Dab2 is an adapter protein involved in receptor-mediated signaling, endocytosis, cell adhesion, hematopoietic cell differentiation, and angiogenesis. It plays a pivotal role in controlling cellular homeostasis. In the immune system, the Dab2 is a Foxp3 target gene and is required for regulatory T (Treg) cell function. Dab2 expression and its biological function in dendritic cells (DCs) have not been described. In this study, we found that Dab2 was significantly induced during the development of mouse bone marrow (BM)-derived DCs (BMDCs) and human monocyte-derived DCs (MoDCs). Even in a steady state, Dab2 was expressed in mouse splenic DCs (spDCs). STAT5 activation, Foxp3 expression, and hnRNPE1 activation mediated by PI3K/Akt signaling were required for Dab2 expression during GM-CSF-derived BMDC development regardless of TGF-β signaling. Dab2-silencing was accompanied by enhanced IL-12 and IL-6 expression, and an improved capacity of DC for antigen uptake, migration and T cell stimulation, which generated strong CTL in vaccinated mice. Vaccination with Dab2-silenced DCs inhibited tumor growth more effectively than did vaccination with wild type DCs. Dab2-overexpression abrogated the efficacy of the DC vaccine in DC-based tumor immunotherapy. These data strongly suggest that Dab2 might be an intrinsic negative regulator of the immunogenicity of DCs, thus might be an attractive molecular target to improve DC vaccine efficacy.
Keywords: BAT, blocking the TGF-β-activated translation element; BM, bone marrow; CFSE, 5, 6-carboxyfluorescein succinimidyl ester; CTL, cytotoxic T lymphocyte; DCs, dendritic cells; Dab2; Dab2, disabled-2 adaptor protein; Dab2KD, Dab2-knockdown; Foxp3, forkhead box P3; GM-CSF, granulocyte-macrophage colony stimulating factor; OT-1 and OT-2 mice, OVA257–264 and OVA323–339-peptide-specific T cell receptor transgenic mice; OVA, ovalbumin; PI3K, phosphoinositide-3 kinase; STAT5, transducer and activator of transcription 5; TGF-β, transforming growth factor-β; Treg, regulatory T; WT, wild type; dendritic cells; hMoDC, human monocyte-derived dendritic cell; hnRNP E1, heterogeneous nuclear ribonucleoprotein E1; imDC, immature DC; immunogenicity; mDC, mature DC; molecular target.