Attendance is taken at Journal Club meetings. Please remember to sign in on the sheet provided before the meeting begins.
Journal Club presentations are required as part of your graduate program. If your presentation date is not workable, arrange to switch dates with another student and inform Dr. Aaron Marshall (Faculty Journal Club Co-ordinator) and the General Office staff. You cannot skip making a presentation.
Journal Club Presenters must send their article title and abstract (NOT the article itself) to Karen Morrow (Immunology Dept. Administrative Assistant) ONE WEEK PRIOR TO THEIR PRESENTATION DATE. Make sure to include THE FULL CITATION (Journal name, volume, date, and page numbers.)
***Presenters: See Instructions for Journal Club Presentations****
| September 2012 | October | November | December |
January 2013 |
| February | March | April | May | June |
| Last year's Journal Club Schedule | ||||
September 10 - Research in Progress
Dr. Afshin Raouf
Department of Immunology
Faculty of Medicine
University of Manitoba
TITLE
September 17 - Nandu Anaparti
Article:
Narni-Mancinelli E, Jaeger BN, Bernat C, Fenis A, Kung S, De Gassart A, Mahmood S, Gut M, Heath SC, Estellé J, Bertosio E, Vely F, Gastinel LN, Beutler B, Malissen B, Malissen M, Gut IG, Vivier E, Ugolini S. Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses. Science. 2012 Jan 20;335(6066):344-8.
Abstract:
Natural killer (NK) cells are lymphocytes involved in antimicrobial and antitumoral immune responses. Using N-ethyl-N-nitrosourea mutagenesis in mice, we identified a mutant with increased resistance to viral infections because of the presence of hyperresponsive NK cells. Whole-genome sequencing and functional analysis revealed a loss-of-function mutation in the Ncr1 gene encoding the activating receptor NKp46. The down-regulation of NK cell activity by NKp46 was associated with the silencing of the Helios transcription factor in NK cells. NKp46 was critical for the subsequent development of antiviral and antibacterial T cell responses, which suggests that the regulation of NK cell function by NKp46 allows for the optimal development of adaptive immune responses. NKp46 blockade enhanced NK cell reactivity in vivo, which could enable the design of immunostimulation strategies in humans.
September 24 - Grace Choi
Article:
Galligan CL, Fish EN. Circulating fibrocytes contribute to the pathogenesis of arthritis. Arthritis Rheum. 2012 Jun 21.
Online library link: http://onlinelibrary.wiley.com.proxy2.lib.umanitoba.ca/doi/10.1002/art.34589/abstract;jsessionid=744C94582612F49444E1402C4B31691D.d03t03 doi: 10.1002/art.34589. [Epub ahead of print]
Abstract:
OBJECTIVES: Rheumatoid arthritis (RA) is a systemic autoimmune disease resulting in joint inflammation. Fibroblast-like synovial (FLS) cells in affected joints are responsible for pannus formation and cytokine/chemokine production, resulting in leukocyte recruitment and bone/cartilage destruction. Previously, we identified a multipotent stem cell population of activated fibrocytes in the blood of RA patients that may have a role in disease pathogenesis, perhaps as FLS cell precursors. The objective of these studies was to further characterize the contribution of circulating fibrocytes to the pathogenesis of RA.
METHODS: Circulating fibrocytes were isolated from mice with collagen-induced arthritis (CIA) and transferred intravenously (iv) into recipient mice induced to develop collagen-antibody induced arthritis (CAIA). The activation status of circulating fibrocytes was determined using multidimensional phosphoflow cytometric analysis of the signaling effectors, STAT5, STAT1, AKT and JNK. Circulating fibrocyte trafficking and matrix metalloproteinase (MMP) activity were assessed in real time using fluorescence molecular tomography (FMT), specifically labeling circulating fibrocytes with CellVue Maroon and measuring MMP activity using MMPSense 680.
RESULTS: Circulating fibrocyte numbers are increased early during onset of CAIA, concomitant with their activation, as measured by phosphorylation of STAT5. Adoptive transfer of circulating fibrocytes augmented disease scores and increased MHCII expression and PB phosphoactivation profiles in recipient mice with CAIA. Notably, adoptively transferred fluorescent labeled circulating fibrocytes rapidly migrated into affected joints in recipient CAIA mice and this was associated with augmented neutrophil recruitment into affected joints and MMP activation.
CONCLUSIONS: Circulating fibrocytes migrate to joints and influence the onset of disease processes in arthritis.
October 1- Natascha Fitch
Article:
Abstract:
October 8 - Thanksgiving Day - University Closed
October 15 - Sajid Mahmood
Article:
Feng Ma, Sheng Xu, Xingguang Liu, Qian Zhang, Xiongfei Xu, Mofang Liu, Minmin Hua, Nan Li, Hangping Yao & Xuetao Cao. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-g. Nature Immunology. Vol. 12, pgs 861-9. July 24, 2011.
Abstract:
Interferon-g (IFN-g) has a critical role in immune responses to intracellular bacterial infection. MicroRNAs (miRNAs) are important in the regulation of innate and adaptive immunity. However, whether miRNAs can directly target IFN-g and regulate IFN-g production post-transcriptionally remains unknown. Here we show that infection of mice with Listeria monocytogenes or Mycobacterium bovis bacillus Calmette-Guérin (BCG) downregulated miR-29 expression in IFN-g-producing natural killer cells, CD4+ T cells and CD8+ T cells. Moreover, miR-29 suppressed IFN-g production by directly targeting IFN-g mRNA. We developed mice with transgenic expression of a ‘sponge’ target to compete with endogenous miR-29 targets (GS29 mice). We found higher serum concentrations of IFN-g and lower L. monocytogenes burdens in L. monocytogenes–infected GS29 mice than in their littermates. GS29 mice had enhanced T helper type 1 (TH1) responses and greater resistance to infection with BCG or Mycobacterium tuberculosis. Therefore, miR-29 suppresses immune responses to intracellular pathogens by targeting IFN-g.Interferon-g (IFN-g) has a critical role in immune responses to intracellular bacterial infection. MicroRNAs (miRNAs) are important in the regulation of innate and adaptive immunity. However, whether miRNAs can directly target IFN-g and regulate IFN-g production post-transcriptionally remains unknown. Here we show that infection of mice with Listeria monocytogenes or Mycobacterium bovis bacillus Calmette-Guérin (BCG) downregulated miR-29 expression in IFN-g-producing natural killer cells, CD4+ T cells and CD8+ T cells. Moreover, miR-29 suppressed IFN-g production by directly targeting IFN-g mRNA. We developed mice with transgenic expression of a ‘sponge’ target to compete with endogenous miR-29 targets (GS29 mice). We found higher serum concentrations of IFN-g and lower L. monocytogenes burdens in L. monocytogenes–infected GS29 mice than in their littermates. GS29 mice had enhanced T helper type 1 (TH1) responses and greater resistance to infection with BCG or Mycobacterium tuberculosis. Therefore, miR-29 suppresses immune responses to intracellular pathogens by targeting IFN-g.
October 22 - Jenna Aviles
Article:
Abstract:
October 29 - Nipun Jayachandran
Article:
Di Wang, Mingzhu Zheng, Lei Lei1, Jian Ji, Yunliang Yao, Yuanjun Qiu, Lie Ma1, Jun Lou, Chuan Ouyang, Xue Zhang, Yuewei He, Jun Chi, Lie Wang, Ying Kuang, Jianli Wang, Xuetao Cao and Linrong Lu. Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling. Nature Immunology. VOLUME 13. 560-568, 06 May 2012
Abstract:
Signaling via the T cell antigen receptor (TCR) during the CD4+CD8+ double-positive developmental stage determines thymocyte selection and lineage commitment. Here we describe a previously uncharacterized T cell–expressed protein, Tespa1, with critical functions during the positive selection of thymocytes. Tespa1−/− mice had fewer mature thymic CD4+ and CD8+ T cells, which reflected impaired thymocyte development. Tespa1 associated with the TCR signaling components PLC-g1 and Grb2, and Tespa1 deficiency resulted in attenuated TCR signaling, as reflected by defective activation of the Erk–AP-1 and Ca2+-NFAT pathways. Our findings demonstrate that Tespa1 is a component of the TCR signalosome and is essential for T cell selection and maturation through the regulation of TCR signaling during T cell development.
November 5 - Jessica Dong
Article:
Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, Glickman JN, Siebert R, Baron RM, Kasper DL, Blumberg RS. Microbial exposure during early life has persistent effects on natural killer T cell function. Science. 2012 Apr 27;336(6080):489-93. doi: 10.1126/science.1219328. Epub 2012 Mar 22.
Abstract:
Exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. Here, we show that in germ-free (GF) mice, invariant natural killer T (iNKT) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma as compared with that of specific pathogen-free mice. This was associated with increased intestinal and pulmonary expression of the chemokine ligand CXCL16, which was associated with increased mucosal iNKT cells. Colonization of neonatal-but not adult-GF mice with a conventional microbiota protected the animals from mucosal iNKT accumulation and related pathology. These results indicate that age-sensitive contact with commensal microbes is critical for establishing mucosal iNKT cell tolerance to later environmental exposures.
November 12 - Remembrance Day (Observed) - University Closed
November 19 - Rachael Erdmann
Article:
Jehl SP, Nogueira CV, Zhang X, Starnbach MN (2012) IFNγ Inhibits the Cytosolic Replication of Shigella flexneri via the Cytoplasmic RNA Sensor RIG-I. PLoS Pathog 8(8): e1002809. doi:10.1371/journal.ppat.1002809
Abstract:
The activation of host cells by interferon gamma (IFNγ) is essential for inhibiting the intracellular replication of most microbial pathogens. Although significant advances have been made in identifying IFNγ-dependent host factors that suppress intracellular bacteria, little is known about how IFNγ enables cells to recognize, or restrict, the growth of pathogens that replicate in the host cytoplasm. The replication of the cytosolic bacterial pathogen Shigella flexneri is significantly inhibited in IFNγ-stimulated cells, however the specific mechanisms that mediate this inhibition have remained elusive. We found that S. flexneri efficiently invades IFNγ-activated mouse embryonic fibroblasts (MEFs) and escapes from the vacuole, suggesting that IFNγ acts by blocking S. flexneri replication in the cytosol. This restriction on cytosolic growth was dependent on interferon regulatory factor 1 (IRF1), an IFNγ-inducible transcription factor capable of inducing IFNγ-mediated cell-autonomous immunity. To identify host factors that restrict S. flexneri growth, we used whole genome microarrays to identify mammalian genes whose expression in S. flexneri-infected cells is controlled by IFNγ and IRF1. Among the genes we identified was the pattern recognition receptor (PRR) retanoic acid-inducible gene I (RIG-I), a cytoplasmic sensor of foreign RNA that had not been previously known to play a role in S. flexneri infection. We found that RIG-I and its downstream signaling adaptor mitochondrial antiviral signaling protein (MAVS)--but not cytosolic Nod-like receptors (NLRs)--are critically important for IFNγ-mediated S. flexneri growth restriction. The recently described RNA polymerase III pathway, which transcribes foreign cytosolic DNA into the RIG-I ligand 5'-triphosphate RNA, appeared to be involved in this restriction. The finding that RIG-I responds to S. flexneri infection during the IFNγ response extends the range of PRRs that are capable of recognizing this bacterium. Additionally, these findings expand our understanding of how IFNγ recognizes, and ultimately restricts, bacterial pathogens within host cells.
November 26 - Mark Collister
Article:
Honglin Dong, Ian Rowland and Parveen Yaqoob (2012). Comparative effects of six probiotic strains on immune function in vitro. British Journal of Nutrition, 108, pp 459470 doi:10.1017/S0007114511005824
Abstract:
There is considerable interest in the strain specificity of immune modulation by probiotics. The present study compared the immunomodulatory properties of six probiotic strains of different species and two genera in a human peripheral blood mononuclear cell (PBMC) model in vitro. Live cells of lactobacilli (Lactobacillus casei Shirota, L. rhamnosus GG, L. plantarum NCIMB 8826 and L. reuteri NCIMB 11951) and bifidobacteria (Bifidobacterium longum SP 07/3 and B. bifidum MF 20/5) were individually incubated with PBMC from seven healthy subjects for 24 h. Probiotic strains increased the proportion of CD69+ on lymphocytes, T cells, T cell subsets and natural killer (NK) cells, and increased the proportion of CD25+, mainly on lymphocytes and NK cells. The effects on activation marker expression did not appear to be strain specific. NK cell activity was significantly increased by all six strains, without any significant difference between strains. Probiotic strains increased production of IL-1β, IL-6, IL-10, TNF-α, granulocyte-macrophage colony-stimulating factor and macrophage inflammatory protein 1α to different extents, but had no effect on the production of IL-2, IL-4, IL-5 or TNF-β. The cytokines that showed strain-specific modulation included IL-10, interferon-γ, TNF-α, IL-12p70, IL-6 and monocyte chemotactic protein-1. The Lactobacillus strains tended to promote T helper 1 cytokines, whereas bifidobacterial strains tended to produce a more anti-inflammatory profile. The results suggest that there was limited evidence of strain-specific effects of probiotics with respect to T cell and NK cell activation or NK cell activity, whereas production of some cytokines was differentially influenced by probiotic strains.
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December 3 - Research in Progress
Presenter TBD:
December 10 - No presentation
December 17 - Chongbo Zhao
Article:
Alexandra Zanin-Zhorova, Jiqiang Lina, Jose Scherb, Sudha Kumaria, David Blaira, Keli L. Hippenc, Bruce R. Blazarc, Steven B. Abramsonb, Juan J. Lafaillea, and Michael L. Dustina. Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function. PNAS January 31, 2012. vol. 109, no. 5. pgs. 1625-1630
Abstract:
Foxp3+CD4+CD25high regulatory T cell (Treg) suppression of inflammation depends on T-cell receptor-mediated Nuclear Factor of Activated T cells c1 (NFATc1) activation with reduced Akt activity. We investigated the role of the scaffold protein Disc large homolog 1 (Dlgh1) in linking the T-cell receptor to this unique signaling outcome. The Treg immunological synapse (IS) recruited fourfold more Dlgh1 than conventional CD4+ T-cell IS. Tregs isolated from patients with active rheumatoid arthritis, or treated with tumor necrosis factor-α, displayed reduced function and diminished Dlgh1 recruitment to the IS. Furthermore, Dlgh1 silencing abrogated Treg function, impaired NFATc1 activation, reduced phosphatase and tensin homolog levels, and increased Akt activation. Dlgh1 operates independently of the negative feedback pathway mediated by the related adapter protein Carma1 and thus presents an array of unique targets to selectively manipulate Treg function.
January 7 - Sonia Charran - POSTPONED DUE TO ILLNESS
January 14 - Forough Khadem
Article:
Abstract:
January 21 - Christopher Wiebe
Article:
Abstract:
January 28 - Shiby Kuriakose
Article:
Abstract:
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February 4 -Emeka Okeke
Article:
Soghoian et al. HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome. Sci. Transl. Med. 4(123): 123ra25 (2012)
Abstract:
Early immunological events during acute HIV infection are thought to fundamentally influence long-term disease outcome. Whereas the contribution of HIV-specific CD8 T cell responses to early viral control is well established, the role of HIV-specific CD4 T cell responses in the control of viral replication after acute infection is unknown. A growing body of evidence suggests that CD4 T cells—besides their helper function—have the capacity to directly recognize and kill virally infected cells. In a longitudinal study of a cohort of individuals acutely infected with HIV, we observed that subjects able to spontaneously control HIV replication in the absence of antiretroviral therapy showed a significant expansion of HIV-specific CD4 T cell responses—but not CD8 T cell responses—compared to subjects who progressed to a high viral set point (P = 0.038). Markedly, this expansion occurred before differences in viral load or CD4 T cell count and was characterized by robust cytolytic activity and expression of a distinct profile of perforin and granzymes at the earliest time point. Kaplan-Meier analysis revealed that the emergence of granzyme A+ HIV-specific CD4 T cell responses at baseline was highly predictive of slower disease progression and clinical outcome (average days to CD4 T cell count <350/ml was 575 versus 306, P = 0.001). These data demonstrate that HIV-specific CD4 T cell responses can be used during the earliest phase of HIV infection as an immunological predictor of subsequent viral set point and disease outcome. Moreover, these data suggest that expansion of granzyme A+ HIV-specific cytolytic CD4 T cell responses early during acute HIV infection contributes substantially to the control of viral replication.
February 11 - Sonia Charran
Article:
Gelderblom M, Weymar A, Bernreuther C, Velden J, Arunachalam P, Steinbach K, Orthey E, Arumugam TV, Leypoldt F, Simova O, Thom V, Friese MA, Prinz I, Hölscher C, Glatzel M, Korn T, Gerloff C, Tolosa E, Magnus T. Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood. 2012 Nov 1;120(18):3793-802. doi: 10.1182/blood-2012-02-412726. Epub 2012 Sep 13.
Abstract:
The devastating effect of ischemic stroke is attenuated in mice lacking conventional and unconventional T cells, suggesting that inflammation enhances tissue damage in cerebral ischemia. We explored the functional role of αβ and γδ T cells in a murine model of stroke and distinguished 2 different T cell-dependent proinflammatory pathways in ischemia-reperfusion injury. IFN-γ produced by CD4(+) T cells induced TNF-α production in macrophages, whereas IL-17A secreted by γδ T cells led to neutrophil recruitment. The synergistic effect of TNF-α and IL-17A on astrocytes resulted in enhanced secretion of CXCL-1, a neutrophil chemoattractant. Application of an IL-17A-blocking antibody within 3 hours after stroke induction decreased infarct size and improved neurologic outcome in the murine model. In autoptic brain tissue of patients who had a stroke, we detected IL-17A-positive lymphocytes, suggesting that this aspect of the inflammatory cascade is also relevant in the human brain. We propose that selective targeting of IL-17A signaling might provide a new therapeutic option for the treatment of stroke. PMID: 22976954 [PubMed - indexed for MEDLINE]
February 18 - Louis Riel Day - University Closed
February 25 - Yujia Sun
Article:
Winkler IG, Barbier V, Nowlan B, Jacobsen RN, Forristal CE, Patton JT, Magnani JL, Lévesque JP. Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. PMID:23086476 Nat Med. 2012 Nov;18(11):1651-7. doi: 10.1038/nm.2969. Epub 2012 Oct 21.
Abstract:
The microenvironment, or niche, surrounding a stem cell largely governs its cellular fate. Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a distinct function for each of these niches remains unclear. Here we report a new role for the adhesion molecule E-selectin expressed exclusively by bone marrow endothelial cells in the vascular HSC niche. HSC quiescence was enhanced and self-renewal potential was increased in E-selectin knockout (Sele−/−) mice or after administration of an E-selectin antagonist, demonstrating that E-selectin promotes HSC proliferation and is a crucial component of the vascular niche. These effects are not mediated by canonical E-selectin ligands. Deletion or blockade of E-selectin enhances HSC survival threefold to sixfold after treatment of mice with chemotherapeutic agents or irradiation and accelerates blood neutrophil recovery. As bone marrow suppression is a severe side effect of high-dose chemotherapy, transient blockade of E-selectin is potentially a promising treatment for the protection of HSCs during chemotherapy or irradiation.
March 4 - Hesam Movassagh
Article:
Segura E, Touzot M, Bohineust A, Cappuccio A, Chiocchia G, Hosmalin A, Dalod M, Soumelis V, Amigorena S. Source. Human Inflammatory Dendritic Cells Induce Th17 Cell Differentiation. Immunity. 2013 Jan 24. pii: S1074-7613(13)00010-1. doi: 10.1016/j.immuni.2012.10.018. [Epub ahead of print]
Abstract:
Dendritic cells (DCs) are critical regulators of immune responses. Under noninflammatory conditions, several human DC subsets have been identified. Little is known, however, about the human DC compartment under inflammatory conditions. Here, we characterize a DC population found in humaninflammatory fluids that displayed a phenotype distinct from macrophages from the same fluids and from steady-state lymphoid organ and blood DCs. Transcriptome analysis showed that they correspond to a distinct DC subset and share gene signatures with in vitro monocyte-derived DCs. Moreover, human inflammatory DCs, but not inflammatory macrophages, stimulated autologous memory CD4(+) T cells to produce interleukin-17 andinduce T helper 17 (Th17) cell differentiation from naive CD4(+) T cells through the selective secretion of Th17 cell-polarizing cytokines. We conclude that inflammatory DCs represent a distinct human DC subset and propose that they are derived from monocytes and are involved in the induction and maintenance of Th17 cell responses. PMID: 23352235
March 11 - Hongzhao Li
Article:
Klein F, Halper-Stromberg A, Horwitz JA, Gruell H, Scheid JF, Bournazos S, Mouquet H, Spatz LA, Diskin R, Abadir A, Zang T, Dorner M, Billerbeck E, Labitt RN, Gaebler C, Marcovecchio PM, Incesu RB, Eisenreich TR, Bieniasz PD, Seaman MS, Bjorkman PJ, Ravetch JV, Ploss A, Nussenzweig MC. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 2012 Dec 6;492(7427):118-22. doi: 10.1038/nature11604. Epub 2012 Oct 24.
Abstract:
Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection. Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time. However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design. Here we re-examine passive antibody transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody monotherapy, combinations of broadly neutralizing antibodies can effectively control HIV-1 infection and suppress viral load to levels below detection. Moreover, in contrast to antiretroviral therapy, the longer half-life of antibodies led to control of viraemia for an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV-1-infected individuals. PMID: 23103874 [PubMed - indexed for MEDLINE]
March 18 - Nonso Onyilagha
Article:
Norris BA, Uebelhoer LS, Nakaya HI, Price AA, Grakoui A, Pulendran B. Chronic but Not Acute Virus Infection Induces Sustained Expansion of Myeloid Suppressor Cell Numbers that Inhibit Viral-Specific T Cell Immunity. Immunity. 2013 Feb 21;38(2):309-21. doi: 10.1016/j.immuni.2012.10.022.
Abstract:
Resolution of acute and chronic viral infections requires activation of innate cells to initiate and maintain adaptive immune responses. Here we report that infection with acute Armstrong (ARM) or chronic Clone 13 (C13) strains of lymphocytic choriomeningitis virus (LCMV) led to two distinct phases of innate immune response. During the first 72 hr of infection, dendritic cells upregulated activation markers and stimulated antiviral CD8(+) T cells, independent of viral strain. Seven days after infection, there was an increase in Ly6C(hi) monocytic and Gr-1(hi) neutrophilic cells in lymphoid organs and blood. This expansion in cell numbers was enhanced and sustained in C13 infection, whereas it occurred only transiently with ARM infection. These cells resembled myeloid-derived suppressor cells and potently suppressed T cell proliferation. The reduction of monocytic cells in Ccr2(-/-) mice or after Gr-1 antibody depletion enhanced antiviral T cell function. Thus, innate cells have an important immunomodulatory role throughout chronic infection.
PMID:23438822
March 25 - Rebecca Dielschneider
April 1 - Vasudeva Bhat
Article:
Tsai JJ, Dudakov JA, Takahashi K, Shieh JH, Velardi E, Holland AM, Singer NV, West ML, Smith OM, Young LF, Shono Y, Ghosh A, Hanash AM, Tran HT, Moore MA, van den Brink MR. Nrf2 regulates haematopoietic stem cell function. Nat Cell Biol. 2013 Feb 24;15(3):309-16. doi: 10.1038/ncb2699. Epub 2013 Feb 24.
Abstract:
Coordinating the balance between haematopoietic stem cell (HSC) quiescence and self-renewal is crucial for maintaining haematopoiesis lifelong. Equally important for haematopoietic function is modulating HSC localization within the bone marrow niches, as maintenance of HSC function is tightly controlled by a complex network of intrinsic molecular mechanisms and extrinsic signalling interactions with their surrounding microenvironment1. In this study we demonstrate that nuclear factor erythroid 2-related factor 2 (Nfe2l2, or Nrf2), well established as a global regulator of the oxidative stress response, plays a regulatory role in several aspects of HSC homeostasis. Nrf2 de ciency results in an expansion of the haematopoietic stem and progenitor cell compartment due to cell-intrinsic hyperproliferation, which was accomplished at the expense of HSC quiescence and self-renewal. We further show that Nrf2 modulates both migration and retention of HSCs in their niche. Moreover, we identify a previously unrecognized link between Nrf2 and CXCR4, contributing, at least partially, to the maintenance of HSC function.
April 8 - Research in Progress
Dr. Ramses Ilarraza
Post Doctoral Fellow
Redwan Moqbel Lab
Department of Immunology
April 15 - Deepak Upreti
Article:
Zhi-Zhang Yang, Deanna M. Grote, Steven C. Ziesmer, Toshiro Niki, Mitsuomi Hiroshima, Anne J. Novak, Thomas E. Witzig, and Stephen M. Ansell. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J Clin Invest. 2012; 122(4):1271–1282.doi:10.1172/JCI59806.PMID22426209
Abstract:
The cytokine IL-12 induces IFN-γ production by T and NK cells. In preclinical models, it contributes to antitumor immunity. However, in clinical testing, it has shown limited benefit in patients with any one of a variety of malignancies. Moreover, in a clinical trial testing a combination of IL-12 and rituximab in patients with follicular B cell non-Hodgkin lymphoma (FL), those treated with IL-12 showed a lower response rate, suggesting that IL-12 actually plays a detrimental role. Here, we investigated whether the failure of IL-12 treatment for FL was due to T cell exhaustion, a condition characterized by reduced T cell differentiation, proliferation,and function, which has been observed in chronic viral infection. We found that extended exposure to IL-12 induced T cell exhaustion and contributed to the poor prognosis in FL patients. Long-term exposure of freshly isolated human CD4+ T cells to IL-12 in vitro caused T cell dysfunction and induced expression of TIM-3, a T cell immunoglobulin and mucin domain protein with a known role in T cell exhaustion, via an IFN-γ–independent mechanism. TIM-3 was required for the negative effect of IL-12 on T cell function. Importantly, TIM-3 also was highly expressed on intratumoral T cells that displayed marked functional impairment. Our findings identify IL-12– and TIM-3–mediated exhaustion of T cells as a mechanism for poor clinical outcome when IL-12 is administered to FL patients.
April 22 - CANCELLED
Article:
Abstract:
April 29 - Xun (Grace) Wu
Article:
Abstract:
May 6 - Fazle Rabbi
Article:
Linda V Sinclair, Julia Rolf, Elizabeth Emslie, Yun-Bo Shi, Peter M Taylor & Doreen A Cantrell. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nature Immunology 2013 May;14(5):500-8. doi: 10.1038/ni.2556. Epub 2013 Mar 24.
Abstract:
T lymphocytes must regulate nutrient uptake to meet the metabolic demands of an immune response. Here we show that the intracellular supply of large neutral amino acids (LNAAs) in T cells was regulated by pathogens and the T cell antigen receptor (TCR). T cells responded to antigen by upregulating expression of many amino-acid transporters, but a single System L (‘leucine-preferring system’) transporter, Slc7a5, mediated uptake of LNAAs in activated T cells. Slc7a5-null T cells were unable to metabolically reprogram in response to antigen and did not undergo clonal expansion or effector differentiation. The metabolic catastrophe caused by loss of Slc7a5 reflected the requirement for sustained uptake of the LNAA leucine for activation of the serine-threonine kinase complex mTORC1 and for expression of the transcription factor c-Myc. Control of expression of the System L transporter by pathogens is thus a critical metabolic checkpoint for T cells. PMID: 23525088
May 13 - Nazanin Tatari - POSTPONED
May 20 - Victoria Day, University Closed
May 27 - Ibrahim Sow
CANCELLED/POST PONED
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June 3 - Jyoti Balhara
Article:
Abstract:
June 10 - Hadeesha Piyadasa
Article:
Qi Yang, Laurel A. Monticelli, Steven A. Saenz, Anthony Wei-Shine Chi, Gregory F. Sonnenberg, Jiangbo Tang, Maria Elena De Obaldia, Will Bailis, Jerrod L. Bryson, Kristin Toscano, Jian Huang, Angela Haczku, Warren S. Pear, David Artis, Avinash Bhandoola, T Cell Factor 1 Is Required for Group 2 Innate Lymphoid Cell Generation. Immunity. Volume 38, Issue 4, 18 April 2013, Pages 694–704
http://dx.doi.org/10.1016/j.immuni.2012.12.003
Abstract:
Group 2 innate lymphoid cells (ILC2) are innate lymphocytes that confer protective type 2 immunity during helminth infection and are also involved in allergic airway inflammation. Here we report that ILC2 development required T cell factor 1 (TCF-1, the product of the Tcf7 gene), a transcription factor also implicated in T cell lineage specification. Tcf7−/− mice lack ILC2, and were unable to mount ILC2-mediated innate type 2 immune responses. Forced expression of TCF-1 in bone marrow progenitors partially bypassed the requirement for Notch signaling in the generation of ILC2 in vivo. TCF-1 acted through both GATA-3-dependent and GATA-3-independent pathways to promote the generation of ILC2. These results are reminiscent of the critical roles of TCF-1 in early T cell development. Hence, transcription factors that underlie early steps of T cell development are also implicated in the development of innate lymphoid cells.
End of Journal Club and Research in Progress for 2012/2013