Induction of allogenic T-cell hyporesponsiveness by galectin-1-mediated apoptotic and non-apoptotic mechanisms.
Galectin-1, a beta-galactoside-binding protein expressed at sites of T-cell activation and immune privilege, has shown specific immunosuppressive properties. Because of the implications of this protein in T-cell tolerance and its potential use to avoid graft rejection, we investigated the immunosuppressive effects of galectin-1 in the course of the human allogenic T-cell response. Galectin-1 induced a dose- and carbohydrate-dependent inhibition of the allogenic T-cell response. Addition of galectin-1 to alloreactive lymphocytes resulted in significant apoptosis of CD45R0-positive cells. This negative regulatory effect was accompanied by caspase activation, Bcl-2 downregulation and was prevented by addition of exogenous IL-2. In addition, a significant decrease of IFN-gamma production was detected in the non-apoptotic cell population, following exposure of alloreactive lymphocytes to galectin-1. Moreover, the immunosuppressive activity of this protein did not involve TGF-beta-mediated mechanisms. Since galectin-1 is expressed by activated T cells and could be acting by an autocrine negative loop to control human T-cell reactivity, we finally examined the regulated expression of this protein throughout the allogenic T-cell response. Expression of endogenous galectin-1 was detected at 24 h of cell culture, reaching its maximal levels after 72 h of allostimulation. The present study sets the basis for a potential use of galectin-1 as a selective immunosuppressive agent to limit T-cell-mediated reactivity during the effector phase of the alloimmune response.
Rabinovich
G A
GA
Division of Immunogenetics, Hospital de Clínicas José de San Martín, University of Buenos Aires, Argentina. gabyrabi@ciudad.com.ar
Ramhorst
R E
RE
Rubinstein
N
N
Corigliano
A
A
Daroqui
M C
MC
Kier-Joffé
E B
EB
Fainboim
L
L
D000328:Adult; D017209:Apoptosis; D002241:Carbohydrates / Q000276:immunology; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D037483:Galectin 1 / Q000096:biosynthesis / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D002241:Carbohydrates; D037483:Galectin 1; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D020169:Caspases