Academic Rank:
Professor
Affiliation(s):
UBC Biomedical Research Center
Location:
UBC Biomedical Research Center

Short Bio:

Sugar molecules attached to proteins expressed at the cell surface are increasingly recognized as playing an important role in the control of cell-cell interaction. Specific oligosaccharides can be recognized by sugar binding proteins (so called lectins) and this interaction has the potential to control how a cell interacts with other cells.  Dr. Ziltener is studying the enzymes, “glycosyltransferases” that allow formation of oligosaccharide groups made from sugars such as sialic acid, fucose, galactose and N-acetylglucosamine to form ligands for selectins. Expression of selectin ligands for instance on cells of the immune system is required for these cells to migrate to a site of inflammation, leave the blood vessel and migrate into the tissue where they then participate in the immune response to e.g. a pathogen. Understanding the mechanisms that control the activities of glycosyltransferases that lead to formation of selectin ligands will thus lead to a better understanding of processes that control migration of cells of the immune system to sites of inflammation.

Academic Backgrounds:
  • Postdoctoral Fellow, The Walter and Eliza Hall Institute of Medical Research, Melbourne. 1984-1987
  • PhD, University of Freiburg, Switzerland, Biochemistry. 1977-1983
  • Diploma, University of Freiburg, Switzerland. 1971-1976
Selected Publications
  • Kidder D, Richards HE, Ziltener HJ, Garden OA, Crocker PR Sialoadhesin ligand expression identifies a subset of CD4+Foxp3- T cells with a distinct activation and glycosylation profile. Journal of Immunology 190:2593-2602, 2013.
  • Mullaly SC, Oudhoff MJ, Min PH, Burrows K, Antignano F, Rattray DG, Chenery A, McNagny KM, Ziltener HJ, Zaph C. Requirement for core 2 O-glycans for optimal resistance to helminth infection. PLoS One. 2013;8(3):e60124.
  • Veerman KM, Carlow DA, Shanina I, Priatel JJ, Horwitz MS, Ziltener HJ. PSGL-1 regulates the migration and proliferation of CD8(+) T cells under homeostatic conditions. J Immunol. 2012 Feb 15;188(4):1638-46.
  • Gossens K, Naus S, Holländer GA, Ziltener HJ. Deficiency of the metalloproteinase-disintegrin ADAM8 is associated with thymic hyper-cellularity. PLoS One. 2010 Sep 15;5(9):e12766.
  • Hickey TB, Ziltener HJ, Speert DP, Stokes RW. Mycobacterium tuberculosis employs Cpn60.2 as an adhesin that binds CD43 on the macrophage surface. Cell Microbiol. 2010 Nov;12(11):1634-47.
  • Kum WW, Lo BC, Deng W, Ziltener HJ, Finlay BB. Impaired innate immune response and enhanced pathology during Citrobacter rodentium infection in mice lacking functional P-selectin. Cell Microbiol. 2010 Sep 1;12(9):1250-71.
  • Naus S, Blanchet MR, Gossens K, Zaph C, Bartsch JW, McNagny KM, Ziltener HJ. The metalloprotease-disintegrin ADAM8 is essential for the development of experimental asthma. Am J Respir Crit Care Med. 2010 Jun 15;181(12):1318-28.
  • Seo W, Ziltener HJ. CD43 processing and nuclear translocation of CD43 cytoplasmic tail are required for cell homeostasis. Blood. 2009 Oct 22;114(17):3567-77.
  • Carlow DA, Gossens K, Naus S, Veerman KM, Seo W, Ziltener HJ. PSGL-1 function in immunity and steady state homeostasis. Immunol Rev. 2009 Jul;230(1):75-96.
  • Carlow DA, Gold MR, Ziltener HJ. Lymphocytes in the peritoneum home to the omentum and are activated by resident dendritic cells. J Immunol. 2009 Jul 15;183(2):1155-65.
  • Gossens K, Naus S, Corbel SY, Lin S, Rossi FM, Kast J, Ziltener HJ. Thymic progenitor homing and lymphocyte homeostasis are linked via S1P-controlled expression of thymic P-selectin/CCL25. J Exp Med. 2009 Apr 13;206(4):761-78.
  • Randhawa AK, Ziltener HJ, Stokes RW. CD43 controls the intracellular growth of Mycobacterium tuberculosis through the induction of TNF-alpha-mediated apoptosis. Cell Microbiol. 2008 Oct;10(10):2105-17.
  • Veerman KM, Williams MJ, Uchimura K, Singer MS, Merzaban JS, Naus S, Carlow DA, Owen P, Rivera-Nieves J, Rosen SD, Ziltener HJ. Interaction of the selectin ligand PSGL-1 with chemokines CCL21 and CCL19 facilitates efficient homing of T cells to secondary lymphoid organs. Nat Immunol. 2007 May;8(5):532-9.
  • Carlow DA, Ziltener HJ. CD43 deficiency has no impact in competitive in vivo assays of neutrophil or activated T cell recruitment efficiency. J Immunol. 2006 Nov 1;177(9):6450-9.
Research:

Research in our laboratory is focused on the role of leukocyte mucin family glycoproteins in both steady state hemopoiesis and inflammation. Leukocyte mucins are heavily glycosylated cell surface molecules that are abundantly expressed; they can have anti-adhesive properties, so-called “molecular Teflon” as well as pro-adhesive properties whereby mucin expressed sugar groups bind selectins or other cell derived lectins such as galectins or sialoadhesins. Given that leukocyte mucins can interact with a range of sugar binding lectins, focus is also on study of the glycosyltransferases that generate the lectin-binding sites on mucin family members.

 

  • CD43: A long-term interest of our research group has been the study of CD43 that is expressed by all hemopoietic cells with the exception of erythrocytes and plasma cells. CD43 is considered to be the most abundant cell surface molecule expressed on blood cells and has been shown to exhibit both anti-adhesive and pro-adhesive activities. The primary functions of CD43 are somewhat controversial. Mice deficient in CD43 have a surprisingly mild phenotype displaying increased adhesiveness of hemopoietic. T cell hyper-responsiveness reported early on was likely due to the mixed 129xC57Bl/6 genetic origin of the null mice analyzed. CD43 undergoes ectodomain shedding but the functional significance of this cleavage remains unknown. Our laboratory has recently shown that CD43 shedding is essential to homeostasis of most cells, with the notable exception of macrophages. CD43 is processed by α- and γ-secretases, in the Regulated Intramembrane Proteolysis (RIP) pathway, which releases the CD43 cytoplasmic tail (CD43ct) from the membrane. Cleaved CD43ct translocates into the nucleus and this translocation is essential for cell homeostasis in that inhibition of either CD43ct release by γ-secretase or its nuclear translocation was found to be pro-apoptotic. Involvement of CD43 in regulation of apoptosis is also consistent with our findings that CD43ct is modified by Small Ubiquitin-like Modifier-1 (SUMO-1), is co-localized with PML nuclear bodies, and that CD43 deficient cells have increased sensitivity to apoptosis. Our most recent data thus implicate an essential function of CD43 processing and nuclear translocation of CD43ct in cell homeostasis and apoptosis. Focus is now on analysis of disease models determining whether presence of CD43 or altered sheddability of CD43 can affect disease outcomes.
  • Cytokine regulation of selectin binding sites: Work on CD43 has allowed our laboratory to develop model systems to study core 2 O-glycan branch formation now recognized as being essential for formation of P-selectin binding sites on the glycoprotein PSGL-1. This modification thereby underpins the essential molecular interactions required for recruitment of effector cells to areas of inflammation. Next to the core 2 O-glycan branching enzymes, other glycosyltransferases also contribute essential components of the P-selectin ligand structure including fucosyltransferases and sialyltransferases. Cytokines, such as IL2, IL4, IL12 and IL15, have been implicated in the regulation of the activities of some of these enzymes. Interestingly while the activities of several key glycosyltransferases can be controlled by cytokines under in vitro conditions we subsequently found that in vivo P-selectin ligand formation proceeded as effectively in absence of any of these cytokines pointing to other, as yet undefined, signals that control formation of this important ligand. Focus is now on identification of the signals that drive P-selectin ligand formation under physiological conditions.
  • Role of PSGL-1 in T cell recirculation: Analysis of T cell subset distribution in PSGL-1 deficient mice provided the unexpected discovery that PSGL-1 not only functions as a pro-adhesive molecule by binding to selectins but has also a chemotaxis enhancing function that is required for efficient homing of naïve T cells into lymph nodes. We found that the secondary lymphoid chemokines CCL21 and CC19, but not SDF-1, bind PSGL-1 on naïve T cells. This chemokine binding to PSGL-1 is associated with an approximate 100% increase in chemotactic response of resting T cells to CCL21 and CCL19, resulting in significantly enhanced homing efficiency into secondary lymphoid organs. The chemotaxis enhancing effect of PSGL-1 was not observed for B cells and was lost on activated T cells. Our discovery of the bi-functional nature of PSGL-1 significantly expands the functional scope of this molecule and introduces another level of complexity in interpreting experiments using PSGL-1 knockout mice or PSGL-1 inhibition. Loss of PSGL-1 in T cells results in a subtle change in T cell homeostasis. Focus is now on delineating these changes and identification of PSGL-1 associated changes in T cell homeostasis in disease.
  • Unlocking the thymus for stem cells: Bone marrow is the home of the stem cells that produce the cells of the blood and most types of blood cells are made in the bone marrow. There is one important exception; these are the T cells (Thymus-derived lymphocytes) that are generated in the thymus from stem cells that travel through the blood from the bone marrow. To elucidate the significance of PSGL-1 binding to P-selectin in T cell formation we have, in collaboration with the laboratory of Fabio Rossi, employed the parabiotic animal model to study trafficking of bone marrow stem cells to the thymus. Our work showed that P-selectin and the chemokine CCL25 expressed in thymic endothelial cells function as gatekeepers that control T cell progenitor importation into the thymus. Levels of thymic P-selectin and thymic CCL25 expression was subject to a feedback loop that is controlled by thymic progenitor content and by T cell numbers in peripheral blood. Follow up work then showed that the peripheral lymphocyte pool can signal back to the thymus via the phospholipid sphingosine-1-phosphate (S1P). Focus is now on how the peripheral lympocyte pool modulates blood S1P levels and on the thymic S1P receptors that transmit the signals controling stem cell entry into the thymus.