Signaling Pathway Blog

The proportion of Tregs was evaluated. To elucidate possible differences in functional properties of Tregs, MFI of FoxP3 and intracellular regulatory cytokines IL-10 and TGF-beta were tested. Differences in Treg proportions and their functional properties were found between the groups. Using our gating strategy (Fig. 1) and antibodies against CD4, CD25, CD127 and FoxP3, we did not find significant differences in the proportion of Tregs in the cord blood of children of healthy and allergic mothers, although the trend towards an increased number of Tregs in the CD4+ lymphocyte population from the allergic group was obvious (P = 0·07) (Fig. 2a). A significantly

increased proportion of Tregs in cord blood of children of allergic mothers was observed when PD0332991 nmr Tregs were considered only as CD4+CD25+ cells Mitomycin C in vivo (P = 0·0117) (Fig. 2b). Different gating strategies together with using different Treg markers may account for variation among the results of different research groups. Transcription factor FoxP3 is considered to be a master marker for identifying Tregs[24] (as CD25 can be expressed on other activated CD4+ T lymphocytes and CD127 is present on various cell types). The values of MFI of

FoxP3 in cord blood of children of allergic mothers followed an opposite trend to the proportion of Tregs. A significantly higher MFI of FoxP3 (P = 0·0159) in cord blood Tregs of children of healthy mothers was detected in comparison to children Teicoplanin of allergic mothers (Fig. 3). To evaluate the possible differences in functional characteristics of Tregs, the presence of regulatory cytokines IL-10 and TGF-beta was estimated by intracellular staining. A significantly

higher number of IL-10+ Tregs in cord blood of children of healthy mothers was detected in comparison to children of allergic mothers (P = 0·0012) (Fig. 4). Similarly, a significantly higher proportion of TGF-beta+ Tregs in cord blood of children of healthy mothers is documented in Fig. 5 (P = 0·0174). The importance of Tregs in immune regulations consists mainly in their role in induction of peripheral tolerance against autoantigens and harmless food and environmental antigens [25]. An insufficiency of Tregs can result in autoimmunity and allergy development [26–29]. We followed the status of newborn Tregs as a possible prognostic marker for future allergy manifestation. It is possible to assume that changes of immune regulation in allergy-prone infants can be evident prior to development of the clinical signs of allergy. We found differences in immune characteristics of Tregs in the cord blood of children of allergic mothers in comparison to children of healthy mothers. Tregs were assessed on the basis of their cell surface markers (CD4, CD25high and CD127low), typical transcription factor FoxP3 and intracellular regulatory cytokines IL-10 and TGF-beta.

1E). We therefore conclude that the observed reduction in the percentage of TGF-β-induced Tregs by TLR7 ligand is mediated indirectly by its effect

on DCs. To investigate whether TLR7 stimulation has an influence on adaptive Treg generation in vivo OVA-specific selleck chemicals T cells isolated from DO11.10/Rag2−/− mice which lack natural Tregs were transferred into BALB/c mice. To induce conversion of naïve CD4+ T cells into Tregs, 5 μg of OVA peptide was injected and Foxp3 expression in the transferred T cells was measured after 4 days. Simultaneous administration of TLR7 ligand R848 significantly reduced the percentage of Tregs, which were induced de novo in spleen and lymph nodes (Fig. 2). Thus, similar to the results obtained in the coculture system in vitro, the generation

Staurosporine purchase of Foxp3-expressing Tregs was inhibited by TLR7 activation also in vivo. Having identified DCs as the cells which are responsible for the reduced percentage of Tregs induced by TGF-β in the presence of TLR7 ligand, we set out to investigate the mechanism of this inhibition of Treg generation. Induction of Foxp3 expression by TGF-β in TLR7−/− T cells stimulated with anti-CD3/anti-CD28 was dose-dependently reduced by adding increasing amounts of supernatant from TLR7-stimulated DCs at the beginning of the 4-day culture (Fig. 3A). Similarly, addition of supernatant from TLR7-stimulated WT DCs reduced the percentage of Foxp3+ cells

induced by TGF-β in the coculture of TLR7−/− T cells with TLR7−/− DCs. In addition, separation of T cells and DCs using a transwell insert did not abrogate the effect of TLR7 ligand on Foxp3 expression (Fig. 3B). Thus, the inhibitory effect of TLR7 ligand on Treg generation is independent of DC–T-cell contact and is largely mediated by soluble factors produced by DCs. We observed a strong induction of IL-6 and IL-12p40 by TLR7 and TLR9 ligands in DC–T-cell cocultures. In comparison, LPS induced only low amounts of IL-6 in the DC–T-cell coculture under our acetylcholine experimental conditions (Fig. 3C), also when higher and lower doses of LPS were used (data not shown). The induction of IL-6 by TLR7 and TLR9 ligands correlated with the induction of IL-17 in the coculture. However, more IL-17 was induced in the coculture stimulated with LPS despite much lower concentrations of IL-6 (Fig. 3C). IL-23 was neither induced by TLR7 and TLR9 ligands nor by TLR4 ligand in DC–T-cell cocultures (data not shown). Thus, the reduction in the percentage of Foxp3+ cells generated in DC–T-cell cocultures in the presence of TLR7 and TLR9 ligands correlates with increased production of IL-6, IL-12, and IL-17 in the coculture. It has been reported that IFN-γ as well as IL-4 which are produced by CD4+ T cells also inhibit Foxp3 expression in an autocrine manner via T-bet and GATA3 induction 22.

Furthermore, repeated sequences from the same individual can vary in copy number in different organs and tissues [16]. The general mechanisms

that lead to changes in copy number include homologous recombination and non-homologous repair mechanisms [17]. Changes in copy number might alter the expression levels of genes included in the CNVR. For example, the salivary amylase gene, AMY1, shows CNV in human populations, and the amount of salivary amylase is directly proportional to the copy number of AMY1[18]. More importantly, CNVs shape tissue transcriptomes on a global scale [19]. Additional copies of genes also provide redundancy that allows some copies to evolve new or modified functions while other copies maintain the original function. CNVs can represent benign polymorphic variations or convey clinical phenotypes by mechanisms such as altered gene dosage and gene disruption. CNV this website can be responsible for sporadic birth defects [20], other sporadic traits, Mendelian diseases and complex traits including autism, schizophrenia, epilepsy, Parkinson

disease, Alzheimer disease, human immunodeficiency virus (HIV) infection and mental retardation [21–23]. Interestingly, the set of genes that vary in copy number seems to be enriched for genes involved in olfaction, immunity and secreted proteins [24]. The following diseases are associated with CNVs of the immune genes: (i) CNVs of FCGR3B and FCGR2C (encoding different Fcγ receptors) have been associated with a range of autoimmune diseases, including Ridaforolimus systemic lupus erythematosus (SLE), polyangiitis, Wegener’s granulomatosis and idiopathic thrombocytopenic purpura [25–27]. (ii) CNVs of the complement genes CFHR1 and CFHR3, which belong to the complement factor H protein family, have been associated with age-related macular degeneration and atypical haemolytic-uraemic syndrome [28–30]. Complement C4 gene copy number has been related directly

with systemic lupus erythematosus (SLE) [31]. (iii) On chromosome 8, a unit of seven β-defensin genes, which encode anti-microbial peptides with other diverse functions such as chemokine activity [32], has variability in its copy number [33]: low copy number has been associated with Crohn’s disease [34,35], and high copy number with predisposition to psoriasis [36]. (iv) In Dipeptidyl peptidase this review, we will examine one of the most striking examples of CNV in the human genome, the chemokine genes CCL3L and CCL4L. Chemokines are a large superfamily of small structurally related cytokines that regulate cell trafficking of various types of leucocytes to areas of injury, and play key roles in both inflammatory and homeostatic processes. Chemokines are classified into four families based on the arrangement of the first two cysteines of the typically conserved four cysteines: CXC, CC, C and CX3C (where X is any amino acid) [37].

albicans following brief exposure to subtherapeutic concentrations of CG was studied. Fifty C. albicans planktonic oral isolates obtained from smokers, diabetics, asthmatics using steroid inhalers, partial denture wearers and healthy individuals were exposed to three subtherapeutic concentrations of CG (0.005%, 0.0025% and 0.00125%) for 1 h. Isolates

unexposed to CG was the control group. Thereafter the antiseptic was removed and the PAFE and phospholipase production was determined by a turbidometric method and a plate assay using an egg yolk agar medium respectively. Mean PAFE (hours) of 50 oral isolates of C. albicans following 1-h exposure to 0.005%, 0.0025% and 0.00125% CG was 6.97, 1.85 and 0.62 respectively. The phospholipase production JQ1 manufacturer of these isolates was significantly suppressed with a percentage reduction of 21.68, 18.20 and 14.04% following exposure to 0.005%, 0.0025% and 0.00125% CG respectively. Brief exposure of C. albicans isolates to subtherapeutic concentrations of CG would wield an antifungal

effect by suppressing growth and phospholipase production, thereby quelling its pathogenicity. ”
“The efficacy of antifungal prophylaxis for prevention of invasive aspergillosis (IA) may depend on whether IA results from recent inhalation of spores or reactivation of latent colonisation. Compare the efficacy of liposomal GDC-0068 in vivo amphotericin B (LAmB) for prophylaxis in acute and reactivation models of IA. In the acute model, mice immunosuppressed from day 0 were challenged at day 3 with an aerosol of Aspergillus fumigatus. LAmB (15 mg kg−1) was administered at day 0 or at challenge. In the reactivation model, naïve mice exposed to A. fumigatus remained untreated until clearance of spores from the lungs, then immunosuppressed to induce reactivation. A single LAmB dose was administered at start of immunosuppression.

In the acute model, a single administration of LAmB at start of immunosuppression was not effective, but an additional administration resulted in a significant decrease in lung fungal burden (P < 0.05 vs. controls). A significant Phosphatidylethanolamine N-methyltransferase prophylactic efficacy was observed when LAmB was administered once at challenge (P < 0.01). In the reactivation model, a single LAmB administration at start of immunosuppression significantly reduced both reactivation rate and fungal burden vs. controls (P < 0.01). Our results show that the conditions under which IA develop and timing of administration of LAmB were determinant variables for prophylactic efficacy. ”
“Malassezia species are part of the normal skin flora and are associated with a number of human and animal skin diseases.

Broad-spectrum protease inhibitors

have a profound anti-schistosomal and anti-pathological effect, demonstrating the essential role of this pathway in schistosome metabolism (66–68). Studies using RNAi approaches alone or in combination with protease-specific inhibitors have now been systematically used to study the network of endopeptidases important for intestinal protein digestion in S. mansoni (69–71). It has been shown that initial degradation of host blood proteins is ordered, occasionally redundant, and substrate-specific. this website The schistosomes treated with dsRNA to SmCB1 were viable, with typical intestinal haematin pigmentation (the result of haemoglobin digestion) and exhibited a significant growth retardation phenotype (69). Experiments targeting another endopeptidase, cathepsin D showed that haematin was apparently not deposited in the gut of schistosomules as it appeared red in colour, indicating the presence of intact rather than digested host haemoglobin (71). Treated schistosomules did not survive to maturity after transfer into mice confirming the essential function of this enzyme in parasite nutrition. Another schistosome protease – the asparaginyl endopeptidase SmAE (also known as Sm32 or legumain), Selleck IWR1 has been proposed to proteolytically convert the inactive precursor of SmCB1 into its mature catalytic

form in vitro (72,73). Although a substantial and specific suppression (>90%) of SmAE transcripts was achieved by RNAi, the authors showed that SmCB1 was fully processed and active. This finding indicated that SmAE may not be essential for SmCB1

activation in vivo (74). Krautz-Peterson and co-workers (75) targeting S. mansoni cathepsin B by RNAi concluded in their work that electroporation was more effective in delivering dsRNA into schistosomula compared to soaking and that both small interfering (si)RNAs (approximately 21 bp) and long dsRNA (>405 bp) demonstrated similar silencing efficiency. Interestingly, complete suppression of the cathepsin B gene was never achieved oxyclozanide regardless of the dsRNA dose, possibly because of difficulties in achieving gene silencing uniformly in a mixed population of cells in a living worm after soaking or electroporation. Recently, however, total ablation of enzyme activity of SmCB1 was reported by our lab (31). We used MMLV virions pseudotyped with VSVG to establish transgene-mediated RNA interference of this schistosomal protease. We designed viral vectors to express targeted dsRNA to specifically silence this key gene in the haemoglobin digestion pathway of schistosomes. After transduction of adult worms with virions expressing the dsRNA hairpin loop specific to SmCB1, transcript levels were knocked down by 80% 72 h after exposure to the virions and this silencing effect was specific to cathepsin B1 only.

CD4+CD25+ Tregs purified from LCMV-immune mice were exposed in vitro to DCs obtained from mice recently challenged with LCMV, which we and others found to harbor an activated phenotype and carry LCMV particles (data not shown, and 38). After 6 days in culture, the Tregs were separated from the DCs and adoptively transferred into B6 RIP-GP check details mice in which autoimmune diabetes was triggered simultaneously by LCMV infection. While the capacity of LCMV-exposed, WT CD4+CD25+ T cells to protect B6 RIP-GP mice from T1D was enhanced after culture with DCs from WT

LCMV-infected mice (Fig. 7B), TLR2−/− Tregs cultured with TLR2−/− DCs had no effect on disease development. These results indicated that Selleckchem R788 LCMV-mediated Treg enhancement could be conferred by DCs and depended on TLR2. Our observations indicate that triggering of TLR2 in a naïve context or upon viral infection confers protection from autoimmune diabetes by promoting the expansion of invigorated CD4+CD25+ Tregs, possibly via DCs. Since P3C-induced signaling occurs through heterodimerization of TLR2 with TLR1, further studies should assess the contribution of TLR1 in induction of immunoregulation and protection from T1D. We did not observe Treg enhancement after treatment of NOD mice with Pam2CSK4 (data not shown), thus

excluding a role for TLR6-TLR2 heterodimerization in this phenomenon. TLR2 was previously shown to promote rather than hinder T1D, notably by inducing TNF-α production by APCs 18. On the other hand, a requirement for TLR2 in the development of T1D was

ifenprodil not supported by a recent study 32. Such opposing roles of TLR2 in this disease might reflect the importance of β-cell antigen release concomitant to TLR signaling for autoimmunity to develop. TLR stimulation indeed causes autoimmune diabetes when triggered in the presence of β-cell antigens 16, 17, but otherwise prevents the disease 24–27. Our previous 12 and present findings suggest that this might be due to the capacity of immunostimulatory factors to enhance immunoregulation. Another, possibly related, important aspect might be the timing at which TLRs, and subsequent release of inflammatory cytokines, are triggered during the prediabetic phase 39. In this regard, previous studies by us and others have shown that TNF-α differentially affects the outcome of T1D depending on the time of action 10, 40, 41. TNF-α may also have opposing effects on CD4+CD25+ Tregs 41–43, which play a crucial role in T1D. Other inflammatory cytokines such as IFNs can also differentially affect autoimmune processes in T1D, as supported by our previous work 12. Finally, while TLR2 delivers pro-inflammatory signals, its engagement also causes the release of anti-inflammatory/immunoregulatory cytokines such as IL-10 44, 45.

A sample of the incoulum (1 mL) was archived at −80 °C for subsequent analysis. The individual and combined effects of

exposure to: (1) HNPs 1 and 2; (2) human β defensins (hβD) 1, 2 and 3; (3) histatins (His) 5 and 8; and (4) cathelicidin (LL37); at physiological concentrations (Table 1) on the microbial composition of extant, in vitro plaques were investigated. Synthetic β defensins were obtained from Peprotech (New Jersey), α defensins and histatin 5 from Sigma-Aldrich (Dorset, UK), whilst histatins 8 and LL37 were obtained from Cambridge Biosciences (Cambridge, UK). HDMs were also exposed to physiological saline (unexposed control microcosm), all HDPs singly, paired combinations within each of the Obeticholic Acid in vivo four groups and all combined. BGB324 clinical trial The resultant plaques and their respective planktonic phases were analysed as outlined below. Culture fluid (25 μL) was applied to 0.2 μm pore size black polycarbonate filters (Whatman, Middlesex, UK). Bacterial cells upon the filters were stained with LIVE/DEAD bacterial-viability kit (BacLight™; Molecular Probes, Leiden, the Netherlands) according to the manufacturers’ instructions. Once stained, the adherent cells were gently washed with 100 μL phosphate-buffered saline (pH 7.0, 0.1 M) mounted and visualized using an epifluorescence

microscope (Axioshop 2; Zeiss, Hertfordshire, UK). Dead (red) and live (red deducted green cells) cells (10 fields of view) were counted, as were bacterial

aggregates (three or more cells in clusters; Ledder et al., 2009). Each hydroxyapatite (HA) disc was gently washed in PBS, immersed in prereduced half-strength thioglycollate broth (0.9 mL) and vortexed. Appropriate serial dilutions (0.1 mL) were then spread plated onto media as follows: Wikins Chalgren agar (total anaerobes), Wilkins Chalgren agar with Gram-negative supplements (total Gram-negative anaerobes), trypticase yeast extract, cysteine, sucrose agar (total streptococci) and Rogosa agar (total lactobacilli). Acyl CoA dehydrogenase Inoculated agars were incubated at 37 °C in an anaerobic chamber (gas mix: 80% N2, 10% CO2 and 10% H2) for up to 5 days. For the enumeration of total aerobes and facultative anaerobes, additional Wilkins Chalgren agar plates were incubated aerobically for 3 days. DNA was extracted from the in vitro plaque samples using DNA Stool Mini kits (Qiagen Ltd., West Sussex, UK) in accordance with manufacturers’ instructions, and DGGE analyses were done according to methods previously described (McBain et al., 2003; Ledder et al., 2007). Dendrograms derived by cluster analysis of community profiles using (McBain et al., 2003) were tested for statistical significance using principal components analysis (PCA). For this, band class data from dendrogram analysis were exported from bionumerics v.1.5.1 and subjected to factor analysis using spss version v.

Coupled with increasing refined approaches for expanding human regulatory T cells or manipulating the suppressive potency of these cells using purified adjuvants,89,90,101,102

these multiple layers of heterogeneity in regulatory T cells reveal many exciting opportunities for therapeutically dissociating the detrimental and beneficial impacts that these cells play in host defence against infection and immune homeostasis. In concluding the seven-volume Chronicles of Narnia series, C.S. Lewis described their adventures as only ‘the cover and title page’. In this regard, given the enormous latent potential and arsenal of immune effectors uncovered with the identification of immune suppressive Treg cells together with the ongoing disproportionate burden https://www.selleckchem.com/products/epacadostat-incb024360.html of infection-related Acalabrutinib diseases that negatively impact human health, more potent and efficacious immune-mediated therapies for infectious disease treatment and prevention are poised for development. With the identification of Treg cells and the tremendous translational potential associated with therapeutically manipulating newly established facets of the dynamic interplay between Treg cells and immune effectors, chapter one of a great story related to reduced burden of infectious diseases is ready to be written.

Given space limitations, we apologize for not being able to discuss in a more in-depth manner the current references, and not being able to cite other important papers. We thank Dr Matthew Mescher for helpful discussions. This work was supported by funding Carnitine palmitoyltransferase II from the NIH/NIDDK F30-DK084674 (to J.H.R.) and NIH/NIAID R01-AI087830 (to S.S.W.). ”
“Mϕs promote tissue injury or repair depending on their activation status and the local cytokine milieu. It remains unclear whether the immunosuppressive effects of transforming growth factor β (TGF-β) serve a nonredundant

role in Mϕ function in vivo. We generated Mϕ-specific transgenic mice that express a truncated TGF-β receptor II under control of the CD68 promoter (CD68TGF-βDNRII) and subjected these mice to the dextran sodium sulfate (DSS) model of colitis. CD68TGF-βDNRII mice have an impaired ability to resolve colitic inflammation as demonstrated by increased lethality, granulocytic inflammation, and delayed goblet cell regeneration compared with transgene negative littermates. CD68TGF-βDNRII mice produce significantly less IL-10, but have increased levels of IgE and numbers of IL-33+ Mϕs than controls. These data are consistent with associations between ulcerative colitis and increased IL-33 production in humans and suggest that TGF-β may promote the suppression of intestinal inflammation, at least in part, through direct effects on Mϕ function. Damage within the gastrointestinal mucosa can be induced by a wide variety of physical, chemical, and/or infectious stimuli 1.

Despite being immortalized, HTR-8/SVneo cells have retained all the phenotypic and functional characteristics

of the parental Vorinostat mw mortal HTR-8 cells. The expressing markers of EVCT in situ are cytokeratins 18 and 8, human placental lactogen (hPL), human chorionic gonadotropin (hCG), human leukocyte antigen G (HLA-G) and type IV collagenase. Meanwhile, another immortalized primary cell clone (HPT-8) exhibited cytokeratin 7, cytokeratin 18, vimentin, cluster of differentiation antigen 9, epidermal growth factor receptor, stromal cell-derived factor 1 and placental alkaline phosphatase. They secreted prolactin, oestradiol, progesterone and hCG and were positive for HLA-G, a marker of extravillous trophoblasts.[14] These cells are permissive for the full replication cycle of human cytomegalovirus.[15, 16] These features make HTR-8/SVneo and HPT-8 cells as an ideal in vitro model for studying the biology of normal trophoblasts. Between October 2005 and January 2009, we recruited women who underwent induced abortion or experienced spontaneous abortion at Nanjing Maternity and Child Health Care Hospital. All of the women were asked about the number of previous MK-2206 mouse miscarriages, the number of stillbirths and the total number of previous pregnancies, and had placental villi and blood samples drawn. The same questionnaire was translated into the native

languages of the women and was used with participants from Nanjing Maternity and Child Health Care Hospital. The study included participants born in the same country who were all over 18 years of age. Women (n = 30) who had a previous history of spontaneous abortion, that is, (i) a history of two or more consecutive spontaneous abortions in the first trimester and (ii) an unexplained aetiology of spontaneous abortion with unexplained vaginal bleeding at 6-8 weeks of gestation, and for whom pregnancy

loss was confirmed by ultrasound scan were considered part of the spontaneous abortion group. Their average age was 28.8 years, and the average gestational age was 56.4 days. These subjects were age- and sex-matched SB-3CT with 30 apparently healthy pregnant women who had no abnormal gynaecological history at 6–8 weeks of gestation and who wanted to have an induced abortion (control group). Their average age was 27.8 years, and the average gestational age was 56.6 days. These women voluntarily sought abortions for family planning purposes. Live pregnancy was confirmed by ultrasound scan. All of the women had regular menstrual cycles, and the gestational age estimates based on the last menstrual period was confirmed by the ultrasound scan. Termination of pregnancy was surgically achieved by vacuum suction as approved by the Ethical Committee of the Chinese Academy of Sciences and Nanjing Maternity and Child Health Care Hospital in Nanjing.

5,9,16,35,36 Once again, a range of cell surface receptors interactions play an important role at this stage. As for DC–T interactions, CD40–CD40L are also important for T–B interactions, as a lack of CD40 expression on B cell prevents activation of B cells by T cells which, in turn, results in decreased Tfh cell numbers.15 In contrast, while CD28 seems to be important at the initial stages of CD4+ T cell activation it

CCI-779 purchase does not seem to be as crucial for Tfh cell development at the later stages of T–B interactions.37,38 A recent study, however, reported that B7.2 expression on B cells was required for GC formation, suggesting the B7–CD28 interactions between T–B cells are important for the function of Tfh cells and the delivery of helper signals to the B cells.39 For the most part, however, another CD28 family member, namely ICOS, seems to be required at this later stage. Consequently, mice in which ICOS–ICOSL interactions are

disrupted, or patients with mutations in ICOS (which results in common variable immunodeficiency), have decreased Tfh cells.26,32,40,41 ICOSL is expressed widely on haematopoietic cells; however, mice that lack ICOSL expression on their B cells show decreased numbers of Tfh cells indicating that, at least in part, this ICOS–ICOSL signal is delivered by B cells.42 This requirement for ICOS signalling seems MI-503 concentration to depend on its ability to activate phosphoinositide-3-kinase (PI3K), as mice expressing a mutant ICOS molecule with defective PI3K activation41 or lacking the p110δ isoform of PI3K in T cells43 also show decreased Tfh cell generation. Several studies have demonstrated that ICOS signalling, via PI3K, is able to up-regulate Tfh cell-associated genes such as c-maf,

IL-4 and IL-21;40,41,43 however, it remains to be determined whether the primary role of ICOS signalling is to induce the differentiation of Tfh cells or simply to maintain those that have already formed. It Progesterone has also become clear that the SLAM family of surface receptors play an important role in Tfh cell generation. The importance of these molecules in T–B interactions first came to light in patients suffering from the immunodeficiency X-linked lymphoproliferative disease (XLP). XLP is caused by mutations in the gene encoding SAP (i.e. SH2D1A), which is a cytoplasmic adaptor molecule that signals downstream of the SLAM family of receptors. Patients with XLP, as well as gene-targeted mice that lack SAP expression, display a deficiency in T-dependent B cell responses.44,45 Furthermore, several groups have demonstrated that loss of SAP can result in decreased numbers of Tfh cells.9,20,46,47 Members of the SLAM family including SLAM itself, CD84 and NTBA (also known as Ly108 in the mouse) are expressed highly on both activated B cells and activated CD4+ T cells, including Tfh cells.8,9,11,20,47–50 As these receptors are homotypic receptors, this expression pattern allows for SLAM family interactions between T and B cells.