Leukocyte Signalling Laboratory

October 2017. Top L-R: Dr Jess Borger (Research Officer), Mr Tim Gottschalk (PhD student), Associate Professor Margaret Hibbs (group leader) Dr Maverick Lau (Research Officer),
Bottom L-R: Dr Evelyn Tsantikos (Research Officer), Ms Lakshanie Wickramasinghe (PhD student), Ms Cassandra Castelino (PhD student)

Research

The Leukocyte Signaling Laboratory is studying signaling pathways that play a role in immune system development and function. We are primarily interested in what regulates the development of immunity and we are trying to understand the processes that are perturbed when autoimmunity and inflammatory diseases develop. We are also interested in understanding what regulates haematopoiesis or blood cell development, and believe that this will give us a greater understanding of the signals that go awry in the development of blood cell cancers. The lab also has a major interest in understanding the mechanisms underlying chronic inflammatory lung disease and we aim to identifying key pathways or targets for therapeutic intervention.

We have been concentrating our studies on Src-family protein tyrosine kinases, enzymes that are found inside cells that play very important roles in transmitting information from the cell surface to the nucleus to initiate a cellular response. Deregulation of the function of Src-family kinases has been linked with cancer, and also to immune system disorders such as autoimmune disease, immunodeficiency, osteopetrosis, and compromised host defence. The Lyn tyrosine kinase is a unique member of the Src-family whose predominant role is to regulate signals through inhibitory receptors, and to promote signal termination.Animal models of Lyn deficiency and constitutive Lyn activity have been developed in the laboratory and are the major focus of our studies. Our studies have demonstrated the importance of Lyn for B lymphocyte development and function, and have identified Lyn as a potential tumour suppressor. We have also recently shown that Lyn can control macrophage activation and susceptibility to inflammatory lung disease.Our research employs a variety of powerful techniques such as mouse models, mutagenesis, multi-colour flow cytometry, RNA interference, real-time PCR, proteomics and micro-array based RNA expression analysis.

Projects

  1. Understanding the mechanisms behind autoimmune disease development using animal models of lupus. Our previous studies have shown that Lyn-deficient mice develop antibody-mediated autoimmune disease that resembles lupus. We have recently shown a requirement for both inflammatory factors and B cells in switching the disease to a pathogenic state. Currently we are trying to define the relationship between inflammation and lymphocyte activation in the development and progression of autoimmune disease.
  2. Identifying Lyn-regulated proteins and genes. We are attempting to identify Lyn regulated proteins and genes using proteomics and microarray technologies. For these studies we are making use of cells from mice expressing a gain of function mutation in Lyn, as they show numerous tyrosine phosphorylated proteins that are likely to be bone fide Lyn substrates.
  3. Determining how Lyn regulates haematopoiesis and progenitor cell number. Our previous studies have shown that Lyn deficiency leads to deregulation of haematopoiesis and increases in progenitor cell numbers. We are actively investigating the basis for these phenotypes.
  4. Defining the role of Lyn in inflammatory lung disease and cancer. We have previously shown that Lyn functions as a negative regulator of lung inflammation. However, we have also found that Lyn can be a positive regulator of signaling: mice expressing a gain of function mutation in Lyn develop destructive lung inflammation. We are now trying to understand how Lyn activation contributes to macrophage deregulation and chronic obstructive pulmonary disease, and whether mutation of Lyn alters susceptibility to lung adenocarcinoma.

Publications

  • Lau M, Tsantikos E, Maxwell MJ, Tarlinton DM, Anderson GP, Hibbs ML. Loss of STAT6 promotes autoimmune disease and atopy on a susceptible genetic background. J Autoimmun. 2012 Dec;39(4):388-97. doi: 10.1016/j.jaut.2012.06.003. Epub 2012 Aug 4. PubMed PMID: 22867713.
  • Tsantikos E, Maxwell MJ, Kountouri N, Harder KW, Tarlinton DM, Hibbs ML. Genetic interdependence of Lyn and negative regulators of B cell receptor signaling in autoimmune disease development. J Immunol. 2012 Aug 15;189(4):1726-36. doi: 10.4049/jimmunol.1103427. Epub 2012 Jul 13. PubMed PMID: 22798664.
  • Xu Y, Huntington ND, Harder KW, Nandurkar H, Hibbs ML, Tarlinton DM. Phosphatidylinositol-3 kinase activity in B cells is negatively regulated by Lyn tyrosine kinase. Immunol Cell Biol. 2012 Oct;90(9):903-11. doi:10.1038/icb.2012.31. Epub 2012 Jul 10. PubMed PMID: 22777522.
  • Duan M, Li WC, Vlahos R, Maxwell MJ, Anderson GP, Hibbs ML. Distinct macrophage subpopulations characterize acute infection and chronic inflammatory lung disease. J Immunol. 2012 Jul 15;189(2):946-55. doi:10.4049/jimmunol.1200660. Epub 2012 Jun 11. PubMed PMID: 22689883.
  • Maxwell MJ, Tsantikos E, Kong AM, Vanhaesebroeck B, Tarlinton DM, Hibbs ML. Attenuation of phosphoinositide 3-kinase δ signaling restrains autoimmune disease. J Autoimmun. 2012 Jun;38(4):381-91. doi: 10.1016/j.jaut.2012.04.001.Epub 2012 Apr 25. PubMed PMID: 22537464.
  • Krebs DL, Chehal MK, Sio A, Huntington ND, Da ML, Ziltener P, Inglese M, Kountouri N, Priatel JJ, Jones J, Tarlinton DM, Anderson GP, Hibbs ML, Harder KW. Lyn-dependent signaling regulates the innate immune response by controlling dendritic cell activation of NK cells. J Immunol. 2012 May 15;188(10):5094-105.doi: 10.4049/jimmunol.1103395. Epub 2012 Apr 9. PubMed PMID: 22491248.
  • Luwor RB, Wang B, Nheu TV, Iaria J, Tsantikos E, Hibbs ML, Sieber OM, Zhu HJ. New reagents for improved in vitro and in vivo examination of TGF-β signalling. Growth Factors. 2011 Oct;29(5):211-8. doi: 10.3109/08977194.2011.615311. PubMed PMID: 21913800.
  • Steinfort DP, Tsui A, Grieve J, Hibbs ML, Anderson GP, Irving LB. Sarcoidal reactions in regional lymph nodes of patients with early stage non-small cell lung cancer predict improved disease-free survival: a pilot case-control study. Hum Pathol. 2012 Mar;43(3):333-8. doi: 10.1016/j.humpath.2011.05.006. Epub 2011 Aug 10. PubMed PMID: 21835432.
  • Maxwell MJ, Duan M, Armes JE, Anderson GP, Tarlinton DM, Hibbs ML. Genetic segregation of inflammatory lung disease and autoimmune disease severity in SHIP-1-/- mice. J Immunol. 2011 Jun 15;186(12):7164-75. doi:10.4049/jimmunol.1004185. Epub 2011 May 13. PubMed PMID: 21572033.
  • Nguyen NY, Maxwell MJ, Ooms LM, Davies EM, Hilton AA, Collinge JE, Hilton DJ, Kile BT, Mitchell CA, Hibbs ML, Jane SM, Curtis DJ. An ENU-induced mouse mutant of SHIP1 reveals a critical role of the stem cell isoform for suppression of macrophage activation. Blood. 2011 May 19;117(20):5362-71. doi:10.1182/blood-2011-01-331041. Epub 2011 Mar 18. PubMed PMID: 21421839
  • Mackay F, Figgett WA, Saulep D, Lepage M, Hibbs ML. B-cell stage and context-dependent requirements for survival signals from BAFF and the B-cell receptor. Immunol Rev. 2010 Sep;237(1):205-25. doi:10.1111/j.1600-065X.2010.00944.x. Review. PubMed PMID: 20727038.
  • Oracki SA, Walker JA, Hibbs ML, Corcoran LM, Tarlinton DM. Plasma cell development and survival. Immunol Rev. 2010 Sep;237(1):140-59. doi:10.1111/j.1600-065X.2010.00940.x. Review. PubMed PMID: 20727034.
  • Perugini M, Brown AL, Salerno DG, Booker GW, Stojkoski C, Hercus TR, Lopez AF, Hibbs ML, Gonda TJ, D'Andrea RJ. Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common beta-subunit. Blood. 2010 Apr 22;115(16):3346-53. doi: 10.1182/blood-2009-08-235846. Epub 2010 Feb 19. PubMed PMID: 20173116; PubMed Central PMCID: PMC2858480.
  • Tsantikos E, Oracki SA, Quilici C, Anderson GP, Tarlinton DM, Hibbs ML. Autoimmune disease in Lyn-deficient mice is dependent on an inflammatory environment established by IL-6. J Immunol. 2010 Feb 1;184(3):1348-60. doi: 10.4049/jimmunol.0901878. Epub 2009 Dec 30. PubMed PMID: 20042579.
  • Oracki SA, Tsantikos E, Quilici C, Light A, Schmidt T, Lew AM, Martin JE, Smith KG, Hibbs ML, Tarlinton DM. CTLA4Ig alters the course of autoimmune disease development in Lyn-/- mice. J Immunol. 2010 Jan 15;184(2):757-63. doi: 10.4049/jimmunol.0804349. Epub 2009 Dec 4. PubMed PMID: 19966213.
  • Tsantikos E, Quilici C, Harder KW, Wang B, Zhu HJ, Anderson GP, Tarlinton DM, Hibbs ML. Perturbation of the CD4 T cell compartment and expansion of regulatory T cells in autoimmune-prone Lyn-deficient mice. J Immunol. 2009 Aug 15;183(4):2484-94. doi: 10.4049/jimmunol.0804346. Epub 2009 Jul 20. PubMed PMID: 19620313.
  • Verhagen AM, Wallace ME, Goradia A, Jones SA, Croom HA, Metcalf D, Collinge JE, Maxwell MJ, Hibbs ML, Alexander WS, Hilton DJ, Kile BT, Starr R. A kinase-dead allele of Lyn attenuates autoimmune disease normally associated with Lyn deficiency. J Immunol. 2009 Feb 15;182(4):2020-9. doi: 10.4049/jimmunol.0803127. PubMed PMID: 19201855.
  • Shayan R, Karnezis T, Tsantikos E, Williams SP, Runting AS, Ashton MW, Achen MG, Hibbs ML, Stacker SA. A system for quantifying the patterning of the lymphatic vasculature. Growth Factors. 2007 Dec;25(6):417-25. doi:10.1080/08977190801932550. PubMed PMID: 18365872.
  • Liu K, Gualano RC, Hibbs ML, Anderson GP, Bozinovski S. Epidermal growth factor receptor signaling to Erk1/2 and STATs control the intensity of the epithelial inflammatory responses to rhinovirus infection. J Biol Chem. 2008 Apr 11;283(15):9977-85. doi: 10.1074/jbc.M710257200. Epub 2008 Feb 13. PubMed PMID: 18276593.
  • Hibbs ML, Quilici C, Kountouri N, Seymour JF, Armes JE, Burgess AW, Dunn AR. Mice lacking three myeloid colony-stimulating factors (G-CSF, GM-CSF, and M-CSF) still produce macrophages and granulocytes and mount an inflammatory response in a sterile model of peritonitis. J Immunol. 2007 May 15;178(10):6435-43. PubMed PMID: 17475873.
  • McColl BK, Paavonen K, Karnezis T, Harris NC, Davydova N, Rothacker J, Nice EC, Harder KW, Roufail S, Hibbs ML, Rogers PA, Alitalo K, Stacker SA, Achen MG. Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2. FASEB J. 2007 Apr;21(4):1088-98. Epub 2007 Jan 22. PubMed PMID: 17242158.
  • Ingley E, Schneider JR, Payne CJ, McCarthy DJ, Harder KW, Hibbs ML, Klinken SP. Csk-binding protein mediates sequential enzymatic down-regulation and degradation of Lyn in erythropoietin-stimulated cells. J Biol Chem. 2006 Oct 20;281(42):31920-9. Epub 2006 Aug 18. PubMed PMID: 16920712.
  • Hibbs ML, Harder KW. The duplicitous nature of the Lyn tyrosine kinase in growth factor signaling. Growth Factors. 2006 Jun;24(2):137-49. PubMed PMID: 16801133.
  • Beavitt SJ, Harder KW, Kemp JM, Jones J, Quilici C, Casagranda F, Lam E, Turner D, Brennan S, Sly PD, Tarlinton DM, Anderson GP, Hibbs ML. Lyn-deficient mice develop severe, persistent asthma: Lyn is a critical negative regulator of Th2 immunity. J Immunol. 2005 Aug 1;175(3):1867-75. PubMed PMID: 16034130.
  • Baldwin ME, Halford MM, Roufail S, Williams RA, Hibbs ML, Grail D, Kubo H, Stacker SA, Achen MG. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol. 2005 Mar;25(6):2441-9. PubMed PMID: 15743836; PubMed Central PMCID: PMC1061605.
  • Xu Y, Harder KW, Huntington ND, Hibbs ML, Tarlinton DM. Lyn tyrosine kinase: accentuating the positive and the negative. Immunity. 2005 Jan;22(1):9-18. Review. PubMed PMID: 15664155.
  • Harder KW, Quilici C, Naik E, Inglese M, Kountouri N, Turner A, Zlatic K, Tarlinton DM, Hibbs ML. Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1. Blood. 2004 Dec 15;104(13):3901-10. Epub 2004 Aug 31. PubMed PMID: 15339845.
  • Odom S, Gomez G, Kovarova M, Furumoto Y, Ryan JJ, Wright HV, Gonzalez-Espinosa C, Hibbs ML, Harder KW, Rivera J. Negative regulation of immunoglobulin E-dependent allergic responses by Lyn kinase. J Exp Med. 2004 Jun 7;199(11):1491-502. Epub 2004 Jun 1. PubMed PMID: 15173205; PubMed Central PMCID: PMC2211776.
  • Maxwell MJ, Yuan Y, Anderson KE, Hibbs ML, Salem HH, Jackson SP. SHIP1 and Lyn Kinase Negatively Regulate Integrin alpha IIb beta 3 signaling in platelets. J Biol Chem. 2004 Jul 30;279(31):32196-204. Epub 2004 May 27. PubMed PMID: 15166241.
  • Hibbs ML, Harder KW, Armes J, Kountouri N, Quilici C, Casagranda F, Dunn AR, Tarlinton DM. Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity. J Exp Med. 2002 Dec 16;196(12):1593-604. PubMed PMID: 12486102; PubMed Central PMCID: PMC2196073.
  • Xu Y, Beavitt SJ, Harder KW, Hibbs ML, Tarlinton DM. The activation and subsequent regulatory roles of Lyn and CD19 after B cell receptor ligation are independent. J Immunol. 2002 Dec 15;169(12):6910-8. PubMed PMID: 12471124.
  • Ernst M, Inglese M, Scholz GM, Harder KW, Clay FJ, Bozinovski S, Waring P, Darwiche R, Kay T, Sly P, Collins R, Turner D, Hibbs ML, Anderson GP, Dunn AR. Constitutive activation of the SRC family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response. J Exp Med. 2002 Sep 2;196(5):589-604. PubMed PMID: 12208875; PubMed Central PMCID: PMC2193996.