DAP12 and FcRγ, which act as signaling adapters for an extensive collection of cell surface receptors [5-7]. Following ligand binding by paired receptors, ITAM signaling via DAP12 and FcRγ in myeloid cells proximally activates

Src-family kinases and Syk kinase to enable downstream signals that are predominantly associated with cellular activation, including inducing NF-κB and MAPK pathways, and prompting the release of intracellular Rutecarpine Ca2+ stores [5]. However, depending on the identity of the associated receptor and other undefined parameters, ITAM-based signaling can also induce inhibitory responses. For example, triggering of the DAP12-coupled TREM-2 receptor can dampen TLR activation in macrophages [8]. In addition, TREM-2 and/or DAP12-deficient macrophages and DCs produce more inflammatory cytokines in response to TLR stimulation [9-12], demonstrating that these adapter molecules can transduce signals attenuating TLR activation. During an inflammatory response, leukocytes in the blood adhere to the activated vascular endothelium through the use of integrins. In particular, members of the β2 integrin family facilitate leukocyte firm adhesion, thereby allowing for cell extravasation into the tissues [13].