The protein tyrosine phosphatase, SHP-1, is an intrinsic central regulator of dendritic cell function

Dendritic cells (DCs) initiate proinflammatory or regulatory T cell responses, depending on their activation state. Despite extensive knowledge of DC-activating signals, mechanisms of DC-inhibitory signals are less well understood. We show that the SH2-domain-containing protein tyrosine phosphatase, SHP-1, is an important inhibitor of DC signaling that targets multiple activation pathways. Downstream of TLR4, SHP-1 showed increased interactions with several proteins including IRAK-4, and modulated LPS signaling through the inhibition of NF-κB, AP-1, ERK and JNK activity, while enhancing p38 activity. In addition, SHP-1 inhibited pro-survival signaling modulated through AKT activation. Further, SHP-1 inhibited CCR7 protein levels and CCR7 mediated cytokine expression. Inhibition of SHP-1 in DCs enhanced proinflammatory cytokines, IL-6, IL-12 and IL-1β, promoted survival and increased the rate DC migration from the periphery to draining lymph nodes. In vivo administration of SHP-1-inhibited DCs loaded with antigen, significantly induced the expansion of antigen-specific cytotoxic T cells and inhibited Foxp3+ regulatory T cell proliferation compared to unmodified DCs. When used in a vaccination protocol, SHP-1-inhibited DCs significantly reduced progression of pre-established mouse melanoma and prostate tumors. Taken together, these data demonstrate that SHP-1 is an intrinsic global regulator of DC function, controlling many facets of T cell-mediated immune responses.