Galectin-9 controls CD40 signaling through a Tim-3 independent mechanism and redirects the cytokine profile of pathogenic T cells in autoimmunity

PLoS One. 2012;7(6):e38708. doi: 10.1371/journal.pone.0038708. Epub 2012 Jun 7.


While it has long been understood that CD40 plays a critical role in the etiology of autoimmunity, glycobiology is emerging as an important contributor. CD40 signaling is also gaining further interest in transplantation and cancer therapies. Work on CD40 signaling has focused on signaling outcomes and blocking of its ligand, CD154, while little is known about the actual receptor itself and its control. We demonstrated that CD40 is in fact several receptors occurring as constellations of differentially glycosylated forms of the protein that can sometimes form hybrid receptors with other proteins. An enticing area of autoimmunity is differential glycosylation of immune molecules leading to altered signaling. Galectins interact with carbohydrates on proteins to effect such signaling alterations. Studying autoimmune prone NOD and non-autoimmune BALB/c mice, here we reveal that in-vivo CD40 signals alter the glycosylation status of non-autoimmune derived CD4 T cells to resemble that of autoimmune derived CD4 T cells. Galectin-9 interacts with CD40 and, at higher concentrations, prevents CD40 induced proliferative responses of CD4(lo)CD40(+) effector T cells and induces cell death through a Tim-3 independent mechanism. Interestingly, galectin-9, at lower concentrations, alters the surface expression of CD3, CD4, and TCR, regulating access to those molecules and thereby redirects the inflammatory cytokine phenotype and CD3 induced proliferation of autoimmune CD4(lo)CD40(+) T cells. Understanding the dynamics of the CD40 receptor(s) and the impact of glycosylation status in immunity will gain insight into how to maintain useful CD40 signals while shutting down detrimental ones.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / immunology*
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • CD40 Antigens / pharmacology*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytokines / immunology*
  • Cytokines / metabolism
  • Female
  • Flow Cytometry
  • Galectins / pharmacology*
  • Hepatitis A Virus Cellular Receptor 2
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Receptors, Virus / immunology
  • Receptors, Virus / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology


  • CD40 Antigens
  • Cytokines
  • Galectins
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Interleukin-2
  • Receptors, Virus
  • galectin 9, mouse
  • Interferon-gamma