title: Transgenic galectin-1 induces maturation of dendritic cells that elicit contrasting responses in naive and activated T cells.
abstract: Dendritic cells (DC) are professional APC that control the balance between T cell immunity and tolerance. Genetic engineering of DC to regulate the outcome of the immune response is an area of intense research. Galectin (gal)-1 is an endogenous lectin that binds to glycoproteins and exerts potent regulatory effects on T cells. Consequently, gal-1 participates in central deletion of thymocytes and exerts therapeutic effects on experimental models of T cell-mediated autoimmune disorders and graft-vs-host disease. Together, these observations strongly indicate that engineering DC to express transgenic (tg) gal-1 may be beneficial to treat T cell-mediated disorders. In this study, we have investigated the impact of the expression of high levels of tg gal-1 on maturation/activation of DC and on their T cell stimulatory function. Murine DC were transduced with a recombinant adenovirus encoding hu gal-1 (gal-1-DC). Tg gal-1 was exported by a nonclassical pathway through exosomes and was retained on the DC surface inducing segregation of its ligand CD43. Expression of tg gal-1 triggered activation of DC determined by induction of a more mature phenotype, increased levels of mRNA for proinflammatory cytokines, and enhanced ability to stimulate naive T cells. Conversely, gal-1-DC induced rapid apoptosis of activated T cells. In vivo, gal-1-DC increased significantly the sensitization phase of contact hypersensitivity assays while inducing a drastic inhibition of the elicitation phase by triggering apoptosis of activated T cells in the dermis. Gal-1-DC represent a novel tool to control differentially the afferent and efferent arms of the T cell response.
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, PA 15213, USA.
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Perone
authors.forename: Adriana T
authors.initials: AT
authors.lastname: Larregina
authors.forename: William J
authors.initials: WJ
authors.lastname: Shufesky
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Papworth
authors.forename: Mara L G
authors.initials: ML
authors.lastname: Sullivan
authors.forename: Alan F
authors.initials: AF
authors.lastname: Zahorchak
authors.forename: Donna Beer
authors.initials: DB
authors.lastname: Stolz
authors.forename: Linda G
authors.initials: LG
authors.lastname: Baum
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
authors.forename: Adrian E
authors.initials: AE
authors.lastname: Morelli
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation* / Q000648:ultrastructure; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D037483:Galectin 1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*
chemical_list: D037483:Galectin 1