CD45 ligation in T cells regulates signal transduction through both the interleukin-2 receptor and the CD3/Ti T-cell receptor complex.
The cytoplasmic domain of the CD45 leukocyte cell surface antigen has recently been shown to possess protein tyrosine phosphatase (PTPase) activity. The existence of a cell membrane-bound PTPase may represent a mechanism by which an activation signal, initiated by ligand binding to a surface receptor, is down-regulated following delivery of the signal. Both the interleukin-2 (IL2) growth factor receptor and the CD3/Ti T-cell antigen receptor contain a subunit which is phosphorylated on tyrosine by an activated protein kinase (PTK) during T-cell activation. We compared the effect of CD45 ligation on signal transduction mediated by the binding of IL2 or anti-CD3 to these two receptors. Immunoblotting with anti-phosphotyrosine antiserum was used to investigate the effect of CD45 ligation on anti-CD3- or IL2-induced protein tyrosine phosphorylation. When CD3 and CD45 were triggered together, changes in the pattern of tyrosine phosphorylation of specific substrates was observed in comparison to the stimulus triggered through CD3 alone. In contrast, CD45 ligation did not alter the pattern of tyrosine-phosphorylated proteins in "resting" T-cell blasts responding to IL2, except for a mobility shift of a 55 kDa protein and increased phosphorylation of a 112 kDa substrate. The proliferative response of T cells to both anti-CD3 or IL2 was inhibited by ligating CD45. The CD45 molecule down-regulated CD3-induced T-cell activation when the CD45 and CD3 molecules were ligated simultaneously with immobilized antibodies. In contrast, immobilized CD45 mAb alone inhibited IL2-induced proliferation, and the inhibition was not potentiated by simultaneously using a CD25 mAb which was non-competitive for IL2-binding.(ABSTRACT TRUNCATED AT 250 WORDS)
Gilliland
L K
LK
Oncogen Corporation, Seattle, Washington.
Schieven
G L
GL
Grosmaire
L S
LS
Damle
N K
NK
Ledbetter
J A
JA
D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000502:physiology*; D000943:Antigens, Differentiation / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D017252:CD3 Complex; D003432:Cross-Linking Reagents; D006649:Histocompatibility Antigens / Q000502:physiology*; D006801:Humans; D017493:Leukocyte Common Antigens; D008213:Lymphocyte Activation / Q000276:immunology; D008970:Molecular Weight; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D003432:Cross-Linking Reagents; D006649:Histocompatibility Antigens; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D011505:Protein-Tyrosine Kinases; D017493:Leukocyte Common Antigens