Drosophila CIAPIN1 homologue is required for follicle cell proliferation and survival

Background: The conserved cytokine‐induced apoptosis inhibitor‐1 (CIAPIN1) gene has been implicated in several processes, such as apoptosis, cell division, angiogenesis and Fe/S protein biogenesis. In this study, we identified the Drosophila CIAPIN1 homologue (D‐CIAPIN1) and studied its role in ovarian development. Results: We found that D‐CIAPIN1 is conserved as it can complement the nonviability of the yeast CIAPIN1‐deletion strain. Several D‐CIAPIN1 alleles were identified, including one allele in which that codon encoding the highly conserved twin cysteine CX₂C motif is mutated, demonstrating for the first time the importance of this motif to protein function. We demonstrated D‐CIAPIN1 is an essential gene required for ovarian development. We found that D‐CIAPIN1 female mutants are sterile, containing rudimentary ovaries. We noted a decrease in follicle cell numbers in D‐CIAPIN1 mutant egg chambers. We further demonstrated that the decrease in follicle cell numbers in D‐CIAPIN1 mutants is due to a reduced mitotic index and enhanced cell death. Conclusions: Our study reveals that D‐CIAPIN1 is essential for egg chamber development and is required for follicle cell proliferation and survival. Developmental Dynamics 242:731–737, 2013. © 2013 Wiley Periodicals, Inc.     

Labelling cell structures and tracking cell lineage in zebrafish using SNAP‐tag

We present a method for the specific labelling of fusion proteins with synthetic fluorophores in Zebrafish. The method uses the SNAP‐tag technology and O⁶‐benzylguanine derivatives of various synthetic fluorophores. We demonstrate how the method can be used to label subcellular structures in Zebrafish such as the nucleus, cell membranes, and endosomal membranes. The stability of the synthetic fluorophores makes them attractive choices for long‐term imaging and allows, unlike most of the autofluorescent proteins, the use of acid fixatives such as trichloroacetic acid. Furthermore, the use of O⁶‐benzylguanine derivatives bearing caged fluorescein allows cell lineage tracing through photo‐deprotection of the fluorophore and its detection either through fluorescence microscopy or through immunohistochemistry after fixation using anti‐fluorescein antibodies. Developmental Dynamics 240:820–827, 2011. © 2011 Wiley‐Liss, Inc.     

Prickle1 stunts limb growth through alteration of cell polarity and gene expression

Background: Wnt/PCP signaling plays a critical role in multiple developmental processes, including limb development. Wnt5a, a ligand of the PCP pathway, signals through the Ror2/Vangl2 or the Vangl2/Ryk complex to regulate limb development along the proximal‐distal axis in mice. Based on the interaction between Van Gogh and Prickle in Drosophila, we hypothesized the vertebrate Prickle1 has a similar function as Vangl2 in limb development. Results: We show Prickle1 is expressed in the skeletal condensates that will differentiate into chondrocytes and later form bones. Disrupted Prickle1 function in Prickle1^C251X/C251X mouse mutants alters expression of genes such as Bmp4, Fgf8, Vangl2, and Wnt5a. These expression changes correlate with shorter and wider bones in the limbs and loss of one phalangeal segment in digits 2–5 of Prickle1C251X mutants. These growth defects along the proximal‐distal axis are also associated with increased cell death in the growing digit tip, reduced cell death in the interdigital membrane, and disrupted chondrocyte polarity. Conclusions: We suggest Prickle1 is part of the Wnt5a/PCP signaling, regulating cell polarity and affecting expression of multiple factors to stunt limb growth through altered patterns of gene expression, including the PCP genes Wnt5a and Vangl2. Developmental Dynamics 242:1293–1306, 2013. © 2013 Wiley Periodicals, Inc.     

Cumulative alterations of p27Kip1‐related cell‐cycle regulators in the development of endometriosis‐associated ovarian clear cell adenocarcinoma

Yamamoto S, Tsuda H, Miyai K, Takano M, Tamai S & Matsubara O
(2010) Histopathology 56, 740–749
Cumulative alterations of p27 ^Kip1 ‐related cell‐cycle regulators in the development of endometriosis‐associated ovarian clear cell adenocarcinoma Aims: To identify the key cell‐cycle dysregulations in the development of endometriosis‐associated ovarian clear cell adenocarcinoma (CCA). Methods and results: Expression of p27^Kip1‐interacting cell‐cycle regulators, such as p27^Kip1 itself, Skp2, cyclin‐dependent kinase subunit 1 (Cks1), cyclin A and cyclin E, and Ki67 labelling index (LI), were analysed by immunohistochemistry in 23 CCAs with 36 endometriotic or atypical endometriotic lesions adjacent to CCA from a cohort of 23 patients, and in 31 cases of solitary endometriosis. The cell‐cycle regulators examined were overexpressed (Skp2, Cks1, cyclin A and cyclin E; P < 0.01, each) or down‐regulated (p27^Kip1, P = 0.044) significantly more frequently in the CCAs than in the adjacent endometriosis. The frequency of Skp2 overexpression was significantly higher in atypical endometriosis than in endometriosis, and the frequency of Skp2 and cyclin A overexpression was significantly higher in CCA than in atypical endometriosis (P < 0.01, each). Mean Ki67 LI increased from endometriosis (8.4%) through atypical endometriosis (21.4%) to CCA (46.9%), with statistical significance between each component (P < 0.01, each). The frequency of cell‐cycle regulator expression and mean Ki67 LIs were not significantly different between solitary endometriosis and endometriosis adjacent to CCA. Conclusions: Alteration of the p27^Kip1‐interacting cell‐cycle regulators appeared strongly involved in the progression of endometriosis‐associated ovarian clear cell carcinogenesis through increasing cell proliferative activity.     

Development of a GSO positron/single-photon imaging detector

We have developed and tested a GSO (gadolinium oxyorthosilicate) position-sensitive gamma detector which can be used with positron and single-photon radionuclides for imaging breast cancer or sentinel lymph node detection. Because GSO has a relatively good energy resolution for annihilation gammas as well as low energy gamma photons, and does not contain any natural radioisotopes, it can be used for positron imaging and lower energy single-photon imaging. The imaging detector consists of a GSO block, 2 inch square multi-channel position-sensitive photo-multiplier tube (PSPMT), and associated electronics. The size of a single GSO element was 2.9 mm x 2.9 mm x 20 mm and these elements were arranged into 15 x 15 matrixes to form a block that was optically coupled to the PSPMT. It was possible to separate all GSO crystals into a two-dimensional position histogram for annihilation gammas (511 keV) and low energy gamma photons (122 keV). The typical energy resolution was 24% FWHM and 37% FWHM for 511 keV and 122 keV gamma photons, respectively. For the positron imaging, coincidence between the imaging detector and a single gamma probe is measured. For the single-photon imaging, a tungsten collimator is mounted in front of the imaging detector. With this configuration, it was possible to image both positron radionuclides and low energy single-photon radionuclides. We measured spatial resolution and sensitivity as well as image quality of the developed imaging detector. Results indicated that the developed imaging detector has the potential to be a new and useful instrument for nuclear medicine.     

Variable immune cell frequencies in peripheral blood of LEW.1AR1‐iddm rats over time compared to other congenic LEW strains

The LEW.1AR1‐iddm rat is an animal model of human type 1 diabetes (T1D), which arose through a spontaneous mutation within the major histocompatibility complex (MHC)‐congenic background strain LEW.1AR1. The LEW.1AR1‐iddm rat is characterized by two phenotypes: diabetes development with a diabetes incidence of 60% and a variable T cell frequency in peripheral blood. In this study the immune cell repertoire of LEW.1AR1‐iddm rats was analysed over time from days 30 to 90 of life and compared to the background strain LEW.1AR1 and the LEW rat strain as well as the LEW.1WR1 rat strain. The LEW.1AR1‐iddm rats are characterized by a high variability of CD3⁺, CD4⁺ and CD8⁺ T cell frequencies in peripheral blood over time, and the frequency is unique for each animal. The variability within the frequencies resulted in changes of the CD4⁺ : CD8⁺ T cell ratio. The other three rat strains studied were characterized by a stable but nevertheless strain‐specific T cell frequency resulting in a specific CD4⁺ : CD8⁺ T cell ratio. The frequency of natural killer (NK) cells and B cells in LEW.1AR1‐iddm rats was increased, with a higher variability compared to the other strains. Only monocytes showed no differences in frequency and variability between all strains studied. These variabilities of immune cell frequencies in the LEW.1AR1‐iddm rats might lead to imbalances between autoreactive and regulatory T cells in peripheral blood as a prerequisite for diabetes development.     

B cell lymphoma and myeloma in murine Gaucher's disease

Multiple myeloma and B cell lymphoma are leading causes of death in Gaucher's disease but the nature of the stimulus driving the often noted clonal expansion of immunoglobulin‐secreting B cells and cognate lymphoid malignancy is unknown. We investigated the long‐term development of B cell malignancies in an authentic model of non‐neuronopathic Gaucher's disease in mice: selective deficiency of β‐glucocerebrosidase in haematopoietic cells [Gba^{tm1Karl/tm1Karl}Tg(Mx1‐cre)1Cgn/0, with excision of exons 9–11 of the murine GBA1 gene, is induced by poly[I:C]. Mice with Gaucher's disease showed visceral storage of β‐glucosylceramide and greatly elevated plasma β‐glucosylsphingosine [median 57.9 (range 19.8–159) nm; n = 39] compared with control mice from the same strain [median 0.56 (range 0.04–1.38) nm; n = 29] (p < 0.0001). Sporadic fatal B cell lymphomas developed in 11 of 21 GD mice (6–24 months) but only two of eight control animals developed tumours by age 24 months. Unexpectedly, most mice with overt lymphoma had absent or few Gaucher cells but local inflammatory macrophages were present. Eleven of 39 of Gaucher mice developed monoclonal gammopathy, but in the control group only one animal of 25 had clonal immunoglobulin abnormalities. Seven of 10 of the B cell lymphomas were found to secrete a monoclonal paraprotein and the lymphomas stained intensely for pan‐B cell markers; reactive T lymphocytes were also present in tumour tissue. In the Gaucher mouse strain, it was notable that, as in patients with this disease, CD138⁺ plasma cells frequently surrounded splenic macrophages engorged with glycosphingolipid. Our strain of mice, with inducible deficiency of β‐glucocerebrosidase in haematopoietic cells and a high frequency of sporadic lethal B cell malignancies, faithfully recapitulates human Gaucher's disease: it serves as a tractable model to investigate the putative role of bioactive sphingolipids in the control of B cell proliferation and the pathogenesis of myelomatosis—the most prevalent human cancer associated with this disorder. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

SOX11 is useful in differentiating cyclin D1‐positive diffuse large B‐cell lymphoma from mantle cell lymphoma

Hsiao S‐C, Cortada I R, Colomo L, Ye H, Liu H, Kuo S‐Y, Lin S‐H, Chang S‐T, Kuo T U, Campo E & Chuang S‐S
(2012) Histopathology  61, 685–693 SOX11 is useful in differentiating cyclin D1‐positive diffuse large B‐cell lymphoma from mantle cell lymphoma Aims: To characterize the frequency and clinicopathological features of cyclin D1‐positive diffuse large B‐cell lymphoma (DLBCL) and the usefulness of SOX11 in the differential diagnosis from mantle cell lymphoma (MCL). Methods and results: We retrospectively stained 206 consecutive DLBCLs for cyclin D1, and identified three (1.5%) positive cases, comprising two in the elderly with necrosis, and a third with a starry‐sky pattern. All three cases shared the same non‐germinal centre B‐cell (non‐GCB) phenotype [CD5?/CD10?/bcl‐6+/MUM1+/SOX11?], Epstein–Barr virus (EBV) negativity, and absence of CCND1 aberrations by fluorescence in‐situ hybridization. The third case showed both BCL6 and MYC rearrangements: a double‐hit lymphoma. In the same period there were 22 MCLs, all expressing cyclin D1, with 89% cases expressing SOX11, a frequency that is statistically different from cyclin D1‐positive DLBCL. Notably, we identified a pleomorphic MCL initially misdiagnosed as DLBCL. A separate cohort of 98 DLBCL cases was negative for SOX11, with only one case expressing cyclin D1 with a GCB phenotype (CD10+/bcl‐6+/MUM1?). The two patients with tumour necrosis rapidly died of disease. The other two were in complete remission after immunochemotherapy. Conclusions: Cyclin D1‐positive DLBCLs are rare, and they are negative for SOX11 or CCND1 aberration. SOX11 is useful in differentiating cyclin D1‐positive DLBCL from MCL.     

Modulation of γδ T‐cell activation by neutrophil elastase

γδ T cells are non‐conventional, innate‐like T cells, characterized by a restricted T‐cell receptor repertoire. They participate in protective immunity responses against extracellular and intracellular pathogens, tumour surveillance, modulation of innate and adaptive immune responses, tissue healing, epithelial cell maintenance and regulation of physiological organ function. In this study, we investigated the role of neutrophils during the activation of human blood γδ T cells through CD3 molecules. We found that the up‐regulation of CD69 expression, and the production of interferon‐γ and tumour necrosis factor‐α induced by anti‐CD3 antibodies was potentiated by neutrophils. We found that inhibition of caspase‐1 and neutralization of interleukin‐18 did not affect neutrophil‐mediated modulation. By contrast, the treatment with serine protease inhibitors prevented the potentiation of γδ T‐cell activation induced by neutrophils. Moreover, the addition of elastase to γδ T‐cell culture increased their stimulation, and the treatment of neutrophils with elastase inhibitor prevented the effect of neutrophils on γδ T‐cell activation. Furthermore, we demonstrated that the effect of elastase on γδ T cells was mediated through the protease‐activated receptor, PAR1, because the inhibition of this receptor with a specific antagonist, RWJ56110, abrogated the effect of neutrophils on γδ T‐cell activation.     

Zebrafish cdx1b regulates differentiation of various intestinal cell lineages

Both antisense morpholino oligonucleotide (MO)‐mediated knockdown and overexpression experiments were performed to analyze zebrafish cdx1b's function in intestinal cell differentiation. Substantial reductions in goblet cell numbers were detected in intestines of 102‐ and 120‐hours post‐fertilization (hpf) cdx1b MO‐injected embryos (morphants) compared to cdx1b‐4‐base mismatched (4mm)‐MO‐injected and wild type embryos. A significant decrease in enteroendocrine cell numbers was also observed in intestines of 96‐hpf cdx1b morphants. Furthermore, ectopic cdx1b expression caused notable increases in respective cell numbers of enteroendocrine and goblet cells in intestines of 96‐ and 98‐hpf injected embryos. Decreased PepT1 expression was detected in enterocytes of intestines in cdx1b morphants from 80 to 102 hr of development. In addition, increased cell proliferation was detected in intestines of cdx1b morphants. Overall, our results suggest that zebrafish cdx1b plays important roles in regulating intestinal cell proliferation and the differentiation of various intestinal cell lineages. Developmental Dynamics 238:1021–1032, 2009. © 2009 Wiley‐Liss, Inc.     

Influence of PD‐L1 cross‐linking on cell death in PD‐L1‐expressing cell lines and bovine lymphocytes

Programmed death‐ligand 1 (PD‐L1) blockade is accepted as a novel strategy for the reactivation of exhausted T cells that express programmed death‐1 (PD‐1). However, the mechanism of PD‐L1‐mediated inhibitory signalling after PD‐L1 cross‐linking by anti‐PD‐L1 monoclonal antibody (mAb) or PD‐1–immunogloblin fusion protein (PD‐1‐Ig) is still unknown, although it may induce cell death of PD‐L1⁺ cells required for regular immune reactions. In this study, PD‐1‐Ig or anti‐PD‐L1 mAb treatment was tested in cell lines that expressed PD‐L1 and bovine lymphocytes to investigate whether the treatment induces immune reactivation or PD‐L1‐mediated cell death. PD‐L1 cross‐linking by PD‐1‐Ig or anti‐PD‐L1 mAb primarily increased the number of dead cells in PD‐L1^high cells, but not in PD‐L1^low cells; these cells were prepared from Cos‐7 cells in which bovine PD‐L1 expression was induced by transfection. The PD‐L1‐mediated cell death also occurred in Cos‐7 and HeLa cells transfected with vectors only encoding the extracellular region of PD‐L1. In bovine lymphocytes, the anti‐PD‐L1 mAb treatment up‐regulated interferon‐γ (IFN‐γ) production, whereas PD‐1‐Ig treatment decreased this cytokine production and cell proliferation. The IFN‐γ production in B‐cell‐depleted peripheral blood mononuclear cells was not reduced by PD‐1‐Ig treatment and the percentages of dead cells in PD‐L1⁺ B cells were increased by PD‐1‐Ig treatment, indicating that PD‐1‐Ig‐induced immunosuppression in bovine lymphocytes could be caused by PD‐L1‐mediated B‐cell death. This study provides novel information for the understanding of signalling through PD‐L1.     

Modulation of cell morphogenesis by tousled‐like kinase in the Drosophila follicle cell

Background: Tousled‐like kinase (Tlk) is a conserved serine/threonine kinase regulating DNA replication, chromatin assembly, and DNA repair. Previous studies have suggested that Tlk is involved in cell morphogenesis in vitro. In addition, tlk genetically interact with Rho1, which encodes a key regulator of the cytoskeleton. However, whether Tlk plays a physiological role in cell morphogenesis and cytoskeleton rearrangement remains unknown. Results: In tlk mutant follicle cells, area of the apical domain was reduced. The density of microtubules was increased in tlk mutant cells. The density of actin filaments was increased in the apical region and decreased in the basal region. Because area of the apical domain was reduced, we examined the levels of proteins located in the apical region by using immunofluorescence. The fluorescence intensities of two adherens junction proteins Armadillo (Arm) and DE‐cadherin (DE‐cad), atypical protein kinase C (aPKC), and Notch, were all increased in tlk mutant cells. The basolateral localized Discs large (Dlg) shifted apically in tlk mutant cells. Conclusions: Increase of protein densities in the apical region might be resulted from disruption of the cytoskeleton and shrinkage of the apical domain. Together, these data suggest a novel role of Tlk in maintaining cell morphology, possibly through modulating the cytoskeleton. Developmental Dynamics 244:852–865, 2015. © 2015 Wiley Periodicals, Inc.     

Comparison of the 2002 and 2010 TNM classification systems regarding outcome prediction in clear cell and papillary renal cell carcinoma

Aims: A novel version of the tumour–node–metastasis (TNM) classification system for renal cell carcinoma (RCC) was introduced in 2010, although the prognostic significance with regard to different histological subtypes has not been explored. Therefore, the aim of our study was to compare the predictive ability of the 2002 and 2010 versions of the TNM classification system for clear cell and papillary RCC. Methods and results: Data from 2263 consecutive clear cell and 309 papillary RCC patients, operated at a single tertiary academic centre, were evaluated. According to TNM 2010, statistically significant differences for cancer‐specific survival (CSS) were observed for pT1a versus pT1b (P < 0.001) and pT3a versus pT3b (P < 0.004) in clear cell RCC; and pT1b versus pT2a (P = 0.002) and pT3b versus pT3c (P = 0.046) in papillary RCC. The c‐index for CSS in clear cell RCC was 0.74 and 0.73, and in papillary RCC 0.79 and 0.78, for the 2002 and 2010 versions of the TNM classification system, respectively. Conclusions: According to our data, the predictive ability of the 2010 version of the TNM classification system regarding CSS is not superior to the 2002 version, either in clear cell or in papillary RCC.     

Peanut-specific B and T cell responses are correlated in peanut-allergic but not in non-allergic individuals

Objective We aim to find what is the relationship between B cell antibody responses and specific T cell help in the specific cases of allergy and tolerance to peanuts. Background B cell antibody responses to foreign proteins usually depend upon antigen‐specific T cell help. However, specific antibody levels can sometimes be maintained lifelong after infections or vaccination. Methods We measured peanut‐specific proliferation and antibody levels in peanut‐allergic and non‐allergic children using tritiated thymidine incorporation and UniCAP, respectively. We also investigated the corresponding tetanus toxoid specific responses in both groups. Results We found that tetanus‐specific IgG did not correlate with lymphocyte proliferation (Spearman rank correlation coefficient r′=0.08, P=0.74) nor with tetanus‐specific cytokine production (IFN‐γ: r′=0.198, P=0.285; TNF‐α: r′=0.274, P=0.146; IL‐4: r′=?0.007, P=0.96; P=0.221; IL‐13: r′=0.363, P=0.056). Conversely, in peanut‐allergic donors, peanut‐specific IgE (average 21 kU/L, median 2.27 kU/L, range 0.34‐100 kU/L) but not peanut‐specific IgG was positively correlated with proliferation (r′=0.751, P=0.003). In these donors, specific IgE was positively correlated with peanut‐specific Th2 cytokines production: r′=0.635, P=0.02 for IL‐4 and r′=0.641, P=0.025 for IL‐13 and negatively correlated with Th1 cytokines (r′=?0.71, P=0.007 for IFN‐γ and r′=?0.746, P=0.005 for TNF‐α, respectively). However, peanut‐specific IgE was not correlated with T cell proliferation or cytokine production in non‐allergic individuals. In conclusion, in allergic individuals, B and T cell responses to peanut antigens are correlated whereas normal immune responses B and T cell responses are uncoupled. Conclusion Our results support the view that B cell responses to allergens but not those to non‐allergenic proteins are correlated with specific T cell responses and therefore specific immunotherapy targeting of such T cells would inhibit allergen‐specific B cells.     

Impairment of T helper and T regulatory cell responses at birth

Background: There is strong evidence that reduced exposures to microbial compounds triggering innate immune responses early in life are critical for the development of allergic illnesses. The underlying mechanisms remain unknown, but will include T‐cell responses either along T helper type 1 (Th1)/Th2 pathways or via T regulatory and Th17 cells. Yet, little is known about innate immune responses and the function of T regulatory/Th17 cells at birth. The aim of this study was to investigate T‐cell responses to innate (Lipid A/LpA, peptidoglycan/Ppg) and adaptive (phytohemagglutinin) stimuli at birth and to compare these findings with adult immune responses. Methods: Cord and peripheral blood mononuclear cells including T regulatory and Th17 cells from 25 neonates and 25 adults were examined for proliferation, cytokine secretion, surface, mRNA expression and functional suppression assays. Results: Proliferation and cytokine responses to innate stimuli were less mature at birth than in adulthood. T regulatory and Th17 cells were less expressed in cord than in adult blood (Ppg‐induced Foxp3, P = 0.001, LpA‐induced CD4⁺ CD25⁺ high, P = 0.02; Th17 : P < 0.0001). Mitogen‐induced suppression of T‐regulatory cells on T‐effector cell function was less efficient in cord than in adult blood (P = 0.01). At both ages, Th17 cells were correlated with Th1/Th2 cells (P < 0.01), but not with interleukin‐10 secretion following innate‐stimulation. Conclusion: Innate immune responses are immature at birth. Furthermore, the function of T regulatory and Th17 cells is impaired. Th17 cells in association with Th1/Th2 cells may be involved in early immuno‐modulation. Potent innate immune stimulation early in life can potentially contribute to protection from allergic diseases.     

Low programmed cell death‐1 (PD‐1) expression in peripheral CD4+ T cells in Japanese patients with autoimmune type 1 diabetes

Programmed cell death‐1 (PD‐1) is a co‐stimulatory molecule that inhibits T cell proliferation. We aimed to clarify PD‐1 expression in CD4⁺ T cells and the association between PD‐1 expression and the 7785C/T polymorphism of PDCD1, with a focus on the two subtypes of type 1 diabetes, type 1A diabetes (T1AD) and fulminant type 1 diabetes (FT1D), in the Japanese population. We examined 22 patients with T1AD, 15 with FT1D, 19 with type 2 diabetes (T2D) and 29 healthy control (HC) subjects. Fluorescence‐activated cell sorting (FACS) and real‐time PCR were utilized to analyse PD‐1 expression quantitatively. Genotyping of 7785C/T in PDCD1 was performed using the TaqMan method in a total of 63 subjects (21 with T1AD, 15 with FT1D and 27 HC). FACS revealed a significant reduction in PD‐1 expression in CD4⁺ T cells in patients with T1AD (mean: 4·2 vs. 6·0% in FT1D, P = 0·0450; vs. 5·8% in T2D, P = 0·0098; vs. 6·0% in HC, P = 0·0018). PD‐1 mRNA expression in CD4⁺ T cells was also significantly lower in patients with T1AD than in the HC subjects. Of the 63 subjects, PD‐1 expression was significantly lower in individuals with the 7785C/C genotype than in those with the C/T and T/T genotypes (mean: 4·1 vs. 5·9%, P = 0·0016). Our results indicate that lower PD‐1 expression in CD4⁺ T‐cells might contribute to the development of T1AD through T cell activation.     

Turning it on and off: regulation of dendritic cell function in Toxoplasma gondii infection

Summary: Because of its intrinsic virulence, Toxoplasma gondii induces a potent interleukin‐12 (IL‐12)‐dependent cell‐mediated immune response that shuts down the growth of the replicative tachyzoite stage, thus promoting host survival and successful transmission through predation. At the same time, this response must be tightly controlled to prevent lethality due to cytokine‐mediated immunopathology. Evidence accumulated in recent years suggests that dendritic cells (DCs) play a major role in the initiation of IL‐12‐driven host resistance and that IL‐12 synthesis by DCs is carefully regulated to avoid overproduction. In addition, this work has revealed a critical role for DCs in determining the highly polarized T‐helper 1 (Th1)‐type response triggered by the parasite. In this review, we summarize our current understanding of how DC function is initiated by Toxoplasma and how parasite‐primed DCs drive Th1 effector choice. In addition, we discuss recent findings concerning the pathways responsible for endogenous regulation of DC IL‐12 production during T. gondii infection.