Data in bar graphs are given PF-02341066 purchase as the mean ± standard deviation (s.d.).

A value of P < 0·05 was considered significant. Monocytes were isolated and cultured with GM-CSF and IL-4; the resulting iDCs were exposed to hypoxia on day 5 for 48 h or to LPS for 24 h to induce cell maturation. Figure 1a shows the analysis of different cellular subpopulations during the differentiation and maturation of DCs. At day 0 we had a high percentage of monocytes (CD14+) and the presence of several lymphocyte subtypes (CD3+, CD20+ and CD56+). During differentiation, the CD14+ population expressed DCs markers (HLA-DR+ and CD11c+) and the lymphocyte percentage diminished after removing the medium and replacing it with fresh culture medium. At the end of the differentiation (at day 7) the purity of DCs was greater than 90% (Fig. 1b). DC population was gathered in two subpopulations, depending on the degree of maturation according to the forward-/side-scatter find more profile and specific phenotypic markers established in our previous study [8]. We also performed

a follow-up of DC differentiation at different time-points. We observed that after hypoxia or LPS stimulus, cells changed their morphology, acquiring a stellate form characteristic of the mDCs shifting to the upper window. LPS stimulus induced a more homogeneous and stronger maturation response, while hypoxia stimulus showed a different magnitude of response (Fig. 1b). To evaluate

further the changing phenotype after stimuli RAS p21 protein activator 1 of the DC population, FACS analysis was performed at days 1, 5 and 7. CD40 mean fluorescence revealed that mDCs appeared at day 5 of decreasing monocytes and iDCs populations. After LPS and hypoxia stimuli at day 7, DCs were well differentiated from non-stimulated cells. To characterize mDCs we used DC-LAMP, a type I transmembrane glycoprotein restricted to mDCs and expressed in the endosomal/lysosomal compartment. DCs exposed to LPS or hypoxia showed a clear DC LAMP-positive up-regulation, confirming the mature phenotype. Dual staining with the Pgp (JSB1) or MRP1 (4124) antibodies also showed an over-expression of Pgp and MRP1 in those DC-LAMP-positive DCs, differing from non-stimulated cells (P < 0·05) (Fig. 2a,b, respectively). This may indicate that in DC maturation there is an increase in Pgp and MRP1 in the cell membrane. Furthermore, this effect was more evident after LPS stimuli than after hypoxia. To evaluate the ABC transporters involvement in DC maturation, PSC833, MK571 or PBN were added to inhibit MDR1, MRP1 and MRP2, respectively. After hypoxia stimulation the percentage of mature DCs was evaluated by the forward-/side-scatter profile. Hypoxia resulted in an induction of 67·8% of mDCs versus 32·2% of iDCs (Fig. 3), lower compared to LPS, which induced 80·8% of mDCs and 19·2% of iDCs (P < 0·05).

We hypothesized that insulin-induced capillary recruitment in skin would correlate with microvascular recruitment

in muscle in a group of subjects displaying a wide variation in insulin sensitivity. Methods:  Capillary recruitment in skin was assessed using capillary videomicroscopy, and skeletal muscle microvascular recruitment (i.e., increase in MBV) was studied using CEU in healthy volunteers (n = 18, mean age: 30.6 ± 11.1 years). Both microvascular measurements were performed during saline infusion, and during a hyperinsulinemic euglycemic clamp. Results:  During hyperinsulinemia, capillary recruitment in skin was augmented from 58.1 ± 18.2% to 81.0 ± 23.9% (p < 0.0001). Hyperinsulinemia increased MBV in muscle from 7.00 (2.66–17.67) to 10.06 (2.70–41.81) units (p = 0.003). Insulin’s vascular effect in skin and muscle this website was correlated (r = 0.57). Insulin’s microvascular

effects in skin and muscle showed comparable strong correlations with insulin-mediated glucose uptake (r = 0.73 and 0.68, respectively). Conclusions:  Insulin-augmented capillary recruitment in skin parallels insulin-mediated microvascular recruitment in muscle and both are related to insulin-mediated glucose uptake. “
“Arterial tone is dependent on the depolarizing and hyperpolarizing currents regulating membrane potential and governing the influx of Ca2+ needed for smooth muscle contraction. Several ion channels Selleck CP-868596 have been proposed to contribute to membrane depolarization, but the underlying molecular mechanisms are not fully understood. In this review, we will discuss the historical and physiological

significance of the Ca2+-activated cation channel, TRPM4, in regulating Tau-protein kinase membrane potential of cerebral artery smooth muscle cells. As a member of the recently described transient receptor potential super family of ion channels, TRPM4 possesses the biophysical properties and upstream cellular signaling and regulatory pathways that establish it as a major physiological player in smooth muscle membrane depolarization. “
“Exposure to SHS, as by passive smoking, seems to increase the incidence of cardiovascular events. It has been shown that active smoking of a single cigarette causes an immediate and significant decrease in microcirculatory blood flow velocity, whereas the acute effects of exposure to SHS on microcirculatory flow have as yet not been demonstrated. Healthy nonsmoking volunteers of both genders were studied during acute exposure to SHS of two cigarettes burning up to 10 minutes. Microvessels were examined by in vivo vital capillaroscopy (Capiflow®), allowing continuous assessment of CBV. CBV decreased from 514 mm/sec (CI 383–646) at baseline to 306 mm/sec (CI 191–420) at end of SHS exposure with a further decrease to a nadir of 240 mm/sec (CI 155–325) four minutes after the end of this exposure (p < 0.0001; ANOVA).

Importantly, our detailed analysis demonstrates that the Equ c 1143–160-specific CD4+ T-cell responses from this, as well as other non-allergic individuals examined, appeared to derive solely from the naive CD4+ T-cell subset (Fig. 4a, b). In contrast, all the Equ c 1143–160-specific CD4+ T-cell responses from allergic subjects derived from the memory CD4+ T-cell subset (Fig. 4a, b). Consequently, the situation with the Equ c 1 allergen appears to be similar to our previous observations with the Bos d 2 and Can f 1 allergens in that allergic subjects have elevated frequencies of CD4+ memory T cells in their peripheral blood.[1, 2] This notion is also

in line with the available data on CD4+ T-cell responses to other allergens, such as cat Fel d 1[3] Bcl-2 inhibitor and peanut

Ara h 1.[4] Taken together, our current results further support the concept that the frequency of allergen-specific CD4+ Talazoparib molecular weight T cells, especially those of the memory phenotype, is higher in allergic subjects.[1-7] As reported above, one non-allergic subject had strong cellular reactivity to Equ c 1, which was derived from the naive CD4+ T-cell subset (Fig. 4a). Although reasons for the reactivity are not known, it can be speculated that this individual has a predisposition for sensitization to Equ c 1. Nevertheless, the finding points to a possibility that healthy subjects are not a homogeneous group with low or non-existent levels of allergen-specific T cells. Therefore, further investigations are clearly necessary to explore the complete repertoire of T-cell reactivity to allergenic proteins among healthy subjects. The estimated frequency of Equ c 1 protein-specific CD4+ T cells was very low, in the range of 1 per 106 CD4+ T cells, in the peripheral blood of sensitized and healthy subjects. Although methodological and other differences between studies may complicate direct comparison, the frequency corresponds well with our previous

estimates with the Bos d 2 and Can f 1 allergens.[1, 2] In line with our observations, the frequency of birch pollen Bet v 1-specific CD4+ T cells was reported to be in the same range in the peripheral blood of sensitized subjects SPTLC1 outside the birch pollen season. At the peak of the season, however, this frequency was strongly increased.[19] It is of interest that a tetramer-based enrichment method showed high frequencies (up to 1 in 7000 cells), and considerable variation, of specific CD4+ T cells to an important animal-derived allergen, cat Fel d 1, in allergic subjects.[7] Elevated frequencies of allergen-specific CD4+ T cells compared with healthy donors have also been found in allergy to the peanut Ara h 1, rye grass Lol p 1, and alder Aln g 1 allergens.[4-6] In the current study, the frequency of Equ c 1-specific CD4+ T cells in most healthy subjects was also lower than that in allergic subjects.

As expected, after STm infection cDCs produced IL-12 28, while moDCs were the main source of early TNF-α and this cytokine profile was maintained throughout the first 48 h of infection

(Fig. 2E). Expression of iNOS by moDCs was not detected by intracellular staining (data not shown). The results show that moDCs and cDCs upregulate costimulatory molecules in the spleen within 24 h of infection and contribute different cytokines to the response. To assess the contribution of moDCs to T-cell priming and differentiation, we used clodronate liposomes to deplete macrophages and monocytes 29. Mice were injected i.p. with either clodronate-liposomes or PBS-liposomes 24 h before STm infection. Pexidartinib clinical trial Spleens were then analyzed by confocal

microscopy and flow cytometry 24 h after infection when moDCs are present in the T zone (Fig. 1A). As shown in Fig. 3A by confocal microscopy, treatment with clodronate-liposomes but not PBS-liposomes depleted red pulp macrophages and moDCs. In mice treated with clodronate liposomes, moDC numbers were tenfold lower after infection compared with those in mice treated with PBS liposomes (Fig. 3B). In contrast, although there was some reduction (30% median fall) in cDC numbers after clodronate depletion, this difference did CHIR-99021 ic50 not reach significance. Furthermore, confocal microscopy confirmed the presence of cDCs in the T zones of both groups of infected mice (Fig. 3B). Depletion of moDCs resulted in an impaired capacity to prime CD4+ T cells after STm as nearly tenfold fewer CD69+ T cells were detected (Fig. 3C, left graph). In contrast, in mice immunized with hk STm, which results in lower levels of moDCs (Fig. 2A), there was no difference in

CD69 expression on T cells (Fig. 3C right graph). Therefore, the use of clodronate-liposomes before infection prevents the accumulation of moDCs in the T zone see more and this results in impaired CD4+ T-cell priming. We next studied what effects depleting moDCs had on T-cell differentiation. Mice were treated with either clodronate or PBS liposomes 24 h before STm-infection and then during infection to maintain depletion. A week after infection, intracellular IFN-γ expression in CD4 T cells was evaluated by ex vivo restimulation. As shown in Fig. 4A, in mice treated with clodronate before STm infection had lower frequencies and numbers of IFN-γ+ T cells compared with PBS-treated STm-infected mice. This lower IFN-γ response was not due to differences in bacterial numbers since bacterial burdens were similar between the two groups that received liposomes, reflecting the findings found in a previous report 30. We next assessed whether moDCs were required to sustain Th1 cells after T-cell priming by depleting moDCs when T-cell responses were established.

Interestingly, in the present study, the VLP internalization mechanism was observed to be different for NK cells: VLPs entered rapidly within large macropinocytosis vacuoles, independently of the clathrin and caveolae pathways (Figs. 4 and 5). RhoGTPase assays suggest the involvement of filopodia during ABT-263 cost VLP uptake (activation of the Cdc42, Fig. 5B) and a concurrent reduction of lamellipodia (inhibition of Rac1 Fig. 5C) 34, as observed by electron microscopy (Fig. 4G and H), and not membrane blebbing, described for host-cell entry of other viruses 24. Interaction of NK cells with VLPs was correlated with CD16 expression and experiments

with CD16 blocking antibody or co-immunoprecipitation confirmed the importance of this receptor for this interaction (Fig. 6A–F). Moreover, VLP internalization induced transient down-modulation of CD16, but no change in NKp46 expression, a receptor involved in Newcastle disease virus binding 35 (data not shown). Our findings are in agreement with those showing that binding of HPV–VLPs is mediated by CD16 on DCs 36 and that uptake of HPV–VLPs by DCs from FcγRIII-deficient mice is strongly reduced compared with wild-type mice 17. CD16 has been shown to be involved in macropinocytosis in CHIR-99021 chemical structure macrophages 37 and in γδ T cells 38. Moreover, transduction of CD16 into a CD8+ T-cell clone was sufficient to increase HPV–VLP entry into these cells (Supporting

Information Fig. 5B).

To exclude an interaction with CD16 mediated by antibodies, we checked the absence of antibodies reacting against VLPs in the human and bovine sera used in culture medium (data not shown). We also performed some experiments without serum and obtained similar results (data not shown). NK cells play a key role in immune responses by exocytosis of cytotoxic granules, and CD16 is a major receptor capable of triggering NK cytotoxicity 21. We showed that VLPs induced cytotoxic activity of NK cells expressing CD16 (Figs. 2A–C and 7A, B). In addition Idoxuridine to killing infected cells, this process could liberate granulysin, present in cytotoxic granules, which works as an alarmin and activates DCs 39. Besides this degranulation activity, through binding of CD16, NK cells are able to activate adaptive immune responses by the secretion of soluble factors such as IFN-γ and TNF-α 40. We showed that VLP stimulation induced the secretion of these cytokines in NK and NK92 CD16+ cells but not in NK92 CD16− cells (Fig. 7). VLPs were produced in insect cells infected with baculovirus coding for HPV16 L1. Because insect baculovirus contaminants have been reported to play a role in the immunogenicity induced by VLPs 41, we used a lysate of insect cells infected with WT baculovirus as a negative control and did not observe cytotoxic activity or cytokine production in this culture condition.

Fixed mandibles were decalcified in 5% formic acid/10% citrate, and embedded in paraffin. The entire mandible was sectioned at 6 μm/section, and every fifth section was stained with haematoxylin & eosin

to identify the lesion area. Images of the stained sections were obtained with a dissecting microscope and imported into IQBase software (Mediacybernetics, Bethesda, MD). Bone loss in appropriate sections was estimated by measuring the distance from SB525334 supplier the first molar proximal root surface to the closest bone edge at the bottom of the root and on both sides using the measurement functions in IQBase. These numbers were obtained for all stained sections spanning the base of the root (four to six sections), and averaged. Neutrophils were identified with antibody 7/418 (AbD Serotec, Raleigh, NC) at 0·22 μg/ml, and macrophages with F4/8019 (Harlan) at 1 : 10; both were detected with biotinylated goat anti-rat antibody and the Vector ELITE ABC kit (Vector https://www.selleckchem.com/products/PLX-4032.html Laboratories, Burlingame, CA). Osteoclasts were identified using a rabbit antiserum to cathepsin

K, as previously described.20 No primary controls were included in each experiment, and there was no reactivity of the secondary antibodies alone. Semi-quantitative estimates of phagocyte accumulation in tissue sections were obtained by measuring the area of intense staining using ImageJ or IQBase: in 3-day samples, the root canal of infected mice stained strongly for neutrophils, and the neutrophil accumulation was estimated by measurement of the length of the pulp chamber occupied by neutrophils. MRIP One to two micrograms RNA prepared from bone blocks (approx. 5 mm3, containing the infected molar and associated bone, from which gingival tissue was removed) was reverse transcribed using standard techniques; for each sample a control reaction was performed without reverse transcriptase. Complementary DNA (cDNA) was subjected to qPCR using primers at 200–300 μm and Sybr green technology in a total volume of 20 μl. Master mix was either purchased from BioRad

(Hercules, CA) or was home-made21 using standard Taq polymerase (NE Biolabs, Ipswich, MA). For each assay, standards were prepared by amplifying a DNA fragment encompassing the qPCR primer sites: this fragment was purified, quantified and used for absolute quantification. Results, in molecules/μl were divided by the geometric mean of results from two control genes: glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and EF1a1,22 to give relative expression. Primers (Invitrogen) for IL-1α, IL-1β, IFN-γ, IL-10 and IL-12p40 were described in Akilesh et al.23 Receptor activator of nuclear factor κB ligand (RANKL) primers are described elsewhere.20 Other primers used were GAPDH: left: 5′-CGAAGGTGGAAGAGTGGGAG-3′; right: 5′-TGAAGCAGGCATCTGAGGG-3′; EF1a1: left: 5′-GGAAA TTCGAGACCAGCAAA-3′; right: 5′-ACACCAGC AGCAACAATCAG-3′; neutrophil elastase: left: 5′-TGTGAACGGCCTAAATTTCC-3′; right: 5′-GGTCAAAG CCATTCTCGAAG-3′.

pylori. We have found that H. pylori-stimulated DCs drive Treg proliferation, and impair their suppressive function through the production of IL-1β. This is corroborated by in-vivo data LY2835219 in vivo showing active division of Tregs in biopsy samples from infected individuals. Dissection of the long-term impact of Treg modulation and dysregulated immunpathology in the context of H. pylori may

provide new insights into the mechanisms underlying the development of H. pylori-associated complications and/or potential targets for the local treatment of inflammation associated with H. pylori in the 15–20% of individuals unresponsive to eradication therapy. Peripheral blood mononuclear cells (PBMCs) were separated from buffy coats provided by the National Blood Transfusion Centre (South Thames, London, UK). CD14+ and CD14− cells were then separated using CD14-Beads (Miltenyi Biotec, Woking, UK), according to the manufacturer’s

instructions. The CD14+ cells were then cultured in RPMI-1640 (Invitrogen, Paisley, UK) Selleckchem Poziotinib with 10% fetal calf serum (FCS; SeraQ, East Grinstead, UK), 50 IU/ml penicillin, 50 μg/ml streptomycin and 2 mM L-glutamine (PSG) (PAA Laboratories GmbH, Pasching, Austria). To develop DCs, IL-4 (10 ng/ml) (First Link, Birmingham, UK) and granulocyte–macrophage colony-stimulating factor (GM-CSF) (20 ng/ml) (kindly donated by Dr S. Brett, GlaxoSmithKline, Stevenage, UK) were added every 2 days before the cells were harvested at day 5. T cells were enriched from PBMCs Farnesyltransferase derived from buffy coats by negative selection. CD4+ T cells were purified using a cocktail of antibodies against CD8, CD33, CD14, CD16, CD19, CD56 and γδ-T cell receptor (TCR). The CD4+ T cells were then divided into CD25+ and CD25− cells using anti-CD25 beads (Dynal Biotech, Oslo, Norway). For the CD25hi separation, CD4+ T cells were stained for CD4 and CD25 using anti-CD4-allophycocyanin (APC) (S3·5;

Caltag, Buckingham, UK) and anti-CD25-phycoerythrin (PE) (3G10; Caltag). The CD4+CD25hi (top 2% for expression of CD25) were then separated from the CD4+CD25− T cell population by fluorescence-activated cell sorting (FACS) using a MoFlo high speed multi-laser cell sorter (Cytomation, Fort Collins, CO, USA) running Summit version 3·1 software (Cytomation). Suppression assays were all carried out in complete medium (RPMI with PSG) containing 10% human serum (Biosera, Ringmer, UK) using 2 × 104 T cells with the following conditions: CD25− alone, CD25− : CD25+ at a 1:1 ratio and CD25+ alone. These cells were stimulated with CD3/CD28 expander beads (Dynal Biotech) in the presence of H. pylori. Alternatively, the T cells were stimulated with 2 × 103 allogeneic DCs treated previously with H. pylori, or medium alone for 8 h. Media were supplemented, or not, as described by IL-1 receptor antagonist (IL-1RA) (10 μg/ml, kindly donated by Dr Keith P. Ray, GlaxoSmithKline, Stevenage, UK), anti-IL-6 (10 μg/ml; R&D Systems, Abingdon, UK) or anti-TNFRII (0·2 μg per well; R&D Systems).

The elevated levels of serum antibodies in patients with L-lep or disseminated disease, compared with the levels found in patients with the T-lep self-limited form,13,14 and the antibodies shown in this Selleckchem CT99021 study at the site of disease may contribute to host defence or immunopathology. The correlation of antibodies with the progressive infection suggests that they play no role in protection but some suggest an early

role in leprosy and other mycobacterial infections.24,25 The production of antibodies at the site of disease demonstrated in this study may also contribute to immunopathology and tissue injury in leprosy. Polyclonal activation of B cells has been well described in leprosy. In fact, studies of leprosy sera have identified a wide spectrum of autoantibodies such as anticardiolipin (aCL), rheumatoid factor and antiphospholipid antibodies. Autoantibodies such as aCL have been reported to be raised in 37–98% of the patients with lepromatous leprosy, providing a mechanism for autoimmunity.26–28 Furthermore, up to 50% of L-lep patients receiving antimicrobial therapy ABT-737 supplier develop acute inflammatory reactions such as ENL, characterized by the eruption of erythematous painful nodules

and other systemic manifestations of tissue injury.7,29–31 The pathogenesis of ENL is attributed to antibodies and immune complex deposition, as evidenced by granular deposits of immunoglobulin and complement in a perivascular8 and extravascular distribution,9 detection of immune complexes

in vessel walls and evidence of damaged endothelial cells.7 An interesting finding is the differential expression of IgA in L-lep versus T-lep lesions. Anti-M. leprae IgA has been previously reported in salivary secretions of leprosy patients,32 and the presence of IgA as well as IgG and IgM has previously been identified from induced blisters over skin lesions from patients with L-lep and ENL.33 Here, we found a correlation of both the messenger all RNA and protein levels of IgA, with L-lep versus T-lep directly in skin lesions, suggesting a role for antibodies including promoting progressive infection. Immunoglobulin A has been described as playing a central role in mucosal immunity, classically as neutralizing microbial pathogens and preventing their attachment to mucosal tissue. However, its role in systemic and cutaneous immunity is not well-studied. The immunoregulatory effects of IgA are mediated by the human IgA Fc receptor (FcαRI, CD89). FcαRI is expressed on cells of the myeloid lineage including neutrophils, monocytes, tissue macrophages, eosinophils and subpopulations of dendritic cells.

On the other hand, negative selection in the HY model was slightly impaired in KSR1−/− mice. However, a defect in negative selection was not apparent in the AND TCR model system or in an endogenous superantigen-mediated Panobinostat in vivo model of negative selection. These results suggest that, despite a requirement for KSR1 for full ERK activation in thymocytes, full and efficient ERK activation is not essential for the majority of thymocyte selection events.

T-cell development is a complex, multistep process that begins with seeding of the thymus by progenitor cells arising from the bone marrow. Progenitor cells progress through three distinct stages before exiting the thymus as mature T cells into the periphery. These developmental stages can be characterized by the expression of the cell-surface markers CD25, CD44, the coreceptors CD4 and CD8, as well as the TCR itself. Early in development, thymocytes that lack expression

of either co-receptor (dominant negative, DN) begin to rearrange and test their TCR α-chains. Once successful generation of the TCR α-chain has been accomplished, thymocytes begin the processes of positive and negative selection. At this stage, Metabolism inhibitor both CD4 and CD8 coreceptors are expressed (DP) and interactions with self-peptide and MHC molecules are critical in determining thymocyte fate. Thymocytes must receive the appropriate signal through their TCR to undergo positive selection in order to escape death by neglect and develop into CD4 or CD8 lineage cells 1, 2. Further, the signal delivered through the TCR via MHC/self-peptide

must not be too strong or the programmed Staurosporine cell death of thymocytes will be induced, a process termed negative selection 3, 4. The critical role of the ERK-MAPK signaling cascade in T-cell development has been well studied but the results have been inconsistent 5–12. Many of these studies used transgenic mice expressing dominant-negative or constitutively active forms of MAPK pathway components. These studies generated conclusions that ERK was implicated in either positive but not negative selection, or in both positive and negative selection 3, 6, 8, 9, 12. A more definitive study used conditional deletion to remove both ERK isoforms at various stages of thymocyte development 7. These studies demonstrated that thymocytes lacking both isoforms of ERK have a partial developmental block at the DN3 stage. If ERK was deleted following the DN3 stage, however, a complete block in positive selection but not negative selection was observed 7, 13. Interestingly, when double ERK knockout mice were analyzed on a TCR transgenic background, some positive selection did occur. This study also suggested that ERK2 plays a more important role in CD4+ T-cell development compared with CD8+ T-cell development 7. A more recent study has suggested that the degree and duration of ERK activation may distinguish positive and negative selection and possibly CD4 versus CD8 lineage decisions 14.

CD1 glycoproteins are a family of antigen-presenting molecules that bind hydrophobic ligands such as lipids, glycolipids and lipopeptides.12 Five CD1 genes have been identified, called CD1A–E, with the corresponding protein products denoted CD1a–e.13 CD1a–d molecules have been shown to present lipidic antigens at the cell surface to T cells, while CD1e remains intracellularly localized and aids in glycolipid processing and loading

by other types of CD1.14–18 https://www.selleckchem.com/products/sch772984.html Like MHC class I molecules, CD1 molecules are synthesized in the endoplasmic reticulum (ER) and then follow the secretory pathway through the Golgi aparatus to the cell surface.19 However, like MHC class II molecules, they then become re-internalized from the plasma membrane and traffic through the endosomal https://www.selleckchem.com/products/rxdx-106-cep-40783.html vesicular system and back out again to the cell surface

in a recycling loop.20 CD1 molecules are thus able to bind lipid ligands within the secretory system, at the cell surface, or within the endosomal system. A striking commonality among the CD1-restricted T cells that have been identified thus far is that, although some of them show highly specific recognition of particular microbial antigens,14,21,22 there also seems to be a high frequency of T cells displaying functional autoreactivity to CD1+ APCs without the need for the addition of foreign lipids.23–25 Hence, T cells that are restricted by CD1a, CD1b or CD1c, may resemble CD1d-restricted Thiamet G NKT cells in having innate-like properties that are regulated by recognition of self antigens. However, an important difference between

CD1d and the other CD1 antigen-presenting molecules is that CD1d is constitutively expressed on most types of myeloid APC, whereas APC expression of CD1a, CD1b or CD1c molecules is markedly up-regulated by exposure to Toll-like receptor (TLR) agonists or other pro-inflammatory stimuli. Therefore, while CD1d-restricted T cells may be active during periods of relative immune quiescence as well as during immunological challenge, T cells that are restricted by CD1a, CD1b or CD1c may mainly function during periods of immune activation by danger signals. The CD1d-restricted T-cell compartment includes an evolutionarily conserved population that is characterized by the usage of a nearly invariant T-cell receptor (TCR)-α chain rearrangement,26,27 and also includes other T cells that do not seem to have such highly restricted TCR structures.28–30 The first population is often referred to as ‘invariant’ (iNKT) or ‘type I’ NKT cells, while the second type is called ‘non-invariant’, ‘diverse’ or ‘type II’ NKT cells. There are data suggesting that, like type I NKT cells, the type II subset may perform beneficial regulatory functions,31–33 although this subset has also been associated with pathological outcomes in a number of systems.