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- Title
Manipulation of EAT-2 expression promotes induction of multiple beneficial regulatory and effector functions of the human innate immune system as a novel immunomodulatory strategy.
- Authors
Aldhamen, Yasser A.; Seregin, Sergey S.; Aylsworth, Charles F.; Godbehere, Sarah; Amalfitano, Andrea
- Abstract
EAT-2 overexpression enhances many functions of human innate immune cellsThe signaling lymphocytic activation molecule (SLAM) receptor-associated adaptor Ewing’s sarcoma-associated transcript-2 (EAT-2) is primarily expressed in innate immune cells including dendritic cells (DCs), macrophages and NK cells. A recent human HIV vaccine study confirmed that EAT-2 expression was associated with the enhanced immunogenicity induced by the MRKAd5/HIV vaccine. We previously harnessed the capability of EAT-2 to modulate signaling mediated by SLAM receptors and demonstrated that by incorporating EAT-2 expression into vaccines, one could enhance innate and adaptive immune responses in mice, even in the face of pre-existing immunity to the vaccine vectors. Herein, we investigated the innate immune responses of human cells exposed to EAT-2-over-expressing vaccines. Our results demonstrate that EAT-2 over-expression can significantly alter the kinetics of critical pro-inflammatory cytokine and chemokine responses elaborated by human PBMCs. In addition, enhanced DC maturation and increased monocyte phagocytosis were observed in EAT-2-transduced human cells. We also found that EAT-2 over-expression improved antigen presentation by human cells. Moreover, EAT-2 over-expression increased the anti-tumor activity of human NK cells against K562 tumor cell targets. Many of these responses were extinguished with use of an EAT-2 variant carrying a mutant SH2 domain (R31Q), suggesting a critical role for the interaction between EAT-2 and SLAM receptors in mediating these responses. In conclusion, these results provide evidence that EAT-2 interacts with key components of multiple arms of the human innate immune system, and that this role highlights the potential for targeting EAT-2 functions so as to improve a number of human immunotherapeutic approaches, including vaccine development.
- Subjects
EWING'S sarcoma; GENE expression; NATURAL immunity; IMMUNOLOGICAL adjuvants; LYMPHOCYTE transformation; CELLULAR signal transduction; MACROPHAGES
- Publication
International Immunology, 2014, Vol 26, Issue 5, p291
- ISSN
0953-8178
- Publication type
Article
- DOI
10.1093/intimm/dxt061