The activation of Csk by CD4 interferes with TCR-mediated activatory signaling.
CD4-Lck recruitment to TCR/CD3, as well as Lck activation is essential for T cell activation. Indeed, the blockage of CD4-Lck recruitment to TCR during antigen recognition exerts a drastic inhibitory effect on T cell activation by interfering with both early and late phases of T cell signaling. In the present work, we report a novel inhibitory mechanism by which CD4 can shut down proximal T cell-activating signals. Indeed, we show that upon ligation of CD4 by antibodies the inhibitory kinase, p50(csk), is strongly induced and prolonged during the time. In contrast, p50(csk) was not activated when TCR and CD4 were properly engaged by their ligands. We also demonstrate that anti-CD4 treatment stimulated Csk kinase associated to the membrane adapter, PAG/Cbp, without affecting the total amount of Csk bound to PAG/Cbp. As a consequence, early tyrosine phosphorylation events as well as downstream signaling pathways leading to IL-2 gene expression induced by TCR were inhibited in anti-CD4 pretreated cells. We suggest a new model to explain the activation of negative signals by CD4 molecule.
Marinari
Barbara
B
Department of Cellular and Developmental Biology, La Sapienza University, I-00185 Rome, Italy.
Simeoni
Luca
L
Schraven
Burkhart
B
Piccolella
Enza
E
Tuosto
Loretta
L
D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D000081247:CSK Tyrosine-Protein Kinase; D004768:Enterotoxins / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases
D015704:CD4 Antigens; D004768:Enterotoxins; D011948:Receptors, Antigen, T-Cell; C049463:enterotoxin E, Staphylococcal; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human