Publications by authors named "Abdallah Badou"

21 Publications

  • Page 1 of 1

Omenn syndrome caused by a novel homozygous mutation in recombination activating gene 1.

Immunobiology 2021 May 28;226(3):152090. Epub 2021 Apr 28.

Laboratory of Genomics and Human Genetics,Institut Pasteur du Maroc, 1 Place Louis Pasteur, 20360 Casablanca, Morocco. Electronic address:

Omenn syndrome (OS) is a type of severe combined immunodeficiency (SCID) that is distinguished by, lymphadenopathy, hepatosplenomegaly, erythroderma, alopecia with normal to elevated T-cell counts, eosinophilia, and elevated serum IgE levels. Recombination activation gene (RAG) 1 or RAG2 mutations that result in partial V(D)J recombination activity are known to be the main cause of OS. Other genes (DCLRE1C, LIG4, IL7RA, common gamma chain, ADA, RMRP, and CHD7) have also been linked to OS, although with low frequency. Here, we report a two-month-old Moroccan girl from consanguineous marriage with chronic diarrhea, recurrent and opportunistic infections, failure to thrive, desquamative erythroderma, hepatosplenomegaly, and axillary lymphadenitis. The immunological assessment showed normal lymphocyte and NK cell counts but an absence of B cells, agammaglobulinemia contrasting with a high level of IgE. On the other hand, Sanger sequencing of RAG1 and RAG2 exon 2 regions revealed a new homozygous deleterious mutation in the RAG1 gene. This c.1184C > T mutation caused a change from Proline to Leucine at position 395 of the protein, leading to a partial loss of function. Early and rapid diagnosis of the disease may facilitate urgent life-saving treatment.
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http://dx.doi.org/10.1016/j.imbio.2021.152090DOI Listing
May 2021

The Promising IgSF11 Immune Checkpoint Is Highly Expressed in Advanced Human Gliomas and Associates to Poor Prognosis.

Front Oncol 2020 2;10:608609. Epub 2021 Feb 2.

Cellular and Molecular Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco.

Glioma is the most prevalent primary brain tumor. Immune checkpoint blockade has made a great stride in mending patient's clinical outcome for multiple types of cancers. However, PD-1, CTLA-4, or VEGF blockade exhibited only poor outcome in glioma patients. This study aimed to explore the expression and role of IgSF11, an emerging immune checkpoint and a ligand of VISTA, in human gliomas. IgSF11 mRNA expression was assessed in human glioma patients at different grades using 2 independent cohorts, a set of 52 Moroccan samples, including 20 glioma tissues, 22 PBMC samples taken before and 10 PBMC samples taken after surgery; and a series of 667 patients from TCGA. In parallel, immunohistochemistry was performed to evaluate IgSF11 protein staining. gene expression was significantly upregulated in high grade glioma tissues, compared to low grade. IgSF11 protein also showed a significant expression in low and high-grade gliomas. Interestingly, IgSF11 expression seemed to correlate positively with other critical immune checkpoints such as PD1, PDL-1, VISTA, and surprisingly negatively with CTLA-4. Although, T cell markers appeared higher in advanced gliomas, T cell-produced pro-inflammatory genes showed similar expression levels, highly likely because of the potent immunosuppressive microenvironment. Indeed, increased expression of IgSF11 in advanced human gliomas associated with a poor overall survival. Our data strongly suggest that IgSF11 is an immune checkpoint, which is upregulated in advanced human gliomas and contributes to the immunosuppressive state resulting in a poor clinical outcome in glioma patients. IgSF11 could be considered as a possible promising therapeutic target in advanced human gliomas.
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http://dx.doi.org/10.3389/fonc.2020.608609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884863PMC
February 2021

Severe Combined Immunodeficiency Disorder due to a Novel Mutation in Recombination Activation Gene 2: About 2 Cases.

Case Reports Immunol 2021 7;2021:8819368. Epub 2021 Jan 7.

Clinical Immunology Unit, Infectious Disease Department; Children Hospital, IBN Rochd University Hospital, Casablanca, Morocco.

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of inherited immunologic disorders with profound defects in cellular and humoral immunity. SCID is the most severe PID and constitutes a pediatric emergency. Affected children are highly susceptible to bacterial, viral, fungal, and opportunistic infections with life-threatening in the absence of hematopoietic stem cell transplantation. We report here two cases of SCID. The first case is a girl diagnosed with SCID at birth based on her family history and lymphocyte subpopulation typing. The second case is a 4-month-old boy with a history of recurrent opportunistic infections, BCGitis, and failure to thrive, and the immunology workup confirms a SCID phenotype. The genetic study in the two cases revealed a novel mutation in the RAG2 gene, c.826G > A (p.Gly276Ser), in a homozygous state. The novel mutation in the RAG2 gene identified in our study may help the early diagnosis of SCID.
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http://dx.doi.org/10.1155/2021/8819368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808801PMC
January 2021

Clinical and Immunological Features of 96 Moroccan Children with SCID Phenotype: Two Decades' Experience.

J Clin Immunol 2021 Apr 7;41(3):631-638. Epub 2021 Jan 7.

Clinical Immunology Unit, Infectious Diseases Department, Children's Hospital, Ibn Rochd University Hospital, Casablanca, Morocco.

Severe combined immunodeficiency (SCID) is a heterogeneous group of primary immunodeficiency diseases (PIDs) characterized by a lack of autologous T lymphocytes. This severe PID is rare, but has a higher prevalence in populations with high rates of consanguinity. The epidemiological, clinical, and immunological features of SCIDs in Moroccan patients have never been reported. The aim of this study was to provide a clinical and immunological description of SCID in Morocco and to assess changes in the care of SCID patients over time. This cross-sectional retrospective study included 96 Moroccan patients referred to the national PID reference center at Casablanca Children's Hospital for SCID over two decades, from 1998 to 2019. The case definition for this study was age < 2 years, with a clinical phenotype suggestive of SCID, and lymphopenia, with very low numbers of autologous T cells, according to the IUIS Inborn Errors of Immunity classification. Our sample included 50 male patients, and 66% of the patients were born to consanguineous parents. The median age at onset and diagnosis were 3.3 and 6.5 months, respectively. The clinical manifestations commonly observed in these patients were recurrent respiratory tract infection (82%), chronic diarrhea (69%), oral candidiasis (61%), and failure to thrive (65%). The distribution of SCID phenotypes was as follows: T-B-NK+ in 44.5%, T-B-NK- in 32%, T-B+NK- in 18.5%, and T-B+NK+ in 5%. An Omenn syndrome phenotype was observed in 15 patients. SCID was fatal in 84% in the patients in our cohort, due to the difficulties involved in obtaining urgent access to hematopoietic stem cell transplantation, which, nevertheless, saved 16% of the patients. The autosomal recessive forms of the clinical and immunological phenotypes of SCID, including the T-B-NK+ phenotype in particular, were more frequent than those in Western countries. A marked improvement in the early detection of SCID cases over the last decade was noted. Despite recent progress in SCID diagnosis, additional efforts are required, for genetic confirmation and particularly for HSCT.
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http://dx.doi.org/10.1007/s10875-020-00960-xDOI Listing
April 2021

T lymphocyte subsets in cancer immunity: Friends or foes.

J Leukoc Biol 2019 02 2;105(2):243-255. Epub 2018 Nov 2.

Cellular and Molecular Pathology Laboratory, Faculty of Medicine and Pharmacy of Casablanca, Hassan II University, Casablanca, Morocco.

Although immune-based therapy is proving to be a success in several cancer types, only a set of patients appear to respond to immune checkpoint blockade including PD-1 and CTLA-4. A better understanding of the crucial components of cancer immunity is therefore necessary. T lymphocytes, a key element, are found within the tumor microenvironment and seem to be critical in determining the efficacy of immune surveillance. In this review, we will depict the pro- and antitumor roles of major T cell subsets in distinct cancer tissues. The central role of the mainly antitumor subsets, cytotoxic T cells and Th1 cells, will be delineated. Subsequently, we will indicate how other subsets including Th2, Th17, and T regulatory cells exhibit ambivalent roles. We will also describe the emerging and favorable role of Th9 cells in cancer immunity. In parallel, we will go through main mechanisms by which these cells operate, and will pinpoint pathways, which could be used as potential therapeutic targets in order to positively impact the immune response and ameliorate patients' clinical outcome.
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http://dx.doi.org/10.1002/JLB.MR0318-097RDOI Listing
February 2019

and Immunomodulator Activities of L.

Evid Based Complement Alternat Med 2018 12;2018:4984659. Epub 2018 Jun 12.

Cellular and Molecular Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, 19 Rue Tarik Ibnou Ziad, B.P. 9154 Casablanca, Morocco.

L. (garlic), which is a species of the onion family, Alliaceae, is one of the most used plants in traditional medicine worldwide. More than 200 chemicals with diverse properties have been found in garlic extracts. Several garlic compounds were suggested to be efficient in improving various pathologies including certain types of cancer. This paper is an overview of data about garlic biological activities and/or on immune cells, on the development of certain inflammatory diseases, and on different types of carcinomas and sarcomas. Garlic and its compounds were found to have notable antioxidant properties. Garlic therapeutic potential has also been studied in several inflammatory diseases such as allergic-airway inflammation, inflammatory bowel disease, arthritic rheumatism, and atherosclerosis. Furthermore, garlic was found to be able to maintain the immune system homeostasis and to exhibit beneficial effects on immune cells especially through regulation of proliferation and cytokine gene expression. Finally, we will show how major garlic components such as sulfur compounds and polyphenols might be responsible for the garlic biological activities revealed in different situations. If identified, specific compounds present in garlic could potentially be used in therapy.
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http://dx.doi.org/10.1155/2018/4984659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020507PMC
June 2018

Anti-inflammatory potential of Capparis spinosa L. in vivo in mice through inhibition of cell infiltration and cytokine gene expression.

BMC Complement Altern Med 2017 Jan 31;17(1):81. Epub 2017 Jan 31.

Environnement and Health team, Polydisciplinary Faculty of Safi, Cadi Ayyad University, Safi, Morocco.

Background: Several chronic inflammatory diseases are characterized by inappropriate CD4+ T cell response. In the present study, we assessed the ability of Capparis spinosa L. (CS) preparation to orientate, in vivo, the immune response mediated by CD4+ T cells towards an anti-inflammatory response.

Methods: The in vivo study was carried out by using the contact hypersensitivity (CHS) model in Swiss mice. Then we performed a histological analysis followed by molecular study by using real time RT-PCR. We also realized a phytochemical screening and a liquid-liquid separation of CS preparation.

Results: Our study allowed us to detect a significantly reduced edema in mice treated with CS preparations relative to control. CS effect was dose dependent, statistically similar to that observed with indomethacin, independent of the plant genotype and of the period of treatment. Furthermore, our histology studies revealed that CS induced a significant decrease in immune cell infiltration, in vasodilatation and in dermis thickness in the inflammatory site. Interestingly, we showed that CS operated by inhibiting cytokine gene expression including IFNγ, IL-17 and IL-4. Besides, phytochemical screening of CS extract showed the presence of several chemical families such as saponins, flavonoids and alkaloids. One (hexane fraction) out of the three distinct prepared fractions, exhibited an anti-inflammatory effect similar to that of the raw preparation, and would likely contain the bioactive(s) molecule(s).

Conclusions: Altogether, our data indicate that CS regulates inflammation induced in vivo in mice and thus could be a source of anti-inflammatory molecules, which could be used in some T lymphocyte-dependent inflammatory diseases.
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http://dx.doi.org/10.1186/s12906-017-1569-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282892PMC
January 2017

Allium sativum L. regulates in vitro IL-17 gene expression in human peripheral blood mononuclear cells.

BMC Complement Altern Med 2016 Sep 29;16(1):377. Epub 2016 Sep 29.

Cellular and Molecular Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, 19 Rue Tarik Ibnou Ziad, B.P. 9154, Casablanca, Morocco.

Background: Allium sativum L. (A.S.) "garlic", one of the most interesting medicinal plants, has been suggested to contain compounds that could be beneficial in numerous pathological situations including cancer. In this work, we aimed to assess the immunomodulatory effect of A.S. preparation on human peripheral blood mononuclear cells from healthy individuals.

Methods: Nontoxic doses of A.S. were identified using MTT assay. Effects on CD4+ or CD8+ T lymphocyte proliferation were studied using flow cytometry. The effect of A.S. on cytokine gene expression was studied using qRT-PCR. Finally, qualitative analysis of A.S. was performed by HPLC approach. Data were analyzed statistically by one-way ANOVA test.

Results: The nontoxic doses of A.S. preparation did not affect neither spontaneous nor TCR-mediated CD4+ or CD8+ T lymphocyte proliferation. Interestingly, A.S. exhibited a statistically significant regulation of IL-17 gene expression, a cytokine involved in several inflammatory and autoimmune diseases. In contrast, the expression of IL-4, an anti-inflammatory cytokine, was unaffected. Qualitative analysis of A.S. ethanol preparation indicated the presence of three polyphenol bioactive compounds, which are catechin, vanillic acid and ferulic acid.

Conclusion: The specific inhibition of the pro-inflammatory cytokine, IL-17 without affecting cell proliferation in human PBMCs by the Allium sativum L. preparation suggests a potential valuable effect of the compounds present in this plant for the treatment of inflammatory diseases and cancer, where IL-17 is highly expressed. The individual contribution of these three compounds to this global effect will be assessed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041567PMC
http://dx.doi.org/10.1186/s12906-016-1365-9DOI Listing
September 2016

Capparis Spinosa L. promotes anti-inflammatory response in vitro through the control of cytokine gene expression in human peripheral blood mononuclear cells.

BMC Immunol 2016 08 2;17(1):26. Epub 2016 Aug 2.

Research team Health and Environment, Cadi Ayyad University, Polydisciplinary Faculty, Safi, Morocco.

Background: Capparis Spinosa L. is an aromatic plant growing wild in dry regions around the Mediterranean basin. Capparis Spinosa was shown to possess several properties such as antioxidant, antifungal, and anti-hepatotoxic actions. In this work, we aimed to evaluate immunomodulatory properties of Capparis Spinosa leaf extracts in vitro on human peripheral blood mononuclear cells (PBMCs) from healthy individuals.

Results: Using MTT assay, we identified a range of Capparis Spinosa doses, which were not toxic. Unexpectedly, we found out that Capparis Spinosa aqueous fraction exhibited an increase in cell metabolic activity, even though similar doses did not affect cell proliferation as shown by CFSE. Interestingly, Capparis Spinosa aqueous fraction appeared to induce an overall anti-inflammatory response through significant inhibition of IL-17 and induction of IL-4 gene expression when PBMCs were treated with the non toxic doses of 100 and/or 500 μg/ml. Phytoscreening analysis of the used Capparis Spinosa preparations showed that these contain tannins; sterols, alkaloids; polyphenols and flavonoids. Surprisingly, quantification assays showed that our Capparis Spinosa preparation contains low amounts of polyphenols relative to Capparis Spinosa used in other studies. This Capparis Spinosa also appeared to act as a weaker scavenging free radical agent as evidenced by DPPH radical scavenging test. Finally, polyphenolic compounds including catechin, caffeic acid, syringic acid, rutin and ferulic acid were identified by HPLC, in the Capparis spinosa preparation.

Conclusion: Altogether, these findings suggest that our Capparis Spinosa preparation contains interesting compounds, which could be used to suppress IL-17 and to enhance IL-4 gene expression in certain inflammatory situations. Other studies are underway in order to identify the compound(s) underlying this effect.
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http://dx.doi.org/10.1186/s12865-016-0164-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969972PMC
August 2016

T Cell Receptor Mediated Calcium Entry Requires Alternatively Spliced Cav1.1 Channels.

PLoS One 2016 27;11(1):e0147379. Epub 2016 Jan 27.

Department of Immunobiology, Yale University School of Medicine, 300 Cedar street, New Haven, CT, 06520, United States of America.

The process of calcium entry in T cells is a multichannel and multi-step process. We have studied the requirement for L-type calcium channels (Cav1.1) α1S subunits during calcium entry after TCR stimulation. High expression levels of Cav1.1 channels were detected in activated T cells. Sequencing and cloning of Cav1.1 channel cDNA from T cells revealed that a single splice variant is expressed. This variant lacks exon 29, which encodes the linker region adjacent to the voltage sensor, but contains five new N-terminal exons that substitute for exons 1 and 2, which are found in the Cav1.1 muscle counterpart. Overexpression studies using cloned T cell Cav1.1 in 293HEK cells (that lack TCR) suggest that the gating of these channels was altered. Knockdown of Cav1.1 channels in T cells abrogated calcium entry after TCR stimulation, suggesting that Cav1.1 channels are controlled by TCR signaling.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147379PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729531PMC
July 2016

Screening of exon 11 of BRCA1 gene using the high resolution melting approach for diagnosis in Moroccan breast cancer patients.

BMC Cancer 2015 Feb 25;15:81. Epub 2015 Feb 25.

Genetics and Molecular Pathology Laboratory, Medical school of Casablanca, Casablanca, Morocco.

Background: Identification of specific mutations in cancer patients may lead to the discovery of genes, which can affect susceptibility and/or prognosis. It has previously been reported that mutations in BRCA1 and BRCA2 genes are linked to breast cancer. Here, we evaluated the use of the High Resolution Melting (HRM) approach to screen for mutations in exon 11 of BRCA1 gene in Moroccan patients.

Methods: HRM analysis was used to screen exon 11 from 71 breast cancer patients in order to detect different variants. Conventional Sanger sequencing was used to confirm the presence of possible mutations. Distribution of different SNPs was determined by SNaPshot analysis software.

Results: In order to assess the efficacy of the HRM approach to screen for mutations, especially in diagnosis, we first used two samples with previously known mutations, "2924delA and 3398delC". Indeed, these previously known sequence variants were detected by the HRM approach and yielded melting curves with atypical shape relative to wild-type control sequences. We then analyzed, 69 samples from breast cancer patients using the HRM method, and were able to detect two samples with atypical curves. Sequencing of the two samples, using the conventional Sanger approach, confirmed the presence of the same SNP (c.2612C > T) in both samples.

Conclusions: Our results strongly suggest that the HRM approach represents a reliable and highly sensitive method for mutation scanning, especially in diagnosis.
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http://dx.doi.org/10.1186/s12885-015-1040-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351675PMC
February 2015

Emerging roles of L-type voltage-gated and other calcium channels in T lymphocytes.

Front Immunol 2013 30;4:243. Epub 2013 Aug 30.

Equipe de recherche Environnement et Santé, Faculté Polydisciplinaire de Safi, Université Cadi Ayyad , Safi , Morocco.

In T lymphocytes, calcium ion controls a variety of biological processes including development, survival, proliferation, and effector functions. These distinct and specific roles are regulated by different calcium signals, which are generated by various plasma membrane calcium channels. The repertoire of calcium-conducting proteins in T lymphocytes includes store-operated CRAC channels, transient receptor potential channels, P2X channels, and L-type voltage-gated calcium (Cav1) channels. In this paper, we will focus mainly on the role of the Cav1 channels found expressed by T lymphocytes, where these channels appear to operate in a T cell receptor stimulation-dependent and voltage sensor independent manner. We will review their expression profile at various differentiation stages of CD4 and CD8 T lymphocytes. Then, we will present crucial genetic evidence in favor of a role of these Cav1 channels and related regulatory proteins in both CD4 and CD8 T cell functions such as proliferation, survival, cytokine production, and cytolysis. Finally, we will provide evidence and speculate on how these voltage-gated channels might function in the T lymphocyte, a non-excitable cell.
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http://dx.doi.org/10.3389/fimmu.2013.00243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757574PMC
December 2013

Defective survival of naive CD8+ T lymphocytes in the absence of the beta3 regulatory subunit of voltage-gated calcium channels.

Nat Immunol 2009 Dec 18;10(12):1275-82. Epub 2009 Oct 18.

Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA.

The survival of T lymphocytes requires sustained, Ca(2+) influx-dependent gene expression. The molecular mechanism that governs sustained Ca(2+) influx in naive T lymphocytes is unknown. Here we report an essential role for the beta3 regulatory subunit of voltage-gated calcium (Ca(v)) channels in the maintenance of naive CD8(+) T cells. Deficiency in beta3 resulted in a profound survival defect of CD8(+) T cells. This defect correlated with depletion of the pore-forming subunit Ca(v)1.4 and attenuation of T cell antigen receptor (TCR)-mediated global Ca(2+) entry in CD8(+) T cells. Ca(v)1.4 and beta3 associated with T cell signaling machinery and Ca(v)1.4 localized in lipid rafts. Our data demonstrate a mechanism by which Ca(2+) entry is controlled by a Ca(v)1.4-beta3 channel complex in T cells.
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http://dx.doi.org/10.1038/ni.1793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785134PMC
December 2009

Requirement for AHNAK1-mediated calcium signaling during T lymphocyte cytolysis.

Proc Natl Acad Sci U S A 2009 Jun 2;106(24):9785-90. Epub 2009 Jun 2.

Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.

Cytolytic CD8(+) T cells (CTLs) kill virally infected cells, tumor cells, or other potentially autoreactive T cells in a calcium-dependent manner. To date, the molecular mechanism that leads to calcium intake during CTL differentiation and function has remained unresolved. We demonstrate that desmoyokin (AHNAK1) is expressed in mature CTLs, but not in naive CD8(+) T cells, and is critical for calcium entry required for their proper function during immune response. We show that mature AHNAK1-deficient CTLs exhibit reduced Ca(v)1.1 alpha1 subunit expression (also referred to as L-type calcium channels or alpha1S pore-forming subunits), which recently were suggested to play a role in calcium entry into CD4(+) T cells. AHNAK1-deficient CTLs show marked reduction in granzyme-B production, cytolytic activity, and IFN-gamma secretion after T cell receptor stimulation. Our results demonstrate an AHNAK1-dependent mechanism controlling calcium entry during CTL effector function.
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http://dx.doi.org/10.1073/pnas.0902844106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701053PMC
June 2009

A scaffold protein, AHNAK1, is required for calcium signaling during T cell activation.

Immunity 2008 Jan;28(1):64-74

Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.

Engagement of the T cell antigen receptor (TCR) during antigen presentation initiates a coordinated action of a large number of signaling proteins and ion channels. AHNAK1 is a scaffold protein, highly expressed by CD4+ T cells, and is a critical component for calcium signaling. We showed that AHNAK1-deficient mice were highly susceptible to Leishmania major infection. AHNAK1-deficient CD4+ T cells responded poorly to TCR stimulation in vitro with low proliferation and low Interleukin-2 production. Furthermore, AHNAK1 deficiency resulted in a reduced calcium influx upon TCR crosslinking and subsequent poor activation of the transcription factor NFAT. AHNAK1 was required for plasma membrane expression of L-type calcium channels alpha 1S (Cav1.1), probably through its interaction with the beta regulatory subunit. Thus, AHNAK1 plays an essential role in T cell Ca2+ signaling through Cav1 channels, triggered via TCR activation; therefore, AHNAK1 is a potential target for therapeutic intervention.
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http://dx.doi.org/10.1016/j.immuni.2007.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2350190PMC
January 2008

Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9.

Hepatology 2007 Nov;46(5):1509-18

Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA.

Unlabelled: Apoptosis of hepatocytes results in the development of liver fibrosis, but the molecular signals mediating this are poorly understood. Degradation and modification of nuclear DNA is a central feature of apoptosis, and DNA from apoptotic mammalian cells is known to activate immune cells via Toll-like receptor 9 (TLR9). We tested if DNA from apoptotic hepatocytes can induce hepatic stellate cell (HSC) differentiation. Our data show that apoptotic hepatocyte DNA and cytidine-phosphate-guanosine oligonucleotides induced up-regulation of transforming growth factor beta1 and collagen 1 messenger RNA both in the human HSC line LX-2 and in primary mouse HSCs. These effects were opposed by TLR9 antagonists. We have recently shown that adenosine inhibits HSC chemotaxis, and we now show that apoptotic hepatocyte DNA also inhibits platelet-derived growth factor (PDGF)-mediated HSC chemotaxis. Inhibition of HSC chemotaxis by PDGF was blocked by TLR9 antagonists, and was absent in primary HSCs from mice deficient in TLR9 or the TLR adaptor molecule MyD88. Stimulation of TLR9 on HSCs blocked signaling by the PDGF signaling molecule inositol 1,4,5-triphosphate and reduced PDGF-mediated increase in cytosolic Ca(2+).

Conclusion: DNA from apoptotic hepatocytes acts as an important mediator of HSC differentiation by (1) providing a stop signal to mobile HSCs when they have reached an area of apoptosing hepatocytes and (2) inducing a stationary phenotype-associated up-regulation of collagen production.
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http://dx.doi.org/10.1002/hep.21867DOI Listing
November 2007

Critical role for the beta regulatory subunits of Cav channels in T lymphocyte function.

Proc Natl Acad Sci U S A 2006 Oct 6;103(42):15529-34. Epub 2006 Oct 6.

Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.

Calcium ion is a universal signaling intermediate, which is known to control various biological processes. In excitable cells, voltage-gated calcium channels (Cav) are the major route of calcium entry and regulate multiple functions such as contraction, neurotransmitter release, and gene transcription. Here we show that T lymphocytes, which are nonexcitable cells, express both regulatory beta and pore-forming Cav1 alpha1 subunits of Cav channels, and we provide genetic evidence for a critical role of the Cav beta3 and Cav beta4 regulatory subunits in T lymphocyte function. Cav beta-deficient T lymphocytes fail to acquire normal functions, and they display impairment in the T cell receptor-mediated calcium response, nuclear factor of activated T cells activation, and cytokine production. In addition, unlike in excitable cells, our data suggest a minimal physiological role for depolarization in Cav channel opening in T cells. T cell receptor stimulation induces only a small depolarization of T cells, and artificial depolarization of T cells using KCl does not lead to calcium entry. These observations suggest that the Cav channels expressed by T cells have adopted novel regulation/gating mechanisms.
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http://dx.doi.org/10.1073/pnas.0607262103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1622857PMC
October 2006

Requirement of voltage-gated calcium channel beta4 subunit for T lymphocyte functions.

Science 2005 Jan;307(5706):117-21

Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.

Calcium is known to play vital roles in diverse physiological processes, and it is known that voltage-gated calcium channels (Cav) mediate calcium influx in excitable cells. However, no consensus exists on the molecular identity of the calcium channels present in nonexcitable cells such as T lymphocytes. Here, we demonstrate that T lymphocytes express both regulatory beta4 and poreforming Cav1 alpha1 subunits of Cav channels. Cav beta4-mutant T lymphocytes fail to acquire normal functions and display impairment in the calcium response, activation of the transcription factor NFAT, and cytokine production. Although Cav1 channels of lymphocytes retain their voltage dependency, T cell receptor stimulation dramatically increases channel opening, providing a new mechanism for calcium entry in lymphocytes.
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http://dx.doi.org/10.1126/science.1100582DOI Listing
January 2005

Activation of CD4 T cells by Raf-independent effectors of Ras.

Proc Natl Acad Sci U S A 2003 May 29;100(10):6003-8. Epub 2003 Apr 29.

Section of Immunobiology, Department of Pathology, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.

Small GTPase Ras is capable of mediating activation in T lymphocytes by using Raf kinase-dependent signaling pathway. Other effectors of Ras exist, however, suggesting that targets of Ras alternative to Raf may also contribute to T cell functions. Here we demonstrate that Ras(V12G37) mutant that fails to bind Raf, potently increases intracellular calcium concentration and cytokine production in primary antigen-stimulated T cells. From three known effectors which retain the ability to interact with Ras(V12G37), overexpression of phospholipase C epsilon but not that of RIN1 or Ral guanine nucleotide exchange factors enhanced cytokine and nuclear factor-activated T cell reporter T cell responses. Hence T cell activation can be critically regulated by the Ras effector pathway independent from Raf that can be mimicked by phospholipase C epsilon.
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http://dx.doi.org/10.1073/pnas.1031494100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC156316PMC
May 2003

Signaling pathways triggered by HIV-1 Tat in human monocytes to induce TNF-alpha.

Virology 2002 Nov;303(1):174-80

Laboratoire d'Immuno-Virologie, EA 3038, Université Paul Sabatier 118, route de Narbonne, 31062, Toulouse Cedex, France.

In this study we investigated the signaling pathways triggered by Tat in human monocyte to induce TNF-alpha. In monocytes, the calcium, the PKA, and the PKC pathways are highly implicated in the expression of cytokine genes. Thus, these three major signaling pathways were investigated. Our data show that (i) PKC and calcium pathways are required for TNF-alpha production, whereas the PKA pathway seems to be not involved; (ii) downstream from PKC, activation of NFkappaB is essential while ERK1/2 MAP kinases, even though activated by Tat, are not directly involved in the pathway signaling leading to TNF-alpha production.
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http://dx.doi.org/10.1006/viro.2002.1676DOI Listing
November 2002