In the follicular pathway, the B cells can differentiate into GC

In the follicular pathway, the B cells can differentiate into GC B cells: centroblasts and centrocytes. GCs are specialized structures forming in the B cell follicles that

provide an environment for antibody affinity maturation, class switching and induction of plasmacytic differentiation. The affinity maturation produces the high-affinity B cell clones by cycles of cell proliferation, somatic hypermutation (SHM) of Ig gene variable regions and selection gaining increased Ig affinity [39] (Fig. 2). The key transcriptional regulator of GC formation and function is Bcl6 (encoded by the B cell lymphoma 6 gene). Bcl6-deficient mice lack GCs and affinity matured B cells [40, 41]. On the other MAPK Inhibitor Library concentration hand, constitutive expression of Bcl6 in B cells in vivo results in increased size of GCs [42]. Within the B cell lineage, Bcl6 mRNA is observed already in pre B cells, mature B cells and GC B selleck chemicals cells but not in plasma cells [43–45]. The expression of Bcl6 protein is highly increased in GC B cells [44] with higher expression in centroblasts than in centrocytes [46]. The expression of Bcl6 in GCs is maintained for example by interleukin-21 (IL-21) [47–49] that is secreted by many cell types, particularly by follicular helper T cells (TFHs) [50,

51]. IL-21 receptor signals via STAT3 and STAT5, which promote Bcl6 expression [48, 52, 53]. Analyses of Bcl6 target genes have revealed that Bcl6 maintains the centroblast gene expression signature that includes repression of genes involved in the detection and response to DNA damage (such as p53, ATR and CHEK1) to allow physiological Mirabegron genomic instability associated with SHM and class switch recombination (CSR) while promoting cell cycle by repressing genes such as CCND2, CDKN1A and CDKN1B [39, 54, 55]. Activation-induced cytidine deaminase is absolutely needed for both SHM and CSR [56–58]. Pax5 controls the expression

of AID, as the AID gene has a binding site for Pax5 that is needed for its expression [59], and the expression of AID in DT40 B cell line depends on Pax5 expression [8]. Interestingly, re-expression of Pax5 in Bcl6-deficient DT40 cells that also undergo spontaneous plasma cell differentiation cannot support the expression of AID (J. Alinikula, K.-P. Nera, S. Junttila and O. Lassila, unpublished observations), showing that Bcl6 is also necessary to sustain SHM and CSR via regulation of AID. Bcl6 knockout mice are capable of producing plasma cells, but not efficiently the long-lived population, supporting the role of Bcl6 in promoting GC B cell functions [41, 60, 61]. Thus, Pax5 and Bcl6 co-operate to maintain the GC phenotype before the induction of plasma cell differentiation.

In EPEC-infected cells, ERK1/2 phosphorylation was coupled to nuc

In EPEC-infected cells, ERK1/2 phosphorylation was coupled to nuclear translocation of these proteins. Interestingly,

EPEC virulence factors are necessary for efficient ERK1/2 nuclear translocation, suggesting additional regulation besides phosphorylation. ATM inhibitor Phosphorylation and degradation of IκΒ−α is directly coupled to the activation of the NF-κB signalling pathway, and indeed, degradation of this inhibitor is essential for triggering and maintaining NF-κB activated [47]. We showed that in contrast to infection with a non-pathogenic E. coli, infection with an EPEC atypical-like strain (E22) also activates NF-κB; although at 4 h of infection, E2348/69 induces a stronger IκB-α phosphorylation as well as degradation. E22 activates NF-κB and ERK1/2, although it lacks BFP, which confirms that BFP is not essential for NF-κB signalling [48]. Besides our finding that flagellin is required

to keep NF-κB activated at later times of EPEC infection, we showed that intimin absence and impaired effector translocation also resulted in NF-κB inhibition. These results emphasize that EPEC intimate adherence participates in NF-κB activation. The fact that intimin is a positive factor for activation of NF-κB, but a negative modulator for ERK1/2 signalling indicates that these learn more pathways are being regulated independently during EPEC infection. Although IL-8 contributes to only 50% of neutrophil recruitment by EPEC-infected cells [32], analysis of other cytokines has hardly been studied. Our group has reported that enterocytes from EPEC-infected rabbit showed increased il-1β, il-6, il-8 and tnf-α mRNA expression, and these increments were intimin dependent [33]. Here, we showed that in HT-29 cells, il-1β and il-8 mRNAs are constitutively produced; however, the synthesis of tnf-α mRNA is activated by EPEC infection

only, indicating differential regulation for cytokine production. In addition, il-1β mRNAs increases Astemizole during infection with both intimin and T3SS mutants. Apparently, EspA is a potent negative modulator of tnf-α mRNA production, since its absence resulted in almost the double amount of tnf-α mRNA compared to WT infection. In contrast to subtle differences in cytokine expression, we found marked effects on cytokine secretion. Even when mock-infected cells expressed il-1β and il-8 mRNAs, these cytokines were not secreted; consistently, non-stimulated cells did not express tnf-α mRNA nor secrete the cytokine. Interaction with non-pathogenic E. coli did not result in IL-1β or TNF-α release, although low levels of IL-8 secretion were detected at 4 h of stimulus. In contrast, EPEC infection induced strong secretion of all three cytokines at 2 h of infection, and IL-8 and TNF-α (but not IL-1β) release decreased by one-third at 4 h. Thus, the order of magnitude of cytokines released during EPEC infection was IL-8 > TNF-α > IL-1β.


three failed cases were found in patients with hyperf


three failed cases were found in patients with hyperfibrinogenemia and needed further reconstruction with another flap. The overall success rate was 88.5% (23/26). Hematologic disorder is not a predicted factor of free flap failure. The key factors for success flap survival in patients with hematologic disorders include BGB324 datasheet preoperative knowledge of the medical condition and monitoring potential post-operative complications, aggressive hematologist consultations, and meticulous non-traumatic surgical anastomosis. © 2014 Wiley Periodicals, Inc. Microsurgery 34:505–510, 2014. “
“The acellular nerve graft that can provide internal structure and extracellular matrix components of the nerve is an alternative for repair of peripheral nerve defects. However, results of the acellular nerve grafting for nerve repair still remain inconsistent. This study aimed to investigate if supplementing bone marrow mesenchymal stromal cells (MSCs) could improve the results of nerve repair with the acellular nerve graft in a 10-mm sciatic nerve defect model in mice. Eighteen mice were divided into three groups (n = 6 for each group) for nerve repairs with the nerve autograft, the acellular nerve

graft, and the acellular nerve graft by supplemented with MSCs (5 × 105) fibrin glue around the graft. The mouse static sciatic Luminespib clinical trial index was evaluated by walking-track testing every 2 weeks. The weight preservation of the triceps surae muscles and histomorphometric assessment of triceps surae muscles and repaired nerves were examined at week 8. The results showed that the nerve DOCK10 repair by the nerve autografting obtained the best functional recovery of limb. The nerve repair with the acellular nerve graft supplemented with MSCs achieved better functional

recovery and higher axon number than that with the acellular nerve graft alone at week 8 postoperatively. The results indicated that supplementing MSCs might help to improve nerve regeneration and functional recovery in repair of the nerve defect with the acellular nerve graft. © 2011 Wiley-Liss, Inc. Microsurgery, 2011. “
“This study aims to compare the major anatomical aspects among anterolateral thigh, parascapular and lateral arm flaps. Sixty flaps were dissected in 20 human cadavers, comparing their vascular pedicle length, flap thickness and arterial/venous pedicle diameters. The vascular pedicle length (from the origin of the vascular pedicle to its entry into the skin flap) of anterolateral thigh flap (13.43 ± 3.92 cm, lateral circumflex femoral artery) was longer than parascapular (9.07 ± 1.20 cm, circumflex scapular artery) and lateral arm flap (8.90 ± 1.65 cm, posterior collateral radial artery) (P < 0.001). The thickness of lateral arm flap (6.32 ± 2.33 mm) was lesser than parascapular (8.59 ± 2.93 mm) and anterolateral thigh flap (9.30 ± 3.54 mm) (P < 0.001). The arterial/venous pedicle diameters of lateral arm flap (2.

7% of the cells remaining Foxp3+, respectively, in the representa

7% of the cells remaining Foxp3+, respectively, in the representative data shown in Fig. 5B. These data suggest 1α25VitD3 contributes to the retention of Foxp3+ expression by human CD4+CD25high T cells. To confirm and extend these data, these experiments were repeated with mouse T cells. When total unfractionated CD4+ cells (>99% pure) were cultured in the absence or presence of 1α25VitD3, Foxp3 expression was increased from 3% to 7.3% with 10−7 M 1α25VitD3 in the example shown (Supporting Information Fig. 2A). When purified CD4+Foxp3GFP+ cells (>97% Foxp3+) were

stimulated with anti-CD3 and IL-2, in the absence of 1α25VitD3, Foxp3 expression was greatly reduced following 7 days of culture. In contrast, in Ku-0059436 price cultures containing

10−7 M and 10−6 M 1α25VitD3, more than 50% of the cells remained Foxp3+ (Supporting Information Fig. 2B). The addition of RA plus TGF-β to all cell cultures enhanced Foxp3 expression as selleck chemicals predicted from independent published data. Collectively, these data support the evidence from experiments with human T cells that 1α25VitD3 enhances the frequency of Foxp3+ cells by maintaining Foxp3 expression in culture. An enrichment in the percentage of Foxp3+ cells was observed in the presence of 10−6 M 1α25VitD3, or in the presence of lower concentrations of 1α25VitD3 plus anti IL-10R antibody. As 1α25VitD3 has well-documented inhibitory effects on T-cell cycle and proliferation, we investigated the capacity of 1α25VitD3 to directly modify the proliferation of Foxp3+ versus Foxp3− T cells using CellTrace Violet. This highly stable dye enabled monitoring of cell division of Foxp3+ and Foxp3− Adenosine triphosphate cells for up to 14 days of culture by flow cytometry. In the absence of 1α25VitD3, comparable proportions of the major Foxp3− and the minor Foxp3+ T-cell populations had proliferated by day 7 and day 14 of culture. The addition of 1α25VitD3 10−6 M to the culture, impaired both FoxP3− and Foxp3+ T-cell

proliferation at days 7 and 14 (Fig. 6A). However, whereas the Foxp3− T-cell proliferative response was almost completely abrogated, a clear Foxp3+ T-cell response, albeit reduced, could still be observed. The difference in the proliferative response between these two populations was significant (Fig. 6B). The addition of anti-IL-10R into cultures containing 10−7 M 1α25VitD3 resulted in a significant increase in cell division in the Foxp3+, but not the Foxp3− T cells at day 7 (Supporting Information Fig. 3) and to a lesser extent at day 14 (data not shown). Together these data suggest that a contributory mechanism by which 1α25VitD3 increases the frequency of Foxp3+ cells is via the preferential inhibition of the proliferation of Foxp3− cells.

Most notable are changes in immune cell phenotypes with increased

Most notable are changes in immune cell phenotypes with increased numbers of cells exhibiting the T regulatory phenotype and suppression selleckchem of Th1 cytokines that promote tolerance to paternal alloantigens. Until recently, interferon τ produced by the ruminant trophectoderm was thought to act exclusively on the uterine endometrium; however, it is now clear that this unique embryonic interferon escapes the uterus and alters gene expression in the CL and in peripheral blood leukocytes (PBL).

In fact, a large number of interferon-stimulated genes are now known to be increased during early pregnancy in PBL. What is not known is how this conceptus-immune system cross-talk affects maternal immune status outside the reproductive tract. It is attractive to hypothesize that some of these effects are designed to counter-balance progesterone-induced immunosuppression so as not to place the dam at a greater risk of infection on top of the tremendous stresses already induced by pregnancy. Furthermore, recent evidence suggests that pregnancy induced changes in peripheral immune cells may aid in orchestrating establishment of pregnancy. Existing evidence points toward a greater convergence of systemic immune responses

to early pregnancy signaling between ruminants and primates. Almost from the beginning of research in the field, a clear dichotomy was revealed surrounding the role of the conceptus in extending luteal function in primates and domestic ruminants. In primates, the conceptus Meloxicam produces a luteinizing hormone (LH)–like hormone termed chorionic gonadotropin (CG) that acts directly on the selleck chemicals llc corpus luteum (CL) via the blood; an action that was described as luteotropic.1–3 Presence of CG in the blood and urine of primates provides a straightforward mechanism for determining the presence of a viable conceptus in these species and is the basis for many home pregnancy tests.4 In contrast,

domestic ruminants (cattle, sheep, goats) produce unique interferons (IFN), closely related to α- and ω-IFN, termed interferon τ (IFN-τ), that do not exhibit luteotropic activity, but rather act locally on the uterus to block luteolysis, an action termed antiluteolytic.1,5,6 Early attempts to identify these substances in the systemic circulation,7–9 urine or cervical mucus10 of ruminants largely failed. There are also species, such as the dog and cat, that do not require a conceptus signal for rescuing CL function.11 In these species, regardless of whether mating establishes a pregnancy, the CL is maintained for a period similar to the length of gestation. Thus, at least during early pregnancy, there is no need for signaling between the uterus and ovary to maintain pregnancy in dogs and cats. Relative to conceptus effects on luteal lifespan, the antiluteolytic versus luteotrophic hypotheses have weathered years of intense investigation and are routinely taught in the classroom.

The primers for PCR were as follows: Fli-1 exon


The primers for PCR were as follows: Fli-1 exon

IX/forward primer (positions 1156–1180), GACCAACGGGGAGTTCAAAATGACG; Fli-1 exon IX/reverse primer (positions 1441–1465), GGAGGATGGGTGAGACGGGACAAAG; and Pol II/reverse primer, GGAAGTAGCCGTTATTAGTGGAGAGG. ICG-001 datasheet DNA was isolated from tail snips (4-week old mice) using a QIAamp Tissue kit (Qiagen, Santa Clarita, CA, USA). PCR conditions were one cycle at 94°C for 10 min followed by 35 cycles at 94°C for 1 min, 68°C for 1 min and 72°C for 1 min. A 309-base pairs (bp) fragment indicates the presence of the WT allele, and a 406-bp fragment is amplified from the mutated allele. BM cells were prepared for FISH using standard techniques. Briefly, cells were cultured overnight in Chang bone marrow culture (BMC) media (Irvine Scientific, Santa Ana, CA, USA), supplemented with penicillin and streptomycin. Then ethidium bromide (Sigma, St Louis, MO, USA) was added to the culture at a concentration of 10 µg/ml and the cells were incubated for 45 min. Next, colcemid (Invitrogen/Gibco, Gefitinib concentration Grand Island, NY, USA) was

added to the culture at 0·1 µg/ml and incubated for an additional 40 min. Red blood cells were disrupted in hypotonic solution buffer (0·075 M KCl). Cells were then fixed in methanol acetic acid solution at the ratio of 5 : 2. Cells were suspended in fixation buffer at 1 × 107 cells/ml. A drop of each sample was placed on a microscope slide. After air-drying, slides were then dehydrated with ethanol. Next, slides were denatured at 65°C in denaturing solution [0·6× standard saline sodium citrate (SSC) and 70% formamide]. Slides were then quenched in 70% ice-cold ethanol and dehydrated again in ethanol. BM cells were then hybridized to Metformin cyanine 3 (Cy3)-labelled mouse X-chromosome paint and fluorescein isothiocyanate (FITC)-labelled mouse Y-chromosome paint in hybridization solution (Cambio, Cambridge, UK) overnight

at 37°C. Slides were then washed in Stringency Wash solution (50% formamide and 0·5 × SSC) at 45°C for 5 min. After washing twice with SSC at 45°C, the slides were incubated with wash detergent solution (4 × SSC, 0·05% Tween-20) for 4 min at 45°C, and mounted with Gelmount (Biomedia, Foster City, CA, USA) containing 125 ng/ml 4,6-diamidino-2-phenylindole (DAPI; Invitrogen-Molecular Probes, Carlsbad, CA, USA). Finally, slides were examined using a Leica epifluorescent microscope with standard epifluorescence filters for FITC, Cy3 and DAPI (Leica, Bannockburn, IL, USA). Two hundred cells were counted from each sample. Mice were placed in metabolic cages for 24-h urine collection every 4 weeks, beginning at the 12 weeks of age after BM transplantation. Antibiotics (ampicillin and gentamicin from Invitrogen and chloramphenicol from Sigma) were added in collection tubes to inhibit bacterial growth. Urinary albumin excretion was determined by enzyme-linked immunosorbent assay (ELISA) as described previously [16].

3e) At all the doses tested, there was no significant difference

3e). At all the doses tested, there was no significant difference in IL-2 production by T cells activated by SD-4+/+ versus SD-4−/− selleck chemicals llc DC. Altogether, SD-4 deletion had no impact on T-cell responses in the absence of accessory signals delivered by DC, but it augmented the DC-induced response (enhanced co-stimulatory signals resulting from lack of the inhibitory function

of DC-HIL/SD-4 between APC and T cells). Since SD-4−/− T cells were hyper-reactive to allo-antigen in the mixed lymphocyte reaction (Fig. 3a), we examined their effect on acute GVHD (Fig. 4). BALB/c mice were γ-irradiated at a sub-lethal dose and then infused with T-cell-depleted allogeneic BM cells (from C57BL/6 mice) with or without CD3+ T cells isolated from KO or WT mice. Body weight was noted weekly and survival was noted daily through to day 100. All mice lost about 30% of initial body weight within a week after BM transplantation,

but recovered some weight during the 2nd week. Thereafter, differentially treated mice displayed disparate HIF-1 cancer outcomes (Fig. 4a). Mice that received BM cells alone completely recovered their weight 3 weeks post-BM transplantation and survived for at least 100 days. Mice that received BM cells plus SD-4+/+ T cells partially recovered their weight, with 50% dying by day 32, and the rest survived for at least 100 days (Fig. 4b). By contrast, mice that received BM cells plus SD-4−/− T cells lost weight progressively (up to 40%) due to severe diarrhoea, with 50% dying by day 14, and all dead by day 32. We also examined proliferation of infused T cells in recipients, by measuring the number of donor-derived T cells (H-2Kb+) in spleen and liver of mice at day 5 post-BM transplantation (Fig. 4c,d). In spleen (Fig. 4c), there was twofold to threefold greater CD4+ and CD8+ SD-4−/− T cells than SD-4+/+ T cells, and also more CD69+ (activated) cells than in recipients of SD-4+/+ T cells. Similar results were observed in liver, which is another major target of acute GVHD (Fig. 4d).[1] These results indicate that infusion of T cells devoid

of SD-4 worsens morbidity and mortality of acute GVHD, most likely through hyper-reactivity to allo-antigen. Because donor-derived Treg cells are known to play a pivotal cAMP role in preventing GVHD induced by co-injection of BM cells and T cells isolated from C57BL/6 mice into total body γ-irradiated BALB/c mice,[24] we studied the influence of SD-4 deletion on the T-cell-suppressive activity of Treg. We examined expression of SD-4 on conventional CD4+ Foxp3− T cells (Tconv) versus CD4+ Foxp3+ Treg cells (Fig. 5). The Tconv and Treg cells freshly isolated from naive WT mice represented 90% and 10%, respectively, and neither expressed SD-4. In contrast, PD-1 was expressed by a minuscule fraction of Tconv cells (4·6%) and by some Treg cells (22% of Foxp3+ cells) (Fig. 5a). The Tconv and Treg cells were activated by culture for 2 days with immobilized anti-CD3/CD28 antibody.

Whether, to what extent and how these general stress genes protec

Whether, to what extent and how these general stress genes protect E. coli biofilms remains to be determined. In several Gram-negative bacteria, coordinated regulation of many genes associated with oxidative stress is mediated by the transcriptional regulator OxyR (Ochsner et al., 2001; Zheng et al., 2001). mTOR inhibitor In P. aeruginosa, oxidized OxyR increases the expression

of ahpCF and katB (both encoding cytoplasmic enzymes) and of ahpB (encoding a periplasmic enzyme) (Ochsner et al., 2001). Panmanee & Hassett (2009) recently showed that these OxyR-controlled antioxidant enzymes play differential roles in planktonic and sessile P. aeruginosa cells. While exposure to H2O2 Small molecule library results in the upregulation of the katB gene in planktonic cells, no such upregulation is observed in sessile cells. In contrast, the treatment of planktonic cultures with H2O2 does not result in a differential expression of ahpC, while this gene is significantly upregulated in sessile cells treated with high (25 mM) H2O2 concentrations. A possible explanation for this is that, due to iron starvation, the catalase activity

in biofilm cells is extremely low, making the increased expression of ahpCF a necessity for survival under these growth conditions (Panmanee & Hassett, 2009). Burkholderia cenocepacia is a Gram-negative bacterium that is well known for causing respiratory infections in individuals with cystic fibrosis (Coenye & Vandamme, 2003; Mahenthiralingam et al., 2008). Most B. cenocepacia strains readily form biofilms on various surfaces, and sessile B. cenocepacia cells are highly resistant against antibiotics and disinfectants (Peeters et al., 2008, 2009). While studying the resistance

of sessile B. cenocepacia cells against disinfection procedures implemented in various infection control guidelines, it was noticed that these sessile cells are highly resistant against H2O2 and NaOCl (Peeters et al., 2008). This observation not only has implications for infection control practices, but, as these Arachidonate 15-lipoxygenase oxidative agents are being produced by neutrophils as part of the endogenous defense against microorganisms (MacDonald & Speert, 2007), may also have implications for pathogenesis. When the transcriptional response of treated vs. untreated B. cenocepacia biofilms was compared, it was observed that the exposure to H2O2 and NaOCl resulted in an upregulation of 315 (4.4%) and 386 (5.4%) genes, respectively (Peeters et al., 2010). Transcription of 185 (2.6%) and 331 (4.6%) genes was decreased in response to H2O2 or NaOCl treatments, respectively. Not surprisingly, many of the upregulated genes in the treated biofilms are involved in (oxidative) stress responses, emphasizing the importance of the efficient neutralization and scavenging of reactive oxygen species.

There is insufficient information to comment on its use in CMV se

There is insufficient information to comment on its use in CMV seronegative recipients of organs from seronegative donors. Extended duration of antiviral prophylaxis

in kidney and lung transplants has been shown to be more effective than standard 3 month prophylaxis. “
“Cases of life-threatening thromboses in pulmonary, coronary, cerebral and peripheral vessels are associated with high-dose intravenous immunoglobulin (IVIg) therapy that is generally considered safe. We experienced a patient Rapamycin mw with a renal graft rupture that developed after high-dose IVIg was administered for desensitization. A needle biopsy performed 4 days prior to the rupture revealed the presence of glomerular thrombosis and mesangiolysis. The ruptured nephrectomy specimen contained

renal infarction around the haemorrhagic segment and arterial wall thickening with intimal fibrosis. This might have contributed to rupturing associated with small arterial and glomerular arteriolar thrombi. This is the first case of a graft rupture as a complication of high-dose IVIg we have encountered. High-dose IVIg is commonly administered to treat immunodeficiencies Panobinostat purchase or various inflammatory disorders such as idiopathic thrombocytopenic purpura and autoimmune haemolytic anaemia. This therapeutic technique has been recently recognized as a modifier of complement activation, suggesting that IVIg could be clinically useful for desensitizing patients about to undergo solid organ transplantation and treating antibody-mediated rejection (AMR).[1, 2] Although high-dose IVIg is generally considered safe, cases of life-threatening thromboses in pulmonary, coronary, cerebral and peripheral vessels associated with this therapy have been reported.[3] The mechanisms underlying thrombosis development are IVIg-induced platelet activation, increased plasma viscosity and coagulation factor XI contamination.[4] A 46-year-old woman was hospitalized for a second renal transplantation from a 59-year-old deceased donor. Before transplantation, the

patient underwent desensitization with rituxan (200 mg/body). PAK5 She also received two rounds of high-dose IVIg (1 g/kg per day for 2 days) due to 100% PRA (panel reactive antibody) against class I and 92% against class IIHLA antigens as well as positive cross-match test results against T cells. The allograft functioned well. Fourteen days after surgery, IVIg was administered at a dose of 1 g/kg per day for 2 days to further reduce allosensitization. No immediate acute toxic reactions were noted. Two days later, the creatinine levels had increased to 2.2 mg/dL. A biopsy showed that thromboembolisms had formed in the glomeruli along with focal segmental mesangiolysis (Fig. 1). Four days later, the patient experienced severe graft pain. The serum creatinine concentration had increased to 3.

Bcl-2 and Bim play a critical role in the establishment


Bcl-2 and Bim play a critical role in the establishment

and maintenance of the immune system by regulating the survival of lymphocytes by apoptosis. The effect of the interaction of Bcl-2 and Bim is dependent on the cell type and/or is tissue-specific: Bcl-2 promotes the survival of naive T cells [7]. In turn, naive T cells from Bim+/– Bcl-2–/– mice die at an accelerated rate in vitro. Bcl-2 is critical to prevent the pro-apoptotic effects of Bim in naive CD8+ T cells in vivo, but other molecules than Bcl-2 might antagonize Bim in CD4+ cells. Bim controls T cell numbers in the periphery by promoting apoptosis and/or decreasing thymic production. Bim-deficient mice have elevated numbers of normal single-positive T cells in the periphery [8]. Bim is a primary trigger for killing autoreactive B cells during their development [9]. In contrast, Bcl-2

is Selleck H 89 required less for the generation and/or maintenance of memory T cells [7]. Bcl-2 and Bim play a critical role in controlling immune responses by regulating the survival, expansion and contraction of lymphocytes by apoptosis. The majority of activated T cells die at the end of a T cell response. Activated T cells exhibit decreased levels of Bcl-2 at the peak of the T cell response, just before they began to die in vivo [10]. A decrease of the pro-survival protein Bcl-2 contributes to apoptosis of activated T cells [11]. Bim deficiency prevents the death of activated T cells in vitro and in vivo, suggesting that the protective effects of Bcl-2 acts solely to neutralize Bim [11]. Thymocytes can be selected negatively by exposure to anti-CD3 antibody, which aggregates the TCR–CD3 complex and kills the CD4+CD8+ population in vivo and

in vitro. Thymocytes lacking the pro-apoptotic Bim are refractory to TCR ligation-induced killing [12]. Stimulation with the superantigen Staphylococcus enterotoxin B (SEB) activates most T cells that express a variable region (V)-β8 TCR. Addition of SEB to fetal thymic organ cultures deletes most developing TCR Vβ8+ thymocytes. In contrast, Ribonucleotide reductase TCR Vβ8+ escapes apoptosis in SEB-treated thymic lobes from Bim–/– embryos [12]. Lymphocytes from Bim–/– mice were found to be relatively resistant to apoptosis upon BH3-only mimetics compared to those from wild-type mice. The presence of Bim affected apoptosis of regulatory T cells (Treg) differently when compared to CD4+8– thymocytes. The loss of pro-apoptotic Bim rescued Treg cells from intrinsically initiated apoptosis [13]. As well as the role of Bim for apoptosis of Treg cells, the absence of Bim also affects the phenotype and function of Treg cells in a manner that indicates loss of function. An exaggerated response of T lymphocytes to luminal antigens is suggested to increase intestinal inflammation in inflammatory bowel disease (IBD).