title: A role for the TIM-3/GAL-9/BAT3 pathway in determining the clinical phenotype of multiple sclerosis.
abstract: 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.
authors.affiliation: Don C. Gnocchi Foundation, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; and msaresella@dongnocchi.it.
authors.forename: Marina
authors.initials: M
authors.lastname: Saresella
authors.affiliation: Don C. Gnocchi Foundation, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; and.
authors.forename: Federica
authors.initials: F
authors.lastname: Piancone
authors.affiliation: Don C. Gnocchi Foundation, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; and.
authors.forename: Ivana
authors.initials: I
authors.lastname: Marventano
authors.affiliation: Don C. Gnocchi Foundation, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; and.
authors.forename: Francesca
authors.initials: F
authors.lastname: La Rosa
authors.affiliation: Don C. Gnocchi Foundation, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; and.
authors.forename: Paola
authors.initials: P
authors.lastname: Tortorella
authors.affiliation: Don C. Gnocchi Foundation, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; and.
authors.forename: Domenico
authors.initials: D
authors.lastname: Caputo
authors.affiliation: Don C. Gnocchi Foundation, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; and.
authors.forename: Marco
authors.initials: M
authors.lastname: Rovaris
authors.affiliation: Don C. Gnocchi Foundation, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; and Department of Physiopathology and Transplants, University of Milan, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000502:physiology; D037161:Galectins / Q000378:metabolism*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D018832:Molecular Chaperones / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000378:metabolism*; D010641:Phenotype; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C092009:BAG6 protein, human; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human; D008565:Membrane Proteins; D018832:Molecular Chaperones
keywords: T cell; apoptosis; myelin basic protein