View More View Less
  • 1 Department of Microbiology and Hygiene, Charité, University Medicine Berlin, Berlin, Germany
  • | 2 Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité, University Medicine Berlin, Berlin, Germany
  • | 3 German Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, Germany
  • | 4 Department of Gastroenterology, Infectology and Rheumatology / Research Center ImmunoSciences (RCIS), Charité, University Medicine Berlin, Berlin, Germany
  • | 5 Institute for Immunology, Jena University Hospital, Jena, Germany
  • | 6 Roche Molecular Systems, Pleasanton, CA, USA
Restricted access


Tim-3 has opposing roles in innate and adaptive immunities. It not only dampens CD4+ and CD8+ T cells responses but also enhances the ability of macrophages to eliminate intracellular pathogens. After peroral infection with 100 cysts of Toxoplasma gondii genetically susceptible C57BL/6 mice develop an unchecked Th1 response associated with the development of small intestinal immunopathology. Here we report that upon infection with T. gondii, both susceptible C57BL/6 and resistant BALB/c mice exhibit increased frequencies of Tim-3+ cells in spleens and mesenteric lymph nodes. The number of Tim-3+ cells was significantly higher in C57BL/6 than in BALB/c mice. Tim-3 was expressed by macrophages, dendritic, natural killer, as well as CD4+ and CD8+ T cells. Highest frequencies of Tim-3+ cells were observed at the peak of Th1 responses (day 7 post infection) concurrent with the development of ileal immunopathology. Infected Tim-3-deficient BALB/c mice did not develop ileal immunopathology nor did their parasite loads differ from those in wildtype BALB/c mice. Thus, although Tim-3 is markedly upregulated upon infection and differentially regulated in susceptible and resistant mice upon infection with T. gondii, the absence of Tim-3 is not sufficient to overcome the genetic resistance of BALB/c mice to the development of Th1-driven small intestinal immunopathology.

  • 1. A Sánchez-Fueyo J Tian D Picarella C Domenig XX Zheng CA Sabatos N Manlongat O Bender T Kamradt VK Kuchroo JC Gutiérrez-Ramos AJ Coyle TB Strom 2003 Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance Nat Immunol 11 1093 10101.

    • Search Google Scholar
    • Export Citation
  • 2. S Frisancho-Kiss JF Nyland SE Davis MA Barrett SJ Gatewood DB Njoku D Cihakova EK Silbergeld NR Rose D Fairweather 2006 Cutting edge: T Cell Ig Mucin-3 Reduces inflammatory heart disease by increasing CTLA-4 during innate immunity J Immunol 176 6411 6415.

    • Search Google Scholar
    • Export Citation
  • 3. T Oikawa Y Kamimura H Akiba H Yagita K Okumura H Takahashi M Zeniya H Tajiri M Azuma 2006 Preferential involvement of Tim-3 in the regulation of hepatic CD8+ T cells in murine acute graft-versus-host disease J Immunol 177 4281 4287.

    • Search Google Scholar
    • Export Citation
  • 4. Y Chen CL Langrish B McKenzie B Joyce-Shaikh JS Stumhofer T McClanahan W Blumenschein T Churakovsa J Low L Presta CA Hunter RA Kastelein DJ Cua 2006 Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis J Clin Invest 116 1317 1326.

    • Search Google Scholar
    • Export Citation
  • 5. M Khademi Z Illés AW Gielen M Marta N Takazawa C Baecher-Allan L Brundin J Hannerz C Martin RA Harris DA Hafler VK Kuchroo T Olsson F Piehl E Wallström 2004 T cell Ig- and mucin-domain containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid derived mononuclear cells in multiple sclerosis J Immunol 172 7169 7176.

    • Search Google Scholar
    • Export Citation
  • 6. C Zhu AC Anderson A Schubart H Xiong J Imitola SJ Khoury XX Zheng TB Strom VK Kuchroo 2005 The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity Nat Immunol 12 1245 1252.

    • Search Google Scholar
    • Export Citation
  • 7. J Leitner A Rieger WF Pickl G Zlabinger K Grabmeier-Pfistershammer P Steinberger 2013 TIM-3 does not act as a receptor for Galectin-9 PLoS Pathog 3 e1003253.

    • Search Google Scholar
    • Export Citation
  • 8. VK Kuchroo JH Meyers DT Umetsu RH DeKruyff 2006 TIM family of genes in immunity and tolerance Adv Immunol 91 227 249.

  • 9. K Koguchi DE Anderson L Yang KC O'Connor VK Kuchroo DA Hafler 2006 Dysregulated T cell expression of TIM3 in multiple sclerosis J Exp Med 203 1413 1418.

    • Search Google Scholar
    • Export Citation
  • 10. AC Anderson DE Anderson L Bregoli WD Hastings N Kassam C Lei R Chandwaskar J Karman EW Su M Hirashima JN Bruce LP Kane VK Kuchroo DA Hafler 2007 Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells Science 318 1141 1143.

    • Search Google Scholar
    • Export Citation
  • 11. RB Jones LC Ndhlovu JD Barbour PM Sheth AR Jha BR Long JC Wong M Satkunarajah M Schweneker JM Chapman G Gyenes B Vali MD Hyrcza FY Yue C Kovacs A Sassi M Loutfy R Halpenny D Persad G Spotts FM Hecht TW Chun JM McCune R Kaul JM Rini DF Nixon MA Ostrowski 2008 Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV 1 infection J Exp Med 205 2763 2779.

    • Search Google Scholar
    • Export Citation
  • 12. K Sakuishi P Jayaraman SM Behar AC Anderson VK Kuchroo 2011 Emerging Tim-3 functions in antimicrobial and tumor immunity Trends Immunol 32 345 349.

    • Search Google Scholar
    • Export Citation
  • 13. P Jayaraman I Sada-Ovalle S Beladi AC Anderson V Dardalhon C Hotta VK Kuchroo SM Behar 2010 Tim3 binding to galectin-9 stimulates antimicrobial immunity J Exp Med 207 2343 2354.

    • Search Google Scholar
    • Export Citation
  • 14. EY Denkers 2003 From cells to signaling cascades: manipulation of innate immunity by Toxoplasma gondii FEMS Immunol Med Microbiol 39 193 203.

    • Search Google Scholar
    • Export Citation
  • 15. O Liesenfeld J Kosek JS Remington Y Suzuki 1996 Association of CD4+ T cell-dependent, interferon-gamma-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii J Exp Med 184 597 607.

    • Search Google Scholar
    • Export Citation
  • 16. O Liesenfeld 2002 Oral infection of C57BL/6 mice with Toxoplasma gondii: A new model of inflammatory bowel disease? J Infect Dis 185 S96 S101.

    • Search Google Scholar
    • Export Citation
  • 17. M Muñoz MM Heimesaat K Danker D Struck U Lohmann R Plickert S Bereswill A Fischer IR Dunay K Wolk C Loddenkemper HW Krell C Libert LR Lund O Frey C Hölscher Y Iwakura N Ghilardi W Ouyang T Kamradt R Sabat O Liesenfeld 2009 Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17 J Exp Med 206 3047 3059.

    • Search Google Scholar
    • Export Citation
  • 18. D Buzoni-Gatel H Debbabi FJ Mennechet V Martin AC Lepage JD Schwartzman LH Kasper 2001 Murine ileitis after intracellular parasite infection is controlled by TGF-beta-producing intraepithelial lymphocytes Gastroenterology 120 914 924.

    • Search Google Scholar
    • Export Citation
  • 19. MM Heimesaat S Bereswill A Fischer D Fuchs D Struck J Niebergall HK Jahn IR Dunay A Moter DM Gescher RR Schumann UB Göbel O Liesenfeld 2006 Gram-negative bacteria aggravate murine small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii J Immunol 177 8785 8795.

    • Search Google Scholar
    • Export Citation
  • 20. JP Moorman JM Wang Y Zhang XJ Ji CJ Ma XY Wu ZS Jia KS Wang ZQ Yao 2012 Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection J Immunol 2 755 766.

    • Search Google Scholar
    • Export Citation
  • 21. L Monney CA Sabatos JL Gaglia A Ryu H Waldner T Chernova S Manning EA Greenfield AJ Coyle RA Sobel GJ Freeman VK Kuchroo 2002 Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease Nature 415 536 541.

    • Search Google Scholar
    • Export Citation
  • 22. V Dardalhon AC Anderson J Karman L Apetoh R Chandwaskar DH Lee M Cornejo N Nishi A Yamauchi FJ Quintana RA Sobel M Hirashima VK Kuchroo 2010 Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells J Immunol 185 1383 1392.

    • Search Google Scholar
    • Export Citation
  • 23. Y Suzuki A Sher G Yap D Park LE Neyer O Liesenfeld M Fort H Kang E Gufwoli 2000 IL-10 is required for prevention of necrosis in the small intestine and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice following peroral infection with Toxoplasma gondii J Immunol 10 5375 5382.

    • Search Google Scholar
    • Export Citation
The author instruction is available in PDF.
Please, download the file from HERE.

Senior editors

Editor(s)-in-Chief: Dunay, Ildiko Rita

Editor(s)-in-Chief: Heimesaat, Markus M.

Vice Editor(s)-in-Chief: Fuchs, Anja

Editorial Board

Chair of the Editorial Board:
Jeffrey S. Buguliskis (Thomas Jefferson University, USA)

  • Jörn Albring (University of Münster, Germany)
  • Stefan Bereswill (Charité - University Medicine Berlin, Germany)
  • Dunja Bruder (University of Megdeburg, Germany)
  • Jan Buer (University of Duisburg, Germany)
  • Jeff Buguliskis (Thomas Jefferson University, USA)
  • Edit Buzas (Semmelweis University, Hungary)
  • Charles Collyer (University of Sydney, Australia)
  • Renato Damatta (UENF, Brazil)
  • Ivelina Damjanova (Semmelweis University, Hungary)
  • Maria Deli (Biological Research Center, HAS, Hungary)
  • Olgica Djurković-Djaković (University of Belgrade, Serbia)
  • Jean-Dennis Docquier (University of Siena, Italy)
  • Anna Erdei (Eötvös Loránd University, Hungary)
  • Zsuzsanna Fabry (University of Washington, USA)
  • Beniam Ghebremedhin (Witten/Herdecke University, Germany)
  • Nancy Guillen (Institute Pasteur, France)
  • Georgina L. Hold (University of Aberdeen, United Kingdom)
  • Ralf Ignatius (Charité - University Medicine Berlin, Germany)
  • Zsuzsanna Izsvak (MDC-Berlin, Germany)
  • Achim Kaasch (University of Cologne, Germany)
  • Tamás Laskay (University of Lübeck, Germany)
  • Oliver Liesenfeld (Roche, USA)
  • Shreemanta Parida (Vaccine Grand Challenge Program, India)
  • Matyas Sandor (University of Wisconsin, USA)
  • Ulrich Steinhoff (University of Marburg, Germany)
  • Michal Toborek (University of Miami, USA)
  • Mary Jo Wick (University of Gothenburg, Sweden)
  • Susanne A. Wolf (MDC-Berlin, Germany)


Dr. Dunay, Ildiko Rita
Magdeburg, Germany

Indexing and Abstracting Services:

  • PubMed Central
  • Scopus
  • ESCI
  • CABI


CrossRef Documents 23
WoS Cites 708
Wos H-index 27
Days from submission to acceptance 219
Days from acceptance to publication 176
Acceptance Rate 70%



European Journal of Microbiology and Immunology
Publication Model Gold Open Access
Submission Fee none
Article Processing Charge 928 EUR/article
Regional discounts on country of the funding agency World Bank Lower-middle-income economies: 50%
World Bank Low-income economies: 100%
Further Discounts Editorial Board / Advisory Board members: 50%
Corresponding authors, affiliated to an EISZ member institution subscribing to the journal package of Akadémiai Kiadó: 100%
Subscription Information Gold Open Access
Purchase per Title  

European Journal of Microbiology and Immunology
Language English
Size A4
Year of
2021 Volume 11
per Year
per Year
Founder Akadémiai Kiadó
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Publisher Akadémiai Kiadó
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Chief Executive Officer, Akadémiai Kiadó
ISSN 2062-509X (Print)
ISSN 2062-8633 (Online)

Monthly Content Usage

Abstract Views Full Text Views PDF Downloads
Feb 2021 9 0 0
Mar 2021 5 0 0
Apr 2021 1 0 0
May 2021 3 0 0
Jun 2021 2 0 0
Jul 2021 5 0 0
Aug 2021 0 0 0