Comparison of the immunosuppressive properties of milk growth factor and transforming growth factors beta 1 and beta 2.
The effects of the newly isolated bovine milk growth factor (MGF) which shows N-terminal homology to transforming growth factor beta 2 were compared with the effects of porcine transforming growth factor beta 1 and beta 2 (pTGF-beta 1 and -beta 2) on human T lymphocyte activation. Freshly isolated human PBMC were stimulated with either PHA, anti-CD3 + phorbol-12,13-dibutyrate (PDBu), or with a combination of ionomycin + PDBu. MGF, pTGF-beta 1, and pTGF-beta 2 decreased mitogen-induced [3H]thymidine incorporation by 30 to 75% in a dose-dependent manner. The maximum degree of inhibition was obtained at 1 ng/ml (40 pM) and could not be increased by increasing the concentration of teh transforming growth factor 10-fold. Stimulation of fresh T cells with the recall Ag tetanus toxoid was also inhibited (85%) by MGF at pM concentrations as was the proliferation of a human T cell clone specific for purified protein derivative. The effects of MGF and pTGF-beta 1 on anti-CD3-mediated increase of intracellular Ca2+ (Cai2+) was investigated by using the Fura-2 method. Neither MGF nor pTGF-beta 1 inhibited this increase in Cai2+ induced by a mitogenic concentration of anti-CD3 antibody. In order to determine whether TGF-beta preferentially inhibited the CD4+ or CD8+ subpopulation of human T cells, a limiting dilution analysis system, which allows every T cell to proliferate, was used. pTGF-beta 1 at a concentration of 5 ng/ml decreased the frequency of proliferating T cell precursors of both the CD4+ and CD8+ subsets to a similar extent. Furthermore, MGF, pTGF-beta 1, and pTGF-beta 2 also decreased IL-2 mediated [3H]thymidine incorporation into human PBL Con A blasts and the IL-4-mediated [3H]thymidine incorporation of purified T lymphocytes costimulated with PDBu by 70%. In conclusion, bovine MGF exerts suppressive effects on human T cells stimulated with Ag, mitogens, or interleukins, and the degree of T cell suppression is similar (or identical) to those of pTGF-beta 1 or -beta 2.
Stoeck
M
M
Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges, Switzerland.
Ruegg
C
C
Miescher
S
S
Carrel
S
S
Cox
D
D
Von Fliedner
V
V
Alkan
S
S
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D017252:CD3 Complex; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D006133:Growth Substances / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007958:Leukocyte Count; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008894:Milk Proteins / Q000276:immunology*; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013234:Stem Cells / Q000276:immunology; D013491:Suppressor Factors, Immunologic / Q000502:physiology*; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology; D013936:Thymidine / Q000378:metabolism; D015291:Transforming Growth Factors / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D006133:Growth Substances; D007376:Interleukin-2; D008894:Milk Proteins; D011948:Receptors, Antigen, T-Cell; D013491:Suppressor Factors, Immunologic; D015847:Interleukin-4; D015291:Transforming Growth Factors; D002118:Calcium; D013936:Thymidine