Antigen receptor signal transduction: activating and inhibitory antigen receptors regulate STAT1 serine phosphorylation

Antigen receptors are crucial regulators of the mammalian immune response. Immediate antigen receptor proximal signal transduction pathways mediated b y tyrosine (Tyr) kinases are well defined. in contrast, much less is known about the network of serine (Ser) kinases and Ser kinase substrates that ar e linked to antigen receptor function. Here we describe a new signaling mod ule for antigen receptors in lymphocytes; a Ser kinase pathway that phospho rylates Ser 727 in STAT1 alpha, a member of the signal transducer and activ ator of transcription gene family. In the present study we have explored th e regulation of STAT1 Ser 727 phosphorylation in human T and B lymphocytes and show that it is controlled by both positive and negative antigen recept or signaling cascades. Ligation of antigen receptors in both B and T cells induce a delayed but then sustained phosphorylation of STAT1 on Ser 727. ST AT1 Ser phosphorylation is induced by the TCR in the absence of STAT1 Tyr p hosphorylation, indicating that in T cells STAT1 Ser and Tyr phosphorylatio n are independent events. Antigen receptor regulation of STAT Ser phosphory lation is dependent on phosphatidylinositol 3-kinase-mediated signals. Furt hermore, the negative regulatory receptor Fc gamma RIIb, which mediates vit al feedback control of B cell responses, prevents antigen receptor-induced phosphorylation of STAT1 Ser 727. The ability of antigen receptors to both positively and negatively regulate STAT1 Ser 727 phosphorylation reveals a Ser kinase network that operated during sustained responses to antigen rece ptor engagement.