Novel CD47: SIRP alpha Dependent Mechanism for the Activation of STAT3 in Antigen-Presenting Cell

作者：Toledano Natan; Gur Wahnon Devorah; Ben Yehuda Adi; Rachmilewitz Jacob^*

来源：PLos One, 2013, 8(9): e75595.

DOI：10.1371/journal.pone.0075595

Cell surface CD47 interacts with its receptor, signal-regulatory-protein alpha (SIRP alpha) that is expressed predominantly on macrophages, to inhibit phagocytosis of normal, healthy cells. This "don't eat me" signal is mediated through tyrosine phosphorylation of SIRP alpha at the cytoplasmic ITIM motifs and the recruitment of the phosphatase, SHP-1. We previously revealed a novel mechanism for the activation of the STAT3 pathway and the regulation of human APC maturation and function that is based on cell: cell interaction. In this study, we present evidence supporting the notion that CD47: SIRP alpha serves as a cell surface receptor: ligand pair involved in this contact-dependent STAT3 activation and regulation of APC maturation. We show that upon co-culturing APC with various primary and tumor cell lines STAT3 phosphorylation and IL-10 expression are induced, and such regulation could be suppressed by specific CD47 siRNAs and shRNAs. Significantly, >50% reduction in CD47 expression abolished the contact-dependent inhibition of T cell activation. Furthermore, co-immunoprecipitation experiments revealed a physical association between SIRP alpha and STAT3. Thus, we suggest that in addition to signaling through the ITIM-SHP-1 complex that transmit an anti-phagocytotic, CD47: SIRP alpha also triggers STAT3 signaling that is linked to an immature APC phenotype and peripheral tolerance under steady state and pathological conditions.

• 出版日期2013-9-20