A role for the TIM-3/GAL-9/BAT3 pathway in determining the clinical phenotype of multiple sclerosis

FASEB J. 2014 Nov;28(11):5000-9. doi: 10.1096/fj.14-258194. Epub 2014 Aug 4.


T-cell immunoglobulin and mucin domain 3 (Tim-3) ligates galectin-9 (Gal-9); this process, resulting in the inhibition of Th1 responses and in the apoptosis of antigen-specific cells, is hampered by binding of the molecular adaptor human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) to the intracellular tail of Tim-3. Apoptosis of myelin basic protein (MBP)-specific T lymphocytes correlates with reduced rates of disease progression in multiple sclerosis (MS). We extensively analyzed the Tim-3/Gal-9/Bat3 pathway in 87 patients with a diagnosis of stable relapsing-remitting MS (RRMS), primary progressive MS (PPMS), or benign MS (BEMS), as well as in 40 healthy control (HC) subjects. Results showed that MBP-specific CD4(+)Tim-3(+), CD4(+)/Gal-9(+), and CD4(+)/Tim-3(+)/AV(+) (apoptotic) T lymphocytes were augmented in the BEMS group, whereas CD4(+)/Bat3(+) and CD8(+)/Bat3(+) T lymphocytes were increased and CD4(+)/Tim-3(+)/AV(+) T cells were reduced in the PPMS group (>2 fold and P<0.05 in all cases). Blocking the Tim-3/Gal-9 interaction with specific mAb reduced T-lymphocyte apoptosis and augmented production of IFNγ and IL-17 in the BEMS, RRMS, and HC groups, but not in the PPMS group. The Tim-3/Gal-9 interaction favors apoptosis of MBP-specific T lymphocytes in BEMS; this process is reduced in PPMS by the up-regulation of Bat3. Therapeutic interventions aimed at silencing Bat3 could be beneficial in MS.

Keywords: T cell; apoptosis; myelin basic protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apoptosis / physiology
  • Galectins / metabolism*
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Male
  • Membrane Proteins / metabolism*
  • Middle Aged
  • Molecular Chaperones / metabolism*
  • Multiple Sclerosis / metabolism*
  • Phenotype
  • Up-Regulation
  • Young Adult


  • BAG6 protein, human
  • Galectins
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • LGALS9 protein, human
  • Membrane Proteins
  • Molecular Chaperones