The Phosphatase Src Homology Region 2 Domain-Containing Phosphatase-1 Is an Intrinsic Central Regulator of Dendritic Cell Function

Abstract

Dendritic cells (DCs) initiate proinflammatory or regulatory T cell responses, depending on their activation state. Despite extensive knowledge of DC-activating signals, the understanding of DC inhibitory signals is relatively limited. We show that Src homology region 2 domain-containing phosphatase-1 (SHP-1) is an important inhibitor of DC signaling, targeting multiple activation pathways. Downstream of TLR4, SHP-1 showed increased interaction with several proteins including IL-1R–associated kinase-4, and modulated LPS signaling by inhibiting NF-κB, AP-1, ERK, and JNK activity, while enhancing p38 activity. In addition, SHP-1 inhibited prosurvival signaling through AKT activation. Furthermore, SHP-1 inhibited CCR7 protein expression. Inhibiting SHP-1 in DCs enhanced proinflammatory cytokines, IL-6, IL-12, and IL-1β production, promoted survival, and increased DC migration to draining lymph nodes. Administration of SHP-1–inhibited DCs in vivo induced expansion of Ag-specific cytotoxic T cells and inhibited Foxp3+ regulatory T cell induction, resulting in an enhanced immune response against 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.

B and T lymphocyte attenuator inhibits LPS-induced endotoxic shock by suppressing Toll-like receptor 4 signaling in innate immune cells

“…It has been reported that BTLA has two immunoreceptor tyrosine-based inhibitory motifs in the cytoplasmic region and interacts directly with SHP-1 and SHP-2 (SHP-1/2) in T cells (9,11). It has also been reported that SHP-1/2 regulates TLR4 signaling and cytokine production in several cell types (25)(26)(27)(28). To determine whether BTLA regulates TLR4 signaling through the activation of SHP-1/2 in DCs, we first examined SHP-1/2 phosphorylation in BTLA −/− BMDCs and WT BMDCs on LPS stimulation.…”

Dendritic Cell-Specific Ablation of the Protein Tyrosine Phosphatase Shp1 Promotes Th1 Cell Differentiation and Induces Autoimmunity

“…This finding is consistent with the recent observation that bone marrow-derived macrophages prepared from me v /me v mice manifested marked impairment of LPS-induced IL-12 production (51). In contrast, Ramachandran et al (22) reported that inhibition of Shp1 activity by a specific inhibitor of Shp1 increased the LPS-driven IL-12 production in bone marrowderived DCs. Such difference may be attributable to that we or Zhou et al (51) used isolated splenic DCs from Shp1 CKO mice or bone marrow-derived macrophages from me v /me v mice, respectively, whereas Ramachandran et al (22) used bone marrowderived DCs from wild-type mice.…”

“…In contrast, Ramachandran et al (22) reported that inhibition of Shp1 activity by a specific inhibitor of Shp1 increased the LPS-driven IL-12 production in bone marrowderived DCs. Such difference may be attributable to that we or Zhou et al (51) used isolated splenic DCs from Shp1 CKO mice or bone marrow-derived macrophages from me v /me v mice, respectively, whereas Ramachandran et al (22) used bone marrowderived DCs from wild-type mice. Thus, the reduced IL-12 production in Shp1 CKO or me v /me v mice may be, in part, an epiphenomenon due to disruption of splenic homeostasis in these mice.…”

“…In addition, examination of the effects of an inhibitor of Shp1 or of RNA interference-mediated knockdown of Shp1 has indicated that Shp1 is an intrinsic but negative regulator of DC functions including the production of proinflammatory cytokines, migration to draining LNs, and the control of many facets of T cell-mediated immune responses (22). The precise role of Shp1 in the regulation of DC functions, especially in vivo, has however remained unclear.…”

Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response

“…This pathway is well described to inhibit macrophage phagocytosis, but more recently, SIRP-α also has been shown to attenuate macrophage activation by LPS by sequestering SHP-2, which is needed for activation of the MAPK and NF-κB pathways (25). In addition, inhibition of SHP-1 in dendritic cells has been reported to enhance CD8 + and CD4 + T-cell responses and reduce regulatory T cells, a response that protected mice against tumor challenge (26). SIRP-α also may negatively regulate cross-presentation by a mechanism not yet understood, perhaps involving recruitment of cross-presentation machinery to phagosomes.…”